A Pivotal Phase 1/2, Single-Arm, Open-label Study to Evaluate the Safety and Efficacy of Ponatinib With Chemotherapy in Pediatric Patients With Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Who Have Relapsed or Are Resistant or Intolerant to a Prior Tyrosine Kinase Inhibitor-Containing Therapy, or Who Have the T315I Mutation
Phase: PHASE1
Conditions: Pediatric Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL), Ph+ Mixed Phenotype Acute Leukemia (MPAL), Philadelphia Chromosome-Like ALL (Ph-like ALL)
Sponsor: Takeda

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PROTOCOL 
A Pivotal Phase 1/2, Single-Arm, Open-label Study to Evaluate the Safety and Efficacy of 
Ponatinib With Chemotherapy in Pediatric Patients With Philadelphia 
Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Who Have Relapsed 
or Are Resistant or Intolerant to a Prior Tyrosine Kinase Inhibitor-Containing Therapy, or 
Who Have the T315I Mutation 
Ponatinib With Chemotherapy in Pediatric Patients With Relapsed, Resistant, or Intolerant 
Ph+ ALL or Have the T315I Mutation 
Sponsor: 
Takeda Development Center Americas, Inc. 
95 Hayden Avenue 
Lexington, MA  
USA 
617-349-0200
Study Number: 
Ponatinib-1501 
EudraCT Number: 
2019-002549-39 
Compound: 
Ponatinib 
Date: 
02 November 2023 
Amendment Number: 
4 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
02 November 2023 
Amendment 4 
Substantial 
Global 
23 May 2023 
Amendment 3 
Substantial 
Global 
23 February 2021 
Amendment 2 
Substantial 
Global 
09 April 2020 
Amendment 1 
Substantial 
Global 
25 July 2019 
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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Ponatinib 
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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 
medical monitor and responsible medical officer are in the site operations manual. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site. 
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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 signatories, as applicable) can 
be found on the signature page. 
Electronic signatures may be found on the last page of this document. 
, MPH 
Study Clinical Lead 
Date 
, MD 
Clinical Science 
 – 
Pediatric Development 
Date 
, MD 
Date 
, PharmD, PhD 
Quantitative Clinical Pharmacology Lead 
Date 
, PhD 
 Study Statistician 
Date 
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CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure, 
package inserts, 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 patients 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 serious adverse events 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 4 Summary of Changes 
Protocol Amendment 4 Summary and Rationale: 
This section describes the changes to the protocol incorporating Amendment 4. The primary 
reasons for this amendment are to incorporate Health Authority requests. 
The protocol was updated to: 
• Modify phase 1 cohort 2 to enroll a single cohort for determination of recommended phase 2 
dose (RP2D) rather than 2 weight groups with separate evaluations. 
• Modify the definition of related adverse events for dose-limiting toxicity (DLT) criteria to: 
– Clarify the definition of “related’ causality assessment. 
– Modify the requirement for DLT criteria. 
– Modify the definition of “DLT-evaluable” patient. 
• Modify dose modifications for ponatinib with the occurrence of lipase elevations and 
pancreatitis. 
• Modify the criteria for beginning a consolidation block or optional continuation therapy. 
In this amendment, minor grammatical, editorial, formatting (including bibliographic references 
format), and administrative changes not affecting the conduct of the study are included for 
clarification and administrative purposes only and may not be listed in the summary of changes 
below. 
Protocol Amendment 4 
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 1.2 Approval 
Updated the list of 
approvers. 
Administrative change. 
2. 
 Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview of 
Study Design 
Section 6.2 Number of 
Patients 
Updated the number of 
patients in phase 1 portion 
of the study: 
“approximately 18 DLT-
evaluable patients...” to 
“approximately 12 DLT-
evaluable patients…”). 
Phase 1 enrollment will be reduced from 
a total of approximately 18 to 
approximately 12 patients, given the 
changes to cohort 2 to enroll 
approximately 6 instead of 12 patients. 
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CONFIDENTIAL 
Protocol Amendment 4 
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 
3. 
 Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview of 
Study Design 
Section 13.1.1 Analysis 
Sets 
Updated the minimum 
percentage and number of 
days of ponatinib dosing 
required for a patient to be 
evaluable for DLTs: “for at 
least 50% of the 
reinduction block days (eg, 
18 or more of the 35 days)” 
to “on at least 70% of the 
reinduction block days (eg, 
25 or more of the 
35 days)”. 
To modify based on Health Authority 
feedback on protocol amendment 3. 
4. 
 Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview of 
Study Design 
Added that ponatinib doses 
for evaluation in phase 1 
cohort 2 will target 
systemic exposures 
comparable to those 
achieved in adults receiving 
15 mg QD. 
To clarify. 
5. 
 Section 2.0 STUDY 
SUMMARY (and 
Figure 2.a) 
Section 6.1 Overview of 
Study Design (and 
Figure 6.a) 
Updated the number of 
patients in phase 1 cohort 2 
(from 12 to 6-12 patients), 
added the minimum 
number of patients with a 
baseline body weight 
<30 kg, removed the 
2 weight groups, and 
updated the minimum 
number of DLT-evaluable 
patients who must complete 
reinduction block and be 
without a DLT so that 
RP2D can be determined (6 
instead of 5 patients in 
cohort 2). 
Added if 2 out of 6 patients 
experienced a DLT, the 
study will be paused to 
determine further 
tolerability of this 
combination. 
To modify based on Health Authority 
feedback on protocol amendment 3 and 
to evaluate RP2D with a single cohort 
remaining consistent with the phase 1 
rolling 6 design. A minimum number of 
patients <30 kg are to be enrolled in 
cohort 2 instead of requiring 2 separate 
weight groups. 
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CONFIDENTIAL 
Protocol Amendment 4 
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 2.0 STUDY 
SUMMARY 
Section 6.1 Overview of 
Study Design 
Added a sentence to clarify 
that patients enrolled into 
phase 1 cohort 2 will be 
assessed together for 
determination of DLTs and 
RP2D. 
To clarify. 
7. 
 Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview of 
Study Design 
Added how RP2D will be 
determined in cohort 2. 
To clarify. 
8. 
 Section 6.3.3 Timeframes 
for Primary and Secondary 
Endpoints to Support 
Disclosures (Table 6.a) 
Updated the definition of 
OS in phase 2 secondary 
endpoints: “from first dose 
of ponatinib until death due 
to any cause” to “from first 
dose of study drug until 
death due to any cause”. 
To correct, consistently with the 
definition of OS in Table 13.a. 
9. 
 Section 8.1.1 
Investigational Therapy: 
Ponatinib 
Clarified information on 
ponatinib treatment in 
phase 1 cohort 2: 
“ponatinib treatment will be 
assigned according to the 
appropriate dose defined in 
Table 8.a” to “ponatinib 
treatment will be assigned 
at the starting dose (15 mg 
adult exposures) and dose 
reductions will be allowed 
according to the dose levels 
defined in Table 8.a”. 
To clarify. 
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CONFIDENTIAL 
Protocol Amendment 4 
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 
10. 
 Section 8.2 Definitions of 
Dose-limiting Toxicities 
Section 10.1.2 Adverse 
Event Definition 
Clarified the relatedness of 
events to be considered 
DLTs in phase 1: “events 
occurring during the first 
35 days on treatment 
(reinduction) that are 
deemed by the investigator 
to be related to ponatinib 
therapy” to “events 
occurring during the first 
35 days on treatment 
(reinduction block) that are 
assessed by the investigator 
as possibly, probably, or 
definitely related to 
ponatinib and must be 
reported as related”. 
Modified the order of 
“possibly”, “probably”, and 
“definitely”. 
To modify based on Health Authority 
feedback on protocol amendment 3 and 
to clarify definition of related causality. 
11. 
 Section 8.2 Definitions of 
Dose-limiting Toxicities 
Clarified the relatedness of 
Grade ≥3 nonhematologic 
toxicity to be considered 
DLTs in phase 1: 
“attributable to ponatinib” 
to “possibly, probably, or 
definitely related o 
ponatinib”. 
To modify based on Health Authority 
feedback on protocol amendment 3 and 
to clarify that “related” includes any 
attribution whether possible, probable, or 
definite. 
12. 
 Section 8.2 Definitions of 
Dose-limiting Toxicities 
Updated the timeframe 
during which failure to 
recover peripheral ANC 
and platelet count is 
considered a DLT: 
“49 days” to “42 days”. 
To modify based on Health Authority 
feedback on protocol amendment 3. 
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CONFIDENTIAL 
Protocol Amendment 4 
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 
13. 
 Section 8.3 Criteria for 
Beginning a Consolidation 
Block or Optional 
Continuation Therapy 
Section 8.1.2 Study 
Treatment Regimen 
(Table 8.b, footnote f and 
Table 8.c, footnote a) 
Appendix A, Schedules of 
Events (Table 5, footnote i) 
Added a reference (van 
Veen et al. 2010) to support 
the platelet count threshold 
required to start the 
consolidation block or 
optional continuation 
therapy. 
To provide a literature reference for the 
50,000 μL platelet count threshold as a 
safe baseline to start multiagent 
chemotherapy. 
14. 
 Section 8.3 Criteria for 
Beginning a Consolidation 
Block or Optional 
Continuation Therapy 
Section 8.1.2 Study 
Treatment Regimen 
(Table 8.b, footnote f and 
Table 8.c, footnote a) 
Appendix A, Schedules of 
Events (Table 5, footnote i) 
Modified criteria for 
beginning consolidation or 
optional continuation block 
with toxicity related to 
treatment from: “must have 
resolved to Grade ≤2, 
except for ALT <10 × ULN 
and direct bilirubin 
<2 × ULN, to the patient’s 
baseline values, or to a 
level considered acceptable 
by the physician” to: “must 
have resolved to Grade 1 or 
baseline or to a level 
considered acceptable by 
the physician”. 
To modify based on Health Authority 
feedback on protocol amendment 3. 
Changes made to align with dose 
modification guidelines and the current 
USPI, and to clarify requirement for 
investigator determination of whether to 
hold or proceed with dosing. 
15. 
 Section 8.3 Criteria for 
Beginning a Consolidation 
Block or Optional 
Continuation Therapy 
Added the statement: “The 
physician may consult with 
the sponsor’s medical 
monitor to determine levels 
that are acceptable based on 
the overall clinical status of 
the patient to continue 
therapy”. 
To clarify requirement for investigator 
determination of whether to hold or 
proceed with dosing. 
16. 
 Section 8.4.1 Early Safety 
Stopping Rules 
Added a sentence to clarify 
that any decision to restart 
enrollment after stopping 
for stopping rules must be 
approved by the applicable 
agencies. 
To modify based on Health Authority 
feedback on protocol amendment 1. 
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CONFIDENTIAL 
Protocol Amendment 4 
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 
17. 
 Section 8.4.2.1 
Nonhematologic 
Treatment-Related 
Toxicity: Ponatinib 
(Table 8.e) 
Modified dose modification 
for ponatinib with the 
occurrence of pancreatitis 
and elevation of lipase. 
To modify based on Health Authority 
feedback on protocol amendment 3 and 
to align with the current USPI. 
18. 
 Section 8.4.2.1 
Nonhematologic 
Treatment-Related 
Toxicity: Ponatinib 
(Table 8.e, footnote d) 
Revised footnote d to 
remove “For Grade 2: 
LVEF <50%-40%, 
Grade 3: LVEF <39-20%, 
Grade 4: refractory CHF or 
LVEF <20%.” 
To correct an error as these gradings are 
not National Cancer Institute Common 
Terminology Criteria for Adverse Events 
gradings. 
19. 
 Section 8.4.3 
Chemotherapy Backbone 
Added a sentence to 
identify the source of any 
reference safety 
information for 
expectedness of serious 
adverse reactions that may 
occur with the 
chemotherapy agents used 
in this trial. 
To modify based on Health Authority 
feedback on protocol amendment 1. 
20. 
 Section 8.4.4.4 Safety 
Monitoring for Cardiac 
Toxicity 
Section 9.3.13.3 Troponin 
and NT-proBNP 
Appendix A, Schedules of 
Events (Table 1, footnote i) 
Added that cardiac troponin 
assessment can be 
performed with either 
troponin T or troponin I and 
that it should be ensured 
that the same type of testing 
is used throughout the 
study. 
To provide additional guidance to sites. 
21. 
 Section 9.3.13.1 
Hematology and Chemistry 
Appendix A, Schedules of 
Events (Table 1, footnote z, 
and Table 2) 
Clarified that hematology 
assessment is required 
while chemistry assessment 
is not required at Day 35 of 
the reinduction block and 
of the consolidation block. 
To clarify because the required 
hematology assessment to evaluate the 
response was moved in protocol 
amendment 3 to the end of the 
reinduction block and of the 
consolidation block (ie, Day 35). 
22. 
 Section 9.3.13.3 Troponin 
and NT-proBNP 
Appendix A, Schedules of 
Events (Table 1) 
Clarified that that both 
troponin and NT-proBNP 
testing are required cardiac 
assessments. 
To clarify and provide additional 
guidance to sites. 
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CONFIDENTIAL 
Protocol Amendment 4 
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 
23. 
 Section 9.3.14.1 Evaluation 
of CR 
Clarified the way CR status 
will be assessed: “CR status 
will be assessed by 
morphology, cytogenetics, 
and flow cytometry at a 
local laboratory” to “CR 
status will be confirmed by 
the investigator upon 
review of blasts in the BM 
morphology report from the 
local laboratory, 
extramedullary disease, 
neutrophil, and platelet 
recovery as well as blasts in 
peripheral blood, if 
applicable”. 
To clarify and provide additional 
guidance to sites. 
24. 
 Section 9.3.14.1 Evaluation 
of CR 
Clarified requirements if 
relapse from CR is 
confirmed: “results of the 
assessments used to 
confirm the relapse, 
including BM assessment, 
and their date must be 
provided in the electronic 
data capture (EDC); in 
addition, a peripheral blood 
sample must be collected 
for molecular mutation 
analysis” to “results of the 
assessments used to 
confirm the relapse, 
including peripheral blood, 
BM, CSF, or radiologic 
assessment, and their dates 
must be provided in the 
electronic data capture 
(EDC). If relapse from CR 
is confirmed, a peripheral 
blood sample must be 
collected for molecular 
mutation analysis”. 
To clarify and provide additional 
guidance to sites. 
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CONFIDENTIAL 
Protocol Amendment 4 
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 
25. 
 Section 9.3.15 Biomarkers 
and Pharmacokinetic 
Measurements 
Added the statement: 
“MRD will be evaluated 
once CR assessment is 
performed and only for 
patients with CR status 
reported by the investigator 
by the end of the 
consolidation block”. 
To clarify the conditions of MRD 
evaluation. 
26. 
 Section 9.3.15.1 Bone 
Marrow Samples for MRD 
Assessment 
Clarified for which patients 
MRD will be evaluated: 
“MRD will be evaluated 
(only in patients with 
Ph+ ALL)” to “MRD will 
be evaluated (only in 
patients with Ph+ ALL and 
only those who achieve CR 
by end of consolidation as 
reported by the 
investigator)”. 
To clarify the conditions of MRD 
evaluation. 
27. 
 Section 13.1.1 Analysis 
Sets 
Updated the definition of 
response-evaluable 
population: “Patients who 
receive at least 1 dose of 
ponatinib…” to “Ph+ ALL 
patients at RP2D who 
receive at least 1 dose of 
ponatinib…”. 
To clarify. 
28. 
 Appendix A, Schedules of 
Events (Table 2, footnote b) 
Corrected that for patients 
in the Optional 
Continuation Regimen, 
follow-up visits after 
2 years will occur annually 
for at least 3 years after 
EOT2 rather than after 
EOT1. 
To correct that the follow-up begins after 
EOT2 and provide additional guidance to 
sites. 
ALL: acute lymphoblastic leukemia; ALT: alanine aminotransferase; ANC: absolute neutrophil count; BM: bone 
marrow; CHF: congestive heart failure; CR: complete remission; CSF: cerebral spinal fluid; DLT: dose-limiting 
toxicities; EOT1: end of treatment 1; EOT2: end of treatment 2; LVEF: left ventricular ejection fraction; MRD: 
minimal residual disease; NT-proBNP: N-terminal pro brain natriuretic peptide; OS: overall survival; Ph+: 
Philadelphia chromosome–positive; QD: once daily; RP2D: recommended phase 2 dose; ULN: upper limit of 
normal; USPI: United States Prescribing Information. 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 4 Summary of Changes...............................................................5 
2.0 
STUDY SUMMARY.........................................................................................................19 
3.0 
STUDY REFERENCE INFORMATION .........................................................................31 
3.1 
Study-Related Responsibilities ....................................................................................31 
3.2 
Principal Investigator/Coordinating Investigator .........................................................31 
3.3 
List of Abbreviations ...................................................................................................32 
3.4 
Corporate Identification ...............................................................................................35 
4.0 
INTRODUCTION AND BACKGROUND ......................................................................36 
4.1 
Background ..................................................................................................................36 
4.1.1 
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in 
Pediatric Patients .................................................................................................36 
4.1.2 
Ponatinib Design and Mechanism of Action .......................................................36 
4.1.3 
Ponatinib Nonclinical Data ..................................................................................37 
4.1.4 
Clinical Studies ....................................................................................................38 
4.2 
Rationale for the Proposed Study ................................................................................40 
4.2.1 
Rationale for Relapsed Population (Ph+ ALL, Ph+ Mixed Phenotype Acute 
Leukemia, and Philadelphia Chromosome–like ALL) ........................................40 
4.2.2 
Rationale for Minimum Age of at Least 1 Year ..................................................41 
4.2.3 
Rationale for Complete Remission as Primary Endpoint ....................................41 
4.2.4 
Rationale for the Doses of Ponatinib ...................................................................41 
4.2.5 
Rationale for Selection of Chemotherapy Backbone Regimen ...........................46 
4.3 
Age-Appropriate Formulation for Ponatinib ...............................................................47 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................47 
5.1 
Objectives ....................................................................................................................47 
5.1.1 
Primary Objectives ..............................................................................................47 
5.1.2 
Secondary Objectives ..........................................................................................47 
5.1.3 
Exploratory Objectives ........................................................................................48 
5.2 
Endpoints .....................................................................................................................48 
5.2.1 
Primary Endpoints ...............................................................................................48 
5.2.2 
Secondary Endpoints ...........................................................................................49 
5.2.3 
Exploratory Endpoints .........................................................................................49 
6.0 
STUDY DESIGN...............................................................................................................50 
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CONFIDENTIAL 
6.1 
Overview of Study Design ...........................................................................................50 
6.2 
Number of Patients ......................................................................................................54 
6.3 
Duration of Study .........................................................................................................54 
6.3.1 
Duration of an Individual Patient’s Study Participation ......................................54 
6.3.2 
End of Study/Study Completion Definition and Planned Reporting...................55 
6.3.3 
Timeframes for Primary and Secondary Endpoints to Support Disclosures .......55 
6.3.4 
Total Study Duration ...........................................................................................57 
6.3.5 
Posttrial Access ...................................................................................................57 
7.0 
STUDY POPULATION ....................................................................................................58 
7.1 
Inclusion Criteria .........................................................................................................58 
7.2 
Exclusion Criteria ........................................................................................................62 
8.0 
STUDY TREATMENT .....................................................................................................64 
8.1 
Study Treatment Administration..................................................................................64 
8.1.1 
Investigational Therapy: Ponatinib ......................................................................64 
8.1.2 
Study Treatment Regimen ...................................................................................66 
8.2 
Definitions of Dose-limiting Toxicities .......................................................................72 
8.3 
Criteria for Beginning a Consolidation Block or Optional Continuation Therapy ......73 
8.4 
Dose Modification Guidelines for Safety ....................................................................73 
8.4.1 
Early Safety Stopping Rules ................................................................................73 
8.4.2 
Dose Reduction for Treatment-related Toxicity ..................................................74 
8.4.3 
Chemotherapy Backbone .....................................................................................80 
8.4.4 
Supportive Care ...................................................................................................90 
8.5 
Excluded Concomitant Medications and Procedures ..................................................94 
8.6 
Permitted Concomitant Medications and Procedures ..................................................95 
8.7 
Precautions and Restrictions ........................................................................................95 
8.8 
Management of Clinical Events ...................................................................................96 
8.9 
Blinding and Unblinding..............................................................................................97 
8.10 
Description of Investigational Agents .........................................................................97 
8.11 
Preparation, Reconstitution, and Dispensation ............................................................97 
8.12 
Packaging and Labeling ...............................................................................................97 
8.12.1 
Ponatinib Tablets .................................................................................................97 
8.12.2 
Ponatinib Age-Appropriate Formulation (AAF) .................................................98 
8.12.3 
Chemotherapy Backbone .....................................................................................98 
8.13 
Storage, Handling, and Accountability ........................................................................98 
8.13.1 
Storage .................................................................................................................98 
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CONFIDENTIAL 
8.13.2 
Handling and Accountability ...............................................................................98 
8.13.3 
Disposition of Used and Unused Study Drug ......................................................99 
8.14 
Other Protocol-Specified Materials .............................................................................99 
9.0 
STUDY CONDUCT ..........................................................................................................99 
9.1 
Study Personnel and Organizations .............................................................................99 
9.2 
Arrangements for Recruitment of Patients ..................................................................99 
9.3 
Study Procedures .......................................................................................................100 
9.3.1 
Screening Period Procedures .............................................................................100 
9.3.2 
Informed Consent/Assent ..................................................................................100 
9.3.3 
Demographics and Medical/Surgical History ...................................................101 
9.3.4 
Physical Examination and Vital Signs ..............................................................101 
9.3.5 
Growth and Development ..................................................................................101 
9.3.6 
Performance Status ............................................................................................101 
9.3.7 
Pregnancy Test ..................................................................................................101 
9.3.8 
Cardiovascular Risk Assessments .....................................................................102 
9.3.9 
Ophthalmological Examination .........................................................................102 
9.3.10 
Concomitant Medications and Procedures ........................................................102 
9.3.11 
Adverse Events ..................................................................................................102 
9.3.12 
Enrollment .........................................................................................................103 
9.3.13 
Clinical Laboratory Evaluations ........................................................................103 
9.3.14 
Disease Assessment ...........................................................................................104 
9.3.15 
Biomarkers and Pharmacokinetic Measurements .............................................104 
9.3.16 
Palatability and Acceptability of Ponatinib Age-Appropriate Formulation ......106 
9.3.17 
Follow-up Assessments .....................................................................................106 
9.3.18 
Changes to Study Procedures Due to COVID-19 Public Health Emergency ...107 
9.4 
Completion of Study Treatment.................................................................................108 
9.5 
Reasons for Discontinuation of Treatment ................................................................108 
9.6 
Withdrawal of Patients From Study ...........................................................................109 
9.7 
Study Compliance ......................................................................................................109 
9.8 
Criteria for Premature Termination or Suspension of the Study ...............................110 
10.0 
ADVERSE EVENTS .......................................................................................................110 
10.1 
Definitions..................................................................................................................110 
10.1.1 
Pretreatment Event Definition ...........................................................................110 
10.1.2 
Adverse Event Definition ..................................................................................110 
10.1.3 
Serious Adverse Event Definition .....................................................................111 
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10.1.4 
Adverse Events of Special Interest Definitions .................................................112 
10.2 
Procedures for Recording and Reporting Adverse Events and Serious Adverse 
Events .........................................................................................................................113 
10.3 
Monitoring of Adverse Events and Period of Observation ........................................114 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........114 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ...................................................................................................................115 
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .........115 
11.0 
STUDY-SPECIFIC COMMITTEES ...............................................................................116 
11.1 
Sponsor Liaison Team ...............................................................................................116 
11.2 
IDMC .........................................................................................................................116 
12.0 
DATA HANDLING AND RECORDKEEPING ............................................................117 
12.1 
eCRFs .........................................................................................................................117 
12.2 
Record Retention .......................................................................................................117 
13.0 
STATISTICAL METHODS ............................................................................................118 
13.1 
Statistical Analysis Plans ...........................................................................................118 
13.1.1 
Analysis Sets .....................................................................................................118 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ........................119 
13.1.3 
Efficacy Analysis ...............................................................................................119 
13.1.4 
Exploratory Analyses ........................................................................................120 
13.1.5 
PK Analysis .......................................................................................................120 
13.1.6 
Safety Analysis ..................................................................................................121 
13.2 
Interim Analysis and Criteria for Early Termination .................................................122 
13.3 
Determination of Sample Size and Justification of Control Rate Assumption ..........122 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...............................................122 
14.1 
Study Site Monitoring Visits .....................................................................................122 
14.2 
Protocol Deviations ....................................................................................................123 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................123 
15.0 
ETHICAL ASPECTS OF THE STUDY .........................................................................124 
15.1 
IRB and/or IEC Approval ..........................................................................................124 
15.2 
Subject Information, Informed Consent, and Subject Authorization ........................125 
15.3 
Subject Confidentiality ..............................................................................................126 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................126 
15.4.1 
Publication .........................................................................................................126 
15.4.2 
Clinical Trial Registration .................................................................................127 
15.4.3 
Clinical Trial Results Disclosure .......................................................................127 
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15.4.4 
Data Sharing ......................................................................................................127 
15.5 
Insurance and Compensation for Injury .....................................................................128 
16.0 
REFERENCES ................................................................................................................128 
 
LIST OF IN-TEXT TABLES 
Table 2.a 
Phase 1 Cohort 2 Ponatinib Doses .........................................................................24 
Table 2.b 
Maximum Serum Creatinine Value (mg/dL) by Age and Sex ..............................26 
Table 2.c 
Mean Values of k by Age ......................................................................................26 
Table 6.a 
Primary and Secondary Endpoints for Disclosures ...............................................55 
Table 7.a 
Maximum Serum Creatinine Value (mg/dL) by Age and Sex ..............................61 
Table 7.b 
Mean Values of k by Age ......................................................................................61 
Table 8.a 
Phase 1 Cohort 2 Ponatinib Doses .........................................................................66 
Table 8.b 
Phase 1 and Phase 2 Treatment Regimen for the Reinduction and 
Consolidation Blocks .............................................................................................67 
Table 8.c 
Details of Phase 1 and Phase 2 Treatment Regimens for the Reinduction and 
Consolidation Blocks .............................................................................................68 
Table 8.d 
Optional Continuation Therapy With Ponatinib: Recommended Combination 
Regimen Following Consolidation ........................................................................72 
Table 8.e 
Dose Modifications for Nonhematologic Treatment-Related Toxicity: 
Ponatinib ................................................................................................................75 
Table 8.f 
Dose Modifications for Peripheral Neuropathy and Neuropathic Pain Per 
Modified “Balis” Pediatric Scale ...........................................................................77 
Table 8.g 
Dose Modifications for Arterial Occlusive Events: Ponatinib ..............................78 
Table 8.h 
Dose Modifications for Venous Thrombotic/Embolic Events: Ponatinib .............79 
Table 8.i 
Daunorubicin Dose Reduction Algorithm for Hyperbilirubinemia .......................82 
Table 8.j 
Vincristine Dose Reduction Algorithm for Hyperbilirubinemia ...........................86 
Table 8.k 
Methotrexate Dose Reduction Algorithm for Toxicity ..........................................89 
Table 9.a 
Primary Specimen Collection ..............................................................................105 
Table 13.a 
Definitions of Efficacy Response Criteria ...........................................................120 
 
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LIST OF IN-TEXT FIGURES 
Figure 2.a 
Study Design Schema ............................................................................................21 
Figure 4.a 
Dose-Response Relationships for Efficacy (MR2 or Better Response) and 
Safety (AOEs) at 1 Year for the Dosing Regimens in the Ongoing OPTIC 
Study Based on Simulations from the Preliminary Exposure-Response Models 
(Based on the Data Cutoff Date of 05 December 2018) ........................................43 
Figure 4.b 
Predicted Pediatric Exposures of Ponatinib in Pediatric Patients Compared 
With Adult Exposures at 15 mg .............................................................................46 
Figure 6.a 
Study Design Schema ............................................................................................53 
 
LIST OF APPENDICES 
Appendix A 
Schedules of Events .............................................................................................134 
Appendix B 
Responsibilities of the Investigator ......................................................................146 
Appendix C 
Investigator Consent to Use of Personal Information ..........................................148 
Appendix D 
Performance Score Scales ....................................................................................149 
Appendix E 
Acceptability and Palatability Questionnaire for the Ponatinib AAF 
(Reinduction Only) ..............................................................................................150 
Appendix F 
Tanner Scale.........................................................................................................152 
Appendix G 
Definition of CNS- 1/2/3 in CSF .........................................................................153 
Appendix H 
Protocol History ...................................................................................................154 
 
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2.0 
STUDY SUMMARY 
Name of Sponsor: Takeda Development Center Americas, Inc. 
Compound:  
Ponatinib 
Title of Protocol: A Pivotal Phase 1/2, Single-Arm, Open-label Study to 
Evaluate the Safety and Efficacy of Ponatinib With Chemotherapy in Pediatric 
Patients With Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic 
Leukemia (ALL) Who Have Relapsed or Are Resistant or Intolerant to a Prior 
Tyrosine Kinase Inhibitor-Containing Therapy, or Who Have the T315I Mutation 
EudraCT No.: 
2019-002549-39 
Study Number: Ponatinib-1501 
Phase: 1/2  
Study Design: 
This is a pivotal phase 1/2, single-arm, open-label, multicenter, study designed to evaluate the safety, tolerability, 
pharmacokinetics (PK), and efficacy of ponatinib when administered in combination with multiagent 
chemotherapy in pediatric patients (aged ≥1 year to ≤21 years) with Philadelphia chromosome-positive (Ph+) 
acute lymphoblastic leukemia (ALL), Ph+ mixed phenotype acute leukemia (MPAL), or Philadelphia 
chromosome–like (Ph-like) ALL with targetable kinase-activating lesions and either (i) or (ii) as follows: (i) For 
non-US sites: Patients who have relapsed or are resistant or intolerant to at least 1 prior therapy that contained a 
breakpoint cluster region (BCR)-Abelson (ABL) 1–targeted tyrosine kinase inhibitor (TKI), or for US sites: 
Patients who have relapsed or are resistant or intolerant to at least 1 prior therapy that contained a second-
generation BCR-ABL1–targeted TKI; or (ii) have a BCR-ABL1 T315I mutation. 
Patients will undergo screening assessments for up to 10 days to determine eligibility (Figure 2.a). In both 
phase 1 and phase 2, eligible patients will receive two 35-day blocks of therapy (reinduction block and 
consolidation block). Each block will include 29 days of study treatment consisting of daily ponatinib and a 
modified United Kingdom (UK) ALL R3 chemotherapy backbone regimen specified in Table 8.b and a rest 
period from chemotherapy for a minimum of 6 days consisting of daily ponatinib only. Disease assessment will 
occur at the end of each block. Patients will undergo an end of treatment (EOT) visit (EOT1) 25-30 days after the 
last dose of study treatment in the consolidation block, or earlier, if the patient is proceeding to alternate therapy 
or optional ponatinib continuation therapy (Appendix A, Table 1). 
Patients completing the EOT1 visit can proceed to alternate therapies not containing ponatinib as off-protocol 
therapy. Alternatively, eligible patients may receive optional ponatinib continuation therapy (either ponatinib 
monotherapy or ponatinib in combination with maintenance-type chemotherapy regimen at the investigator’s 
discretion and with sponsor agreement) after completing the 2 blocks of study treatment and the EOT1 visit. 
Patients who receive optional ponatinib continuation therapy will be followed per the schedule of events (SOE) 
and proceed to a second EOT visit (EOT2) 30 to 40 days after the last dose of ponatinib, or earlier, if the patient 
is proceeding to alternate therapy (Appendix A, Table 2). Patients who discontinue ponatinib early in the 
reinduction block or consolidation block will be discontinued from study treatment and proceed to the EOT1 
visit. All patients will be followed for at least 3 years from EOT1, with primary analysis performed 
approximately 6 months after the last patient has been enrolled. 
Phase 1 of the study (approximately 12 dose-limiting toxicities [DLT]-evaluable patients) is a PK/safety lead-in 
phase for dose confirmation to establish the recommended phase 2 dose (RP2D) of ponatinib administered either 
as the tablet formulation or the age-appropriate formulation (AAF: mini-tablet–containing capsules, ie minitab 
capsules) (Table 2.a) in combination with the chemotherapy backbone (Table 8.b). 
The initial ponatinib doses evaluated in cohort 1 of the phase 1 portion of the study were selected to target 
systemic exposures comparable to those achieved in adults receiving 30 mg once daily (QD) based on the results 
of population PK modeling and simulation (see Section 4.2.4.1). The ponatinib doses evaluated in cohort 2 of the 
phase 1 portion of the study are expected to provide systemic exposures comparable to those achieved in adults 
receiving 15 mg QD based on the results of population PK modeling and simulation (see Section 4.2.4.2). 
A staggered enrollment is being applied. Phase 1 cohort 1 was initiated with the tablet formulation in patients 
able to swallow solid oral dosage forms and weighing at least 30 kg (as the AAF was not available during that 
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enrollment period). As of protocol amendment 3, both the tablet formulation and AAF are available for use in 
phase 1. 
The PK, safety, and tolerability data from phase 1 will inform selection of the recommended dose of ponatinib 
for confirmatory evaluation of safety and efficacy in the phase 2 portion of the study. A rolling 6 design will be 
followed for all phase 1 cohorts. 
As of phase 1 cohort 2, patients will be reviewed on an ongoing basis to determine whether the patient meets the 
criteria to be DLT-evaluable. DLT-evaluable patients must have received ponatinib doses on at least 70% of the 
reinduction block days (eg, 25 or more of the 35 days) per protocol or experienced a confirmed DLT. 
Ponatinib doses for evaluation in phase 1 cohort 2 will target exposures comparable to those achieved in adults 
receiving 15 mg QD based on the results of population PK modeling and simulation (see Section 4.2.4.3). For 
phase 1 cohort 2, approximately 6 DLT-evaluable patients with a body weight of at least 5 kg will be enrolled, 
with a minimum of 2 patients with a baseline body weight <30 kg. No more than 1 DLT-evaluable patient may 
be >16 years of age in cohort 2. 
To determine the RP2D, a minimum of 6 DLT-evaluable patients in cohort 2 must complete the reinduction 
block. If 2 out of 6 patients experience a DLT, the study will be paused to determine further tolerability of this 
combination. All patients enrolled in cohort 2 under protocol amendment 3 and those enrolled under protocol 
amendment 4 will be assessed together in a single cohort for determination of DLTs and RP2D as defined in 
protocol amendment 4. 
Upon review of patients in cohort 2, if dose level 1 is determined not to be tolerated or fails to achieve the 
desired target systemic exposures and RP2D is not confirmed with cohort 2, then no further cohorts are planned 
to be tested. 
The RP2D of ponatinib will be determined after evaluating the available safety and PK data from the first 
6 patients enrolled in phase 1 cohort 2. Up to an additional 6 patients may be enrolled to further characterize the 
safety, PK, and preliminary efficacy of the RP2D of ponatinib before the start of phase 2. 
In phase 2, patients will receive daily ponatinib at the RP2D determined from the phase 1 portion of the study, in 
combination with the same chemotherapy backbone regimen (Table 8.b). Phase 2 will evaluate the efficacy and 
safety of ponatinib at the RP2D in combination with chemotherapy in the study population and include patients 
from phase 1 who completed the reinduction block at the RP2D in combination with chemotherapy.  
Figure 2.a presents the design schema for the study. 
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Figure 2.a 
Study Design Schema 
 
AAF: age-appropriate formulation; EOT1: end of treatment 1; EOT2: end of treatment 2; RP2D: recommended 
phase 2 dose. 
“equivalent” refers to adult equivalent/target dose. 
a Each block consists of 29 days of study treatment with ponatinib and chemotherapy followed by a 
chemotherapy rest period of a minimum of 6 days consisting of daily ponatinib only. Ponatinib should not be 
interrupted unless the patient has toxicity suspected to be related to ponatinib. 
b Patients will undergo evaluation for disease status at the end of the reinduction block and the consolidation 
block. Patients tolerating treatment at the end of the reinduction block will proceed to the consolidation block 
regardless of their remission status. 
c Patients will have their first EOT visit (EOT1) 25 to 30 days after last dose of ponatinib in the consolidation 
block, or earlier, if the patient is proceeding to alternate therapy or optional ponatinib continuation therapy. 
d Patients who receive optional continuation therapy containing ponatinib will have an additional EOT visit 
(EOT2) 30 to 40 days after last dose of ponatinib, or earlier, if the patient is proceeding to alternate therapy. See 
Table 8.d for optional ponatinib continuation therapy regimen. Patients who are receiving clinical benefit from 
ponatinib treatment may continue therapy for a maximum of 12 months. If patients continue deriving clinical 
benefit after 12 months of optional continuation therapy, they may remain on ponatinib treatment if the 
investigator provides the evidence of clinical benefits and confirms with the sponsor. 
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Primary Objectives: 
Phase 1 Primary Objective 
• 
To determine the RP2D of ponatinib (tablet and AAF) in combination with chemotherapy. 
Phase 2 Primary Objective 
• 
To determine the efficacy of ponatinib in combination with chemotherapy as measured by the rate of CR at 
the end of the reinduction block. 
Secondary Objectives (Including PK and Safety Objectives): 
Phase 1 Secondary Objectives 
• 
To define and describe the phase 1 efficacy of ponatinib (tablet and AAF) in combination with 
chemotherapy. 
Phase 2 Secondary Objectives 
• 
Ph+ ALL only: To describe the proportion of patients who achieved CR at the end of consolidation. 
• 
Ph+ ALL only: To describe the proportion of patients with minimal residual disease (MRD) status <0.01% 
among those who achieved CR at the end of each treatment block. 
• 
To determine the proportion of patients who relapsed or progressed. 
• 
To determine event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) at 
6 months, 1 year, 18 months, 2 years, and 3 years. 
• 
To determine duration of response (for CR). 
• 
To determine the proportion of patients who underwent hematopoietic stem cell transplantation (HSCT) 
following study treatment. 
Phase 1 PK Objective 
• 
To characterize the PK of ponatinib in combination with chemotherapy. 
Phase 2 PK Objective 
• 
To collect plasma concentration–time data to contribute to population PK and exposure-response analyses of 
ponatinib. 
Phase 1 and Phase 2 Safety Objective 
• 
To describe the safety profile of ponatinib in combination with chemotherapy for each treatment block 
(ie, reinduction and consolidation). 
Exploratory Objectives: 
• 
To explore the risk of cardiotoxicity in patients with elevated cardiac troponin and N-terminal pro-brain 
natriuretic peptide (NT-proBNP). 
• 
Ph+ ALL: To characterize biomarkers of sensitivity and resistance to ponatinib-containing therapy, which 
may include molecular mutations (eg, BCR-ABL1, IKZF1, CDKN2A/2B) in samples both prior to and 
following ponatinib treatment. 
• 
To assess the acceptability and palatability of the AAF of ponatinib using the palatability questionnaire 
(Appendix E). 
• 
To determine OS for patients who receive HSCT and patients who do not receive HSCT. 
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Patient Population:  
Patients (aged ≥1 year to ≤21 years and weighing at least 5 kg) with Ph+ ALL, Ph+ MPAL, or Ph-like ALL with 
targetable kinase-activating lesions must have bone marrow (BM) involvement and either (i) or (ii) as follows:  
(i) 
For non-US sites: Patients who have relapsed or are resistant or intolerant to at least 1 prior 
therapy that contained a BCR-ABL1–targeted TKI; OR 
For US sites: Patients who have relapsed or are resistant or intolerant to at least 1 prior therapy that 
contained a second-generation BCR-ABL1–targeted TKI; OR 
(ii) 
Have a BCR-ABL1 T315I mutation. Referring institutions laboratory results will be accepted for 
enrollment; however, the mutation needs to be confirmed by the central laboratory. If the 
mutational status is not concordant, the patient will be withdrawn from the study and excluded from 
analyses. 
Number of Patients: 
Phase 1 of the study will enroll approximately 12 DLT-evaluable patients; 
phase 2 of the study will enroll approximately 68 patients, including DLT-
evaluable patients enrolled to phase 1 who completed the reinduction block and 
dosed at the RP2D. 
Number of Sites: 
Approximately 74 study 
sites in approximately 
17 countries. 
Dose Level(s): 
In phase 1 cohort 1, only patients with a body weight of ≥30 kg and able to 
swallow solid oral dosage forms were enrolled because the AAF was not 
available. As of protocol amendment 3, patients weighing at least 5 kg or who are 
unable to swallow solid oral dosage forms are eligible for enrollment as the AAF 
is available. 
Ponatinib will be administered QD in combination with the chemotherapy 
backbone (Table 8.b). In phase 1 cohort 1, pediatric patients received fixed doses 
of ponatinib based on body weight ranges that were expected to achieve systemic 
exposures that approximately matched adult exposures at 30 mg QD based on 
simulations from an allometrically scaled adult population PK model. Patients 
who experienced treatment-emergent adverse events (TEAEs) that required dose 
reductions had their ponatinib dose reduced to dose level -1. 
For phase 1 cohort 2, patients will also receive fixed doses of ponatinib based on 
body weight ranges provided in Table 2.a that are expected to achieve systemic 
exposures that approximately match adult exposures after administration of 
15 mg QD based on simulations from an allometrically scaled adult population 
PK model. Patients experiencing TEAEs will have their ponatinib doses reduced 
as per Table 2.a. The PK, safety, and tolerability of ponatinib at cohort 2 dose 
level 1 will be reviewed to inform selection of the RP2D. If the initially selected 
doses are not adequately tolerated or fail to achieve the target systemic exposures, 
then the study will close. 
Route of Administration: 
Oral 
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Table 2.a 
Phase 1 Cohort 2 Ponatinib Doses 
 
Body Weight 
 
≥45 kg 
30 kg to 
<45 kg 
15 kg to 
<30 kg 
5 kg to 
<15 kg 
Cohort 2 Dose Level 1 
15 mg 
10 mg 
7.5 mg 
5 mg 
Cohort 2 Dose Level -1 
10 mg 
7.5 mg 
5 mg 
2.5 mg 
 
In the phase 2 portion of the study, ponatinib will be administered QD in 
combination with the chemotherapy backbone at the RP2D determined after 
review of available data from the phase 1 portion of the study. 
 
Duration of Treatment: 
All patients enrolled will receive two 35-day blocks of study treatment (ponatinib 
in combination with chemotherapy). 
At the discretion of the treating physician and with sponsor agreement, optional 
ponatinib continuation therapy may be used beyond the end of the consolidation 
block as monotherapy or in combination with maintenance-type chemotherapy 
until more definitive therapy is initiated. 
Period of Evaluation: 
At least 36 months 
Main Criteria for Inclusion: 
Phase 1 cohort 1 (enrollment and treatment completed) eligibility criteria at the time of enrollment for 
patients to be administered ponatinib as the tablet formulation: 
• 
Patients must have a body weight ≥30 kg. 
• 
Patients must be able to swallow solid oral dosage forms.  
Phase 1 cohort 2 eligibility criteria at the time of enrollment: 
• 
Patients must be aged ≥1 year and have a body weight of at least 5 kg.  
Each patient must meet all the following inclusion criteria to be enrolled in the study for phase 1 and phase 2. 
1. Diagnosis: Patients must have a diagnosis of Ph+ ALL, Ph+ MPAL, or Ph-like ALL with: 
a. Involvement of BM with ALL, including one of the following: 
i. 
M2 BM (5%-24% lymphoblasts): by morphology with confirmatory testing consisting of at least 
one of the following: flow cytometry lymphoblasts ≥5%, or BCR-ABL1 fluorescence in situ 
hybridization, or ≥10-2 leukemic clone identified by immunoglobulin heavy chain–T-cell receptor 
polymerase chain reaction, OR 
ii. 
M3 BM (≥25% lymphoblasts): by morphology, OR 
iii. 
Patients with combined BM (as defined above) and extramedullary disease. 
b. Evidence of Ph+ ALL, MPAL, or Ph-like ALL: 
i. 
Definite evidence of BCR-ABL1 fusion (Ph) for Ph+ ALL and MPAL, OR  
ii. 
Definite evidence of Ph-like ALL with targetable kinase-activating lesions involving any of the 
following kinase genes: ABL1, ABL2, CSF1R, and PDGFRB. 
Ph-like ALL diagnosis requires the identification of specified targetable kinase-activating lesions 
preferably by RNA sequencing or by alternative accredited method used by the site. Referring 
institution’s laboratory results will be accepted for diagnosis and study enrollment. No confirmation 
by a sponsor central laboratory is required. 
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c. 
Disease status: 
i. 
For non-US sites: patients who have relapsed (post 0 or 1 HSCT) or are resistant or intolerant to at 
least 1 prior therapy that contained a BCR-ABL1–targeted TKI, OR 
For US sites: patients who have relapsed (post 0 or 1 HSCT) or are resistant or intolerant to at least 
1 prior therapy that contained a second-generation BCR-ABL1–targeted TKI (ie, dasatinib, nilotinib, 
and bosutinib); OR  
ii. 
Have a BCR-ABL1 T315I mutation irrespective of relapse, resistance/intolerance, or transplant status 
and irrespective of any prior TKI use. Referring institution’s laboratory results will be accepted for 
enrollment; however, the mutation needs to be confirmed by the central laboratory. If the mutational 
status is not concordant, the patient will be withdrawn from the study and excluded from analyses for 
RP2D and efficacy, but included for safety. 
A patient will be defined as intolerant if they had a Grade ≥3 nonhematologic toxicity or a Grade 4 
hematologic toxicity considered related to the last TKI and lasting for >2 weeks, and led to discontinuation 
of therapy. 
2. Age and weight: Patients must be ≥1 and ≤21 years of age and weighing at least 5 kg at the time of 
enrollment. 
3. Performance Status: Karnofsky performance status ≥50% for patients ≥16 years of age or Lansky Play 
Scale ≥50% for patients <16 years of age. 
Prior Therapy 
4. Patients must have recovered to less than Grade 2 National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) Version 5.0, or to baseline, from any nonhematologic toxicities (except 
alopecia) due to previous therapy. 
5. Patients must meet the following criteria related to prior therapies: 
Cytoreduction with hydroxyurea: Hydroxyurea can be initiated and continued for up to 24 hours before 
the start of protocol therapy. 
Patients who relapsed while receiving cytotoxic therapy: At least 14 days must have passed since the 
completion of the last dose of chemotherapy before the first dose of ponatinib can be given except for the 
following: intrathecal chemotherapy and/or maintenance therapy such as vincristine, mercaptopurine, 
methotrexate, or glucocorticoids. There is no waiting period for those relapsing on maintenance-like therapy. 
HSCT: Patients who have experienced relapse after a HSCT are eligible, provided they have no evidence of 
acute or chronic graft-versus-host disease (GVHD), are not receiving GVHD prophylaxis or treatment, and 
are at least 90 days posttransplant at the time of enrollment. 
Hematopoietic growth factors: Before the first dose of ponatinib, at least 7 days must have passed since 
completion of therapy with granulocyte colony-stimulating factor or other growth factors, and at least 
14 days must have passed since completion of therapy with pegfilgrastim. 
Biologics and targeted therapies: Before the first dose of ponatinib, at least 7 days must have passed since 
the last dose of a biologic agent. For agents that have known AEs occurring beyond 7 days after 
administration, this period must be extended beyond the time during which AEs are known to occur. The 
duration of this interval must be discussed with the sponsor’s medical monitor/designee. 
Monoclonal antibodies: After the last dose of monoclonal antibody, at least 3 half-lives of the administered 
antibody must have passed before the first dose of ponatinib. 
Immunotherapy: Before the first dose of ponatinib, at least 30 days must have passed after the completion 
of any type of immunotherapy (eg, tumor vaccines, chimeric antigen receptor T-cell [CAR-T cell]). 
Immunosuppressive therapy: Before the first dose of ponatinib, at least 14 days must have passed after the 
completion of immunosuppressive therapy (including regimens following stem cell transplant). 
Radiotherapy: No washout period is necessary for radiation given to any extramedullary site other than 
central nervous system (CNS); ≥90 days must have passed if patient received prior total body irradiation or 
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craniospinal or cranial radiotherapy. 
Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m2 of doxorubicin equivalents of 
anthracyclines. 
Organ Function Requirements 
6. Patients must have adequate renal and hepatic function as indicated by the following laboratory values: 
a) Adequate renal function defined as: Estimated glomerular filtration rate (eGFR) using the Schwartz 
formula, OR radioisotope glomerular filtration rate (GFR) ≥70 mL/min/1.73 m2, OR a normal serum 
creatinine based on age and sex as in Table 2.b: 
Table 2.b 
Maximum Serum Creatinine Value (mg/dL) by Age and Sex 
Age (years) 
Male 
Female 
1 to <2 
0.6 
0.6 
2 to <6 
0.8 
0.8 
6 to <10 
1 
1 
10 to <13 
1.2 
1.2 
13 to <16 
1.5 
1.4 
≥16 
1.7 
1.4 
The threshold creatinine values were derived from the Schwartz formula for estimating glomerular filtration 
rate (Schwartz and Gauthier 1985) using child length and stature data published by the Centers for Disease 
Control and Prevention. 
 
Schwartz formula: eGFR (mL/min/1.73 m2) = (k × L) / Pcr 
k: proportional constant (see Table 2.c); L: height (cm); Pcr: plasma creatinine (mg/dL) 
Table 2.c 
Mean Values of k by Age 
Age Group 
k 
(mean value) 
Low birth weight infants ≤1 year 
0.33 
Full-term infants ≤1 year 
0.45 
Children >1-12 years 
0.55 
Females 13-21 years 
0.55 
Males 13-21 years 
0.70 
Source: (Schwartz et al. 1987) 
 
a) Adequate liver function defined as: Direct bilirubin ≤1.5 times the upper limit of normal (ULN) for 
age AND alanine aminotransferase ≤5 times the ULN for age. 
7. No clinical, radiological or laboratory evidence of pancreatitis, including: 
a) Serum lipase must be <2 times the ULN, AND 
b) Serum amylase must be <2 times the ULN. 
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8. Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram (ECHO) OR left 
ventricular ejection fraction of ≥50% by ECHO or multigated acquisition scan (MUGA). 
9. Normal QT interval with Fridericia correction method (QTcF) on screening electrocardiogram (ECG), 
defined as QTcF of ≤450 ms. 
10. Voluntary written informed consent and assent (as dictated by the institutional review board/independent 
ethics committee and required by applicable local regulations) 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 (if of the age of consent) or the patient’s parent or legal guardian at any time 
without prejudice to future medical care. 
Prevention of Pregnancy 
11. Female patients who: 
a) Are surgically sterile, OR 
b) If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 
1 additional effective (barrier) method at the same time, from the time of signing the informed 
consent/assent through at least 6 months after end of therapy, OR 
c) 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.) 
12. 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 at 
least 6 months after end of therapy, 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 for the 
female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods 
of contraception. Female and male condoms should not be used together.) 
Exclusion Criteria: 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. A history or current diagnosis of Burkitt leukemia/lymphoma or mature B-cell leukemia. 
2. A history or current diagnosis of chronic myeloid leukemia. 
3. Diagnosis of ALL, MPAL, or Ph-like ALL with targetable kinase-activating lesions after treatment with 
cytotoxic therapy for another cancer. 
4. Diagnosis of another concurrent primary malignancy. 
5. Clinically significant cardiovascular disease, including but not limited to: 
a) Any history of myocardial infarction or unstable angina. 
b) History of or presence of heart block, and/or clinically significant ventricular or atrial arrhythmias. 
c) Uncontrolled hypertension, defined as persistent elevation of systolic and/or diastolic blood pressures to 
≥95th percentile based on age, sex, and height percentiles despite appropriate antihypertensive 
management. 
6. Current systemic use of drug(s) that are known to have a risk of causing prolonged corrected QT interval or 
torsades de pointes unless drug(s) can be changed to acceptable alternatives (ie, an alternate class of agents 
that do not affect the cardiac conduction system) or the patient can safely discontinue the drug(s). 
7. Uncontrolled hypertriglyceridemia (triglycerides ≥450 mg/dL).  
8. Current systemic use of any medications or herbal supplements that are known to be strong inhibitors or 
strong inducers of cytochrome P450 3A (CYP3A) within 7 days before the first dose of study drug. 
9. Previous treatment with ponatinib. 
10. Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or immunotherapy 
while patient is on study treatment. 
11. Known allergy or contraindications to any of the drugs (active or excipient) used in the study. 
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12. Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption of 
ponatinib. 
13. Patients with DNA fragility syndromes, such as Fanconi anemia and Bloom syndrome. 
14. Patients with Down syndrome. 
15. Patients with uncontrolled systemic infection, known laboratory and/or clinical evidence of active infection 
with HIV, hepatitis B, or hepatitis C. 
16. Patients with pre-existing significant CNS pathology, including history of severe brain injury, dementia, 
cerebellar disease, organic brain syndrome, psychosis, coordination /movement disorder, or autoimmune 
disease with CNS involvement are not eligible.  
17. Patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible. 
(Patients with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic 
deficits and causative factor(s) have resolved.) 
18. Uncontrolled seizure disorder. (Patients with seizure disorders that do not require antiepileptic drugs, or are 
well controlled with stable doses of antiepileptic drugs are eligible.) 
19. History of severe coagulopathy or cardiovascular or peripheral vascular events. 
20. Any condition or illness that, in the opinion of the investigator or sponsor, would compromise patient safety 
or interfere with the evaluation of the safety or efficacy of ponatinib. 
21. Admission or evidence of illicit use, drug abuse, or alcohol abuse. 
22. Pregnancy and breastfeeding exclusions: 
a) Female patients who are pregnant are excluded since fetal toxicities and teratogenic effects have been 
noted for several of the study treatments. A pregnancy test is required for female patients of 
childbearing potential. 
b) Lactating women who plan to breastfeed their infants. 
23. Treatment with live attenuated vaccinations within 30 days prior to initiation of study treatment regimen. 
Endpoints and Assessments: 
Primary Endpoints 
Phase 1 Primary Endpoint 
• 
RP2D of ponatinib (tablet and AAF) in combination with chemotherapy. 
Phase 2 Primary Endpoint 
• 
CR at the end of the reinduction block. CR is defined as <5% blasts in BM, normal maturation of all cellular 
components in the BM, no evidence of extramedullary disease, absolute neutrophil count (ANC) >1000/µL, 
and platelet count of >100,000/µL. 
Secondary Endpoints (Including PK and Safety Endpoints) 
Phase 1 Secondary Endpoints 
• 
CR at the end of the reinduction block. CR is defined as <5% blasts in BM, normal maturation of all cellular 
components in the BM, no evidence of extramedullary disease, ANC >1000/µL, and platelet count 
of >100,000/µL. 
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Phase 2 Secondary Endpoints 
• 
Ph+ ALL only: Proportion of patients who achieved CR at the end of consolidation. 
• 
Ph+ ALL only: Proportion of patients with MRD-negative status (<0.01%) among those who achieved CR 
at the end of each treatment block. 
• 
Proportion of patients who relapsed or progressed. 
• 
EFS, PFS, and OS at 6 months, 1 year, 18 months, 2 years, and 3 years. 
• 
Duration of response (for CR). 
• 
Proportion of patients who underwent HSCT following study treatment. 
Phase 1 PK Endpoint 
• 
Summary statistics of ponatinib PK parameters including maximum observed plasma concentration (Cmax), 
time of first occurrence of Cmax (tmax), and area under the plasma concentration–time curve from time 0 to 
the time of the last quantifiable concentration (AUClast). 
Phase 1 and Phase 2 Safety Endpoint 
• 
Adverse events (AEs), serious adverse events (SAEs), arterial occlusive events (AOEs), venous 
thrombotic/embolic events (VTEs), and any other AEs of special interest (AESIs). 
Exploratory Endpoints 
• 
Change from baseline in laboratory values and cardiovascular outcomes associated with elevated cardiac 
troponin and NT-proBNP. 
• 
Ph+ ALL only: Biomarkers of potential sensitivity and resistance to ponatinib-containing therapy, which 
may include molecular mutations (eg, BCR-ABL1, IKZF1, CDKN2A/2B) in samples both prior and 
following ponatinib treatment. 
• 
Acceptability and palatability of the AAF of ponatinib based on the palatability questionnaire administered 
during reinduction (Appendix E). 
• 
OS for patients who receive HSCT and patients who do not receive HSCT. 
Statistical Considerations: 
Approximately 68 patients aged ≥1 to ≤21 years with Ph+ ALL with targetable kinase activating lesions (no 
minimum number) who either (i) (non-US sites) have relapsed or are resistant or intolerant to at least 1 prior 
therapy that contained a BCR-ABL1–targeted TKI or (US sites) have relapsed or are resistant or intolerant to at 
least 1 prior therapy that contained a second-generation BCR-ABL1–targeted TKI, or (ii) have the T315I 
mutation, will be enrolled in the study. Ph+ MPAL and Ph-like ALL are rare, and few patients with Ph+ MPAL 
or Ph-like ALL are expected to enroll in this study. Data from these patients will not be included in the response-
evaluable population analysis and will be analyzed as a separate subset. 
Patients with Ph-like ALL and Ph+ MPAL will not be included in efficacy analyses. These patients will be 
included in the safety and other descriptive analyses. 
The phase 1 portion of the study will enroll approximately 12 DLT-evaluable patients, and a rolling 6 design will 
be followed to determine the RP2D. Once the pediatric RP2D has been confirmed, approximately 68 patients 
with Ph+ ALL will be enrolled in the phase 2 portion of the study (any patient dosed at the RP2D and completed 
the reinduction block during phase 1 will be counted towards the 68 evaluable patients for phase 2). 
The primary data analysis will be conducted 6 months after the last patient is enrolled in the phase 2 portion of 
the study, where the major efficacy summary will focus on: 
• 
CR at the end of reinduction block and duration of CR.  
• 
Time-to-event analysis (EFS, PFS, and OS) at 6 months, 1 year, 18 months, 2 years, and 3 years. 
• 
Proportion of patients who underwent HSCT. 
In addition, the safety analysis will cover short-term AE, SAE, and AESI rates, and changes in laboratory values 
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from baseline. 
Sample Size Determination: 
The Wilson Score confidence interval (CI) approach will be used for the sample size determination. The Wilson 
Score interval is an improvement over the normal approximation interval in that the actual coverage probability 
is closer to the nominal value. Based on the Wilson Score CI approach and assuming N = 68 patients to reject the 
null hypothesis of a 67% CR rate (see Section 13.3 for justification of control rate assumption), a 2-sided type I 
error of 0.1, and that under the alternative hypothesis the ponatinib CR rate is 80% based on simulations with 
1,000,000 iterations, the power of the trial equals 81.5%. This simulation also demonstrated that under the null 
hypothesis, the type I error is controlled at a nominal level of 0.1 (2-sided). 
 
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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 activities 
identified in the clinical supplier list in the site operations manual. The identified 
sponsor-designated vendors will perform specific study-related activities either in full or in 
partnership with the sponsor. 
3.2 
Principal Investigator/Coordinating Investigator 
The sponsor 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 
AAF 
age-appropriate formulation 
ABL 
Abelson 
AE 
adverse event 
AESI 
adverse events of special interest 
ALL 
acute lymphoblastic leukemia 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AOE 
arterial occlusive event 
AP 
accelerated phase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration–time curve 
AUClast 
area under the plasma concentration–time curve from time 0 to the time of the last quantifiable 
concentration 
BCR 
breakpoint cluster region 
BCR-ABL 
breakpoint cluster region-Abelson 
BID 
twice daily 
BM 
bone marrow 
BSA 
body surface area 
BP 
blast phase 
CAD 
coronary artery disease 
CHF 
congestive heart failure 
CI 
confidence interval 
Cmax 
maximum observed plasma concentration 
CML 
chronic myeloid leukemia 
CMT 
Charcot-Marie-Tooth disease 
CNS 
central nervous system 
COG 
Children’s Oncology Group 
COVID-19 
coronavirus disease 2019 
CP 
chronic phase 
CR 
complete remission 
CR2 
second complete remission 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
CT 
computerized tomography 
CYP3A 
cytochrome P450 3A 
DLT 
dose-limiting toxicities 
DTP 
direct-to-patient 
ECG 
electrocardiogram 
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ECHO 
echocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EFS 
event-free survival 
eGFR 
estimated glomerular filtration rate 
eIC 
electronic informed consent 
EMA 
European Medicines Agency 
EOT 
end of treatment 
EOT1 
end of treatment 1 
EOT2 
end of treatment 2 
EU 
European Union 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GVHD 
graft-versus-host disease 
HDPE 
high-density polyethylene 
HLT 
High Level Term 
HPMC 
hydroxypropyl methylcellulose 
HSCT 
hematopoietic stem cell transplantation 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IM 
intramuscularly 
IRB 
institutional review board 
IT 
intrathecal 
IV 
intravenous(ly) 
LBBB 
left bundle branch block 
MACE 
major adverse cardiac event 
MaHR 
major hematologic response 
MCyR 
major cytogenetic response 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MI 
myocardial infarction 
MPAL 
mixed phenotype acute leukemia 
MR2 
molecular response with 2-log reduction (BCR-ABL1/ABL1 ≤1%) 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition scan 
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NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NMDA 
N-methyl-d-aspartate 
NOAEL 
no observed-adverse effect level 
NS 
normal saline 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
OS 
overall survival 
Pcr 
plasma creatinine 
PEG 
polyethylene glycol 
PFS 
progression-free survival 
Ph+ 
Philadelphia chromosome-positive 
Ph-like 
Philadelphia chromosome–like 
PK 
pharmacokinetic(s) 
PO 
by mouth (orally) 
PP 
predicative probability 
PT 
Preferred Term 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QT interval with Fridericia correction method 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SLT 
Sponsor Liaison Team 
SmPC 
summary of product characteristics 
SOC 
System Organ Class 
SOE 
schedule of events 
SUSARs 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
TIA 
transient ischemic attack 
TKI 
tyrosine kinase inhibitor 
TLS 
tumor lysis syndrome 
tmax 
time of first occurrence of maximum observed plasma concentration 
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 Japan 
Takeda Development Center Japan 
TDC Asia 
Takeda Development Center Asia, Pte Ltd 
TDC Europe 
Takeda Development Centre Europe Ltd 
TDC Americas 
Takeda Development Center Americas, Inc 
TDC 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
Takeda 
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, 
as applicable 
 
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4.0 
INTRODUCTION AND BACKGROUND 
4.1 
Background 
4.1.1 
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Pediatric 
Patients 
Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and is the most 
common form of childhood leukemia, representing 75% to 80% of leukemias among children 
(Brown et al. 2020). The age-adjusted incidence of ALL in the United States (US) is 1.38 per 
100,000 individuals per year (Brown et al. 2020) with approximately 5930 new cases and 
1500 deaths estimated in 2019 (Brown et al. 2020). The median age at diagnosis is 15 years with 
55.4% of new diagnoses occurring in patients younger than 20 years of age (Brown et al. 2020). 
Philadelphia chromosome-positive (Ph+) ALL is a rare malignancy of the blood and bone 
marrow (BM), accounting for approximately 3% to 5% of pediatric ALL (Arico et al. 2010; 
Schlieben et al. 1996). 
Ph+ ALL results from a translocation of chromosomes 9 and 22, referred to as the Philadelphia 
chromosome, and leading to the fusion of the breakpoint cluster region (BCR) coding sequence 
with the tyrosine kinase coding region of Abelson (ABL) 1. 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) (Deininger et al. 2000). 
4.1.2 
Ponatinib Design and Mechanism of Action 
Ponatinib (Iclusig) is the product of a computational and structure-based approach to the design 
of a small-molecule tyrosine kinase inhibitor (TKI) (O'Hare et al. 2009). 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 other 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 (Zhou et al. 2011). 
This not only leads 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 Crk-like protein (pCRKL), thereby promoting 
apoptosis and cell death in BCR-ABL1–positive cells (O'Hare et al. 2009). Ponatinib has also 
been shown to potently inhibit the activity of other activated tyrosine kinases, including ABL2 
(also known as ARG), CSF1R (also known as FMS), and PDGFRB (Gozgit et al. 2013).  
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4.1.3 
Ponatinib Nonclinical Data 
Nonclinical studies have demonstrated that ponatinib potently inhibits native BCR-ABL1, and all 
single-mutation variants, at clinically relevant concentrations (Gozgit et al. 2013; O'Hare et al. 
2009). 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 (Bradeen et al. 2006), a concentration between 20 nM and 40 nM of ponatinib was 
found to suppress the emergence of any resistant BCR-ABL1 mutation (O'Hare et al. 2009). 
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 (O'Hare et al. 2009; Zabriskie et al. 2014). 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 compound mutations is a risk associated with sequential use of 
BCR-ABL1 TKIs (Shah et al. 2007), whereby expansion of a leukemic progenitor cell that has a 
single resistance mutation provides a template on which a second mutation can develop. 
Nonclinical safety assessment studies were performed on ponatinib, including 6-month oral 
toxicity studies in rats and cynomolgus monkeys. In a 6-month oral toxicity study, the 
no-observed-adverse-effect level (NOAEL) in the rat was 0.25 mg/kg/day. At 0.75 and 
2.0 mg/kg/day, there was early mortality and moribundity, reduced body weight, and reduced 
food consumption with lymphoid depletion at 2.0 mg/kg/day. The early deaths occurred as early 
as Day 21, and cause of death or moribundity was generally not determined; however, 
moribundity was considered to be related to urinary tract or skin inflammation in 3 animals. 
Additionally, at 0.75 and 2.0 mg/kg/day there was a reduction in femoral physeal chondrocytes 
(sometimes with reduced trabecular bone); the physeal lesion was still present after a 2-month 
recovery period. Administration of ponatinib to cynomolgus monkeys for 6 months at oral dose 
levels of 0.25, 0.75, or 2 mg/kg/day was well tolerated, with no ponatinib-related microscopic 
findings being observed at any dose level. However, there were irreversible increases in alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) at all doses; therefore, the NOAEL 
was determined to be ≤0.25 mg/kg/day. Taken together, the rat and monkey toxicology studies 
indicate the following key target organs of ponatinib toxicity: gastrointestinal tract, skin, thyroid 
gland, kidney, bone, thymus, pancreas, liver, lung, testes, and ovaries. 
A juvenile toxicity study was conducted in rats to assess relative sensitivity of immature versus 
mature animals to the effects of ponatinib, both before and after weaning, followed by a 4-week 
recovery period. Daily oral administration of ponatinib at 3 mg/kg/day to juvenile rats, beginning 
Day 15 postpartum, resulted in mortality related to inflammatory effects in several organs within 
6 to 7 days of treatment initiation. Administration of 0.75 or 1.5 mg/kg/day ponatinib from 
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Days 15 to 35 postpartum caused adverse reductions in body weight gain during preweaning and 
early postweaning treatment phases. These reductions were recovered during posttreatment 
Days 35 to 63 postpartum. Importantly, despite clear evidence of overt toxicity and adverse 
effects on body weight gain in juvenile rats, no other adverse effects of ponatinib on juvenile rat 
developmental parameters (vaginal opening, preputial separation, or bone measurements) were 
observed, and there were no microscopic changes in bone. Based on the occurrence of adverse 
body weight changes at tolerated dose levels, the NOAEL of ponatinib in juvenile rats was not 
identified. However, the NOAEL for ponatinib on key developmental endpoints was 
1.5 mg/kg/day. In conclusion, the toxicity profile in juvenile rats was comparable to that 
determined in general toxicity studies in adult rats. 
The ages of animals at the beginning of the juvenile study (Day 15 postpartum) were considered 
equivalent to a human infant, and by the end of the study (Day 35 postpartum) were considered 
equivalent to a child; the ages of rats at the initiation of the 6-month study were 7 to 10 weeks 
postpartum and were equivalent to a human adolescent (Baldrick 2010). Thus, these nonclinical 
studies cover the pediatric population. 
Additional details are provided in the investigator’s brochure in the section describing 
nonclinical studies. 
4.1.4 
Clinical Studies 
The phase 2 PACE study (Study AP24534-10-201) is the pivotal study upon which full 
marketing approval was granted by the US Food and Drug Administration (FDA) and the 
European Union (EU) European Medicines Agency (EMA). In the US, the indications described 
in the current Iclusig label are the following: (1) treatment of adult patients with chronic phase 
(CP), accelerated phase (AP), or blast phase (BP) CML or Ph+ ALL for whom no other TKI 
therapy is indicated and (2) treatment of adult patients with T315I-positive CML (CP, AP, or 
BP) or T315I-positive Ph+ ALL (Iclusig (ponatinib) Tablets for Oral Use 2022). In the EU, 
ponatinib is indicated in adults patients with (1) CP, AP, or BP-CML who are resistant to 
dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent 
treatment with imatinib is not clinically appropriate; or who have the T315I mutation or (2) Ph+ 
ALL who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent 
treatment with imatinib is not clinically appropriate; or who have the T315I mutation (Iclusig 
(ponatinib) 15 and 30 and 45 mg Film-Coated Tablets 2022). 
The PACE study enrolled 449 CML (CP, AP, or BP) or Ph+ ALL patients resistant or intolerant 
to dasatinib or nilotinib, or with BCR-ABL1 T315I mutation (32 Ph+ ALL patients were 
included in this study) (Cortes et al. 2013). All patients had previously been treated with at least 
1 approved BCR-ABL1 inhibitor, with the majority having been treated with 3 or more. A 
starting dose of ponatinib 45 mg was used, which was the recommended dose established in the 
phase 1 study (Study AP24534-07-101) (Cortes et al. 2012). 
Patients were assigned to 1 of 6 cohorts in accordance with disease group, prior therapy, and 
presence of the T315I mutation. Ph+ ALL patients were combined with BP-CML patients 
(referred to as BP-CML/Ph+ ALL) and included in cohort E if they were resistant/intolerant or 
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cohort F if they had T315I mutation. Ninety-four patients were included in the BP-CML/Ph+ 
ALL group (48 in cohort E and 46 in cohort F). The primary response endpoints of the study 
were met, based on analysis of the primary endpoints of major cytogenetic response (MCyR) by 
12 months (CP-CML patients) and major hematologic response (MaHR) by 6 months (AP-CML 
and BP-CML/Ph+ ALL patients) using 2-sided exact 95% confidence intervals (CIs) for MCyR 
and MaHR in the per protocol population in each cohort. For patients with BP-CML/Ph+ ALL, 
the prespecified variables for achieving the primary endpoint were met (95% CI, 10% to 30%). 
The overall MaHR rate by 6 months was 34.0% (treated population; 32/94 patients; 95% CI, 
24.6% to 44.5%) and 35.6% (per protocol population; 32/90 patients; 95% CI, 25.7% to 46.3%). 
In cohort E (resistant/intolerant), the MaHR rates were 35.4% and 37.0% (treated and per 
protocol populations, respectively), with a 95% CI of 23.2% to 52.5% in the per protocol 
population. In cohort F (T315I), the MaHR rates were 32.6% and 34.1% (treated and per 
protocol populations, respectively), with a 95% CI of 20.5% to 49.9% in the per protocol 
population. Of note, the overall MaHR rate was also higher than the MaHR rate attained with the 
most recent dasatinib or nilotinib therapy (34.0% versus 24.2%); by cohort the rates were 35.4% 
vs 25.0% in cohort E (resistant/intolerant) and were 32.6% versus 23.3% in cohort F (T315I), 
indicating clinically meaningful responses in these patients with advanced disease. 
The median progression-free survival (PFS) for the overall BP-CML/Ph+ ALL disease group 
(N = 94) was estimated as 91 days, with the probability of remaining progression-free at 26, 52, 
and 104 weeks estimated as 28.3%, 15.9%, and 7.9%, respectively. Median overall survival (OS) 
for the BP-CML/Ph+ ALL disease group was estimated as 209 days, and the probability of 
survival at 1, 2, and 3 years was estimated as 32.6%, 16.9%, and 9.7%, respectively. 
Preliminary results of 2 ongoing investigator-initiated studies (ponatinib in combination with 
chemotherapy (Jabbour et al. 2015; Short et al. 2017) and ponatinib in combination with steroids 
(Martinelli et al. 2017)) have provided evidence of the benefit of ponatinib in the treatment of 
newly diagnosed patients with Ph+ ALL. In addition, an investigator-initiated phase 2 study in 
patients with chronic phase CML resistant or intolerant to 1 previous TKI showed that 4 out of 
5 (80%) patients achieved a complete cytogenetic response, reinforcing the efficacy of ponatinib 
in patients failing a prior TKI (Sanford et al. 2015). 
In summary, clinical data are consistent with the following: 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. 
Details regarding the ponatinib clinical development program are provided in the investigator’s 
brochure in the section describing clinical studies. 
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4.2 
Rationale for the Proposed Study 
4.2.1 
Rationale for Relapsed Population (Ph+ ALL, Ph+ Mixed Phenotype Acute 
Leukemia, and Philadelphia Chromosome–like ALL) 
Historically, Ph+ ALL was consistently associated with poor outcomes in children and 
adolescents, with a 5-year event-free survival (EFS) of 40%, despite intensive chemotherapy 
regimens and allogeneic hematopoietic stem cell transplantation (HSCT) (Arico et al. 2010; 
Cazzaniga et al. 2018; Schultz et al. 2009). 
The introduction of treatment with imatinib, a first-generation TKI approved as front-line 
treatment for children with Ph+ ALL, dramatically improved the prognosis for these patients. 
Before the use of TKIs, only 45% of children with Ph+ ALL were alive 7 years after diagnosis 
(Arico et al. 2010). The combination of imatinib with standard chemotherapy led to an overall 
higher long-term disease-free survival in both adults and children (Leoni and Biondi 2015; 
Schultz et al. 2009; Schultz et al. 2014). However, the development of resistance to imatinib due 
to the presence or acquisition of mutations in the kinase domain is a common cause of disease 
recurrence (Leoni and Biondi 2015; Miller et al. 2014). In fact, some patients may harbor 
resistant mutations before TKI treatment (Pfeifer et al. 2012). Imatinib and the second-generation 
TKI dasatinib are the only BCR-ABL1 TKI treatments that are currently approved for use in 
pediatric patients with Ph+ ALL. The approach for the treatment of pediatric patients with 
suboptimal responses, resistance, or intolerance to imatinib and/or dasatinib is not well 
established. 
Other second-generation TKIs approved for use in Ph+ CML (ie, nilotinib and bosutinib) have 
activity against many kinase domain mutations that are not inhibited by imatinib. However, none 
of these agents, including dasatinib, have shown the ability to inhibit the T315I mutation (Leoni 
and Biondi 2015; Miller et al. 2014; Tamai et al. 2018) and they are expected to have the same 
limitations of resistance to this and other BCR-ABL1 mutations in the proposed pediatric 
population as they do in adults. The incidence of resistant mutations in the pediatric population is 
unknown; however, ABL1-kinase domain mutations account for resistance in over 80% of cases 
of Ph+ ALL relapse in adults. Specifically, the T315I mutation is the most frequent mutation 
detectable in TKI-resistant adult patients (Foà et al. 2011; Soverini et al. 2014; Watanabe et al. 
2012). In one study with dasatinib, the T315I mutation was observed in 75% of relapsed patients 
(Rousselot et al. 2016). Ponatinib may represent a major step in overcoming drug resistance for 
pediatric patients with relapsed or resistant Ph+ ALL (Leoni and Biondi 2015). 
Mixed phenotype acute leukemia (MPAL) is a very rare type of acute leukemia with an 
approximate incidence of 1% to 2.5% of acute leukemias in the pediatric population (Weinberg 
and Arber 2010). Patients with Ph+ MPAL generally have inferior outcomes compared to 
patients with lineage-specific leukemias. However, patients who have Ph+ MPAL respond 
favorably to a TKI-containing regimen (Matutes et al. 2011; Shimizu et al. 2014). 
Philadelphia chromosome–like (Ph-like) ALL has a similar gene expression profile to that of 
Ph+ ALL and is associated with a poor outcome. It has an incidence of 10% in children with 
standard-risk ALL, 21% in adolescents with ALL, and 27% among young adults with ALL 
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(Rheingold et al. 2017; Roberts et al. 2014; Roberts et al. 2012). Kinase activating mutations 
were found in 91% of patients with Ph-like ALL. Cell lines and human leukemic cells expressing 
ABL1, ABL1 CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib. The high 
frequency of kinase-activating lesions in patients with Ph-like ALL predicts that TKI therapy is 
likely to be effective in these patients. 
Rationale therefore exists that there is an unmet medical need for a more potent TKI for the 
treatment of pediatric patients with Ph+ ALL, Ph+ MPAL, or Ph-like ALL with ABL1-class 
fusions who have relapsed or are resistant or intolerant to a prior TKI-containing therapy, or 
Ph+ ALL with T315I mutation. Compared with earlier generation TKIs, ponatinib is a more 
potent, pan-inhibitory TKI with the potential to be more effective than other TKIs. The 
increased potency of ponatinib, along with its activity toward the single mutations associated 
with resistance to earlier generation TKIs, supports the investigation of ponatinib in combination 
with chemotherapy in the treatment of pediatric patients with Ph+ ALL, Ph+ MPAL, or Ph-like 
ALL who have relapsed or are resistant or intolerant to a prior TKI-containing therapy, or with 
T315I mutation in this phase 1/2 study. 
4.2.2 
Rationale for Minimum Age of at Least 1 Year 
ALL in infants (<1 year of age) is rare compared to the incidence of ALL in older children, and 
is biologically different from ALL in older children (Pieters et al. 2007). In addition to the 
vulnerability of infants to complications and toxicity of aggressive treatment regimens, there are 
several complex physiologic processes that undergo rapid changes during the first year of life 
such that infants have a distinct physiology that should be considered in designing chemotherapy 
treatment protocols (Brown 2013). Generally, specific protocols are used for ALL patients 
<1 year of age (Ibagy et al. 2013). 
4.2.3 
Rationale for Complete Remission as Primary Endpoint 
The rationale for using complete remission (CR) as the primary endpoint for this study is based 
on findings that assessing for remission at the end of the induction phase of therapy, both in 
front-line and relapse salvage therapies, has long been common practice in pediatric ALL as this 
has been an important response milestone that predicts long-term outcome. Additionally, the 
degree of reduction of the leukemic clone during remission has independent prognostic value 
(Bruggemann et al. 2006; Dworzak et al. 2002; Panzer-Grumayer et al. 2000; Pui et al. 2001; Pui 
and Evans 2006; Zhou et al. 2007). 
4.2.4 
Rationale for the Doses of Ponatinib 
Because relapsed Ph+ ALL is an aggressive disease, phase 1 of this study is a dose confirmation 
rather than a dose escalation phase. 
4.2.4.1 
Cohort 1 of the Phase 1 Portion of the Study 
For phase 1 cohort 1, the ponatinib doses in combination with multiagent chemotherapy for the 
treatment of pediatric patients were selected to target exposures achieved in adults after 
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administration of 30 mg once daily (QD) doses. The selection of adult 30 mg exposures as the 
target for the pediatric population was based on benefit-risk considerations using the available 
adult clinical experience, and was additionally supported by a comparison of systemic exposures 
to in vitro estimates of pharmacologic potency for BCR-ABL1 inhibition. 
The adult phase 1 Study AP24534-07-101 supported a 45 mg ponatinib dose as the 
recommended phase 2 dose (RP2D) in patients with resistant hematologic cancers, including 
CML and Ph+ ALL. Thus, the pivotal PACE study (Study AP24534-10-201), conducted in adult 
patients with refractory CML or Ph+ ALL, used a ponatinib dose of 45 mg. Continued follow-up 
in the PACE study demonstrated a high incidence of arterial occlusive events (AOEs) at the 
45 mg dose. Two logistic regression analyses of dose intensity-adverse event (AE) relationships 
have been conducted on safety data collected in the ponatinib clinical development program. The 
first analysis was conducted using data from the PACE study, and a subsequent integrated 
analysis was conducted on data from across the phase 1 Study AP24534-07-101, the phase 2 
PACE study, and the phase 3 Study AP24534-12-301 (EPIC, which was a study conducted in 
patients with newly diagnosed CP-CML). These analyses have consistently indicated a 
dose-dependent increase in AEs, and notably AOE rates, which are of specific importance for 
ponatinib. Dose intensity was a statistically significant predictor of AOE rates, and these 
analyses demonstrated that the 30 mg QD dose can be expected to have a superior safety profile 
compared with 45 mg QD. In addition, the 30 mg QD dose is anticipated to provide 
pharmacologically active exposures of ponatinib because the geometric mean steady-state 
average concentration was 36.5 ng/mL based on the adult population pharmacokinetics (PK) 
analysis, which exceeds the 21.3 ng/mL (40 nM) IC50 for all BCR-ABL1 mutations in a 
cell-based assay. 
Preliminary exposure-response analyses have also been conducted using available preliminary 
data from the adult OPTIC study as of the 05 December 2018 data cutoff date. The OPTIC study 
is an ongoing, randomized, open-label, phase 2 study of ponatinib in patients with resistant 
CP-CML, in which eligible patients are randomized to receive QD administration of 1 of 
3 starting doses of ponatinib: 45, 30, or 15 mg. Patients starting at 45 or 30 mg have their daily 
dose reduced to 15 mg upon achievement of a molecular response with 2-log reduction 
(ie, BCR-ABL1/ABL1 ≤1%) (MR2) or better. 
For the preliminary exposure-efficacy analysis, the relationship between ponatinib exposure and 
molecular response states was described using a discrete-time, first-order, 4-state Markov model. 
The exposure-safety analysis described the relationship between ponatinib exposure and the risk 
of AOEs using a parametric time-to-event model. In these analyses, exposure-related increases 
were observed for both efficacy (MR2 or better response) and safety (AOEs). Simulations of 
dose-response using the developed exposure-response models were performed for the dosing 
regimens in the OPTIC study, and the results were overlaid (Figure 4.a). 
In the model-based dose-response simulations, a starting dose of 30 mg was predicted to have an 
AOE rate of approximately 9% at 1 year, representing only a modest increase as compared to the 
15 mg dose (approximately 7% AOE rate). In contrast, the starting dose of 45 mg was predicted 
to have an AOE rate of approximately 13%. The predicted dose-response relationship for 
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efficacy suggests a greater relative increase in the percentage of patients with MR2, or better 
response at 30 mg (44%) versus 15 mg (35%), as compared to 45 mg (49%) versus 30 mg (44%). 
Taken together, these preliminary analyses of the available OPTIC study data as of the 
05 December 2018 data cutoff date indicate a potentially better benefit-risk profile for the 30 mg 
starting dose compared to the 15 or 45 mg starting doses. 
Figure 4.a 
Dose-Response Relationships for Efficacy (MR2 or Better Response) and 
Safety (AOEs) at 1 Year for the Dosing Regimens in the Ongoing OPTIC 
Study Based on Simulations from the Preliminary Exposure-Response 
Models (Based on the Data Cutoff Date of 05 December 2018) 
 
AOE: arterial occlusive event; MR2: molecular response with 2-log reduction. 
 
Accordingly, pediatric doses in phase 1 cohort 1 targeted adult exposures achieved at the 30 mg 
dose as this dose provides pharmacologically relevant exposures in the efficacious range, while 
reducing the risk for treatment-related toxicities relative to the 45 mg dose. Furthermore, 
ponatinib is being administered in combination with multiagent chemotherapy, thereby favoring 
selection of a lower dose than the approved adult single-agent dose of 45 mg. 
Because no pediatric clinical PK data are currently available for ponatinib, an allometric scaling 
approach was used to project the pediatric PK of ponatinib from the adult population PK model. 
The use of an allometric scaling approach is supported by knowledge of clearance mechanisms 
for ponatinib and their corresponding ontogeny. Ponatinib is metabolized predominantly by 
cytochrome P450 3A (CYP3A) with additional contributions by esterases and/or amidases. 
These clearance pathways are expected to be at adult levels by 1 year of age (CYP3A), or be 
at >60% of adult levels within the first year of life (esterases/amidases) (Boberg et al. 2017; 
Hines et al. 2016; Shi et al. 2011; Upreti and Wahlstrom 2016). Accordingly, simulations based 
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on the population PK model, developed using adult data, have been performed to guide dose 
selection for the phase 1 dose confirmation portion of the study. 
The adult population PK model describes ponatinib PK in cancer patients as a 2-compartment 
model with linear clearance and absorption via 2 sequential transit compartments before entering 
the central compartment. Age and body weight on the central volume of distribution were the 
only significant covariates in the model (Hanley et al. 2022). 
For the purpose of predicting pediatric doses that would match adult exposures at 30 mg QD, the 
model was adapted by removing the previously estimated adult covariate effects and including 
allometric scaling coefficients of 0.75 and 1 on clearance and volume parameters, respectively. 
The adapted model, through simulation, was used to predict the target exposure (area under the 
plasma concentration–time curve [AUC]) in adult patients and to simulate pediatric exposures 
after administration of fixed doses of ponatinib. 
Ponatinib doses of 20 mg for pediatric patients weighing between 30 kg and 45 kg, and 30 mg 
for pediatric patients weighing ≥45 kg were predicted to result in systemic exposures that 
approximately match adult exposures following a 30 mg dose. Therefore, dose level 1 of phase 1 
cohort 1 enrolled patients ≥30 kg who were able to swallow solid oral dosage forms (ie, tablets) 
as the age-appropriate formulation (AAF) was not available prior to protocol amendment 3. 
Patients weighing between 30 and 45 kg received 20 mg ponatinib, and patients weighing ≥45 kg 
received 30 mg ponatinib. Patients experiencing treatment-emergent adverse events (TEAEs) 
that required dose reductions had their ponatinib dose reduced to dose level -1. 
Enrollment to cohort 1 of the phase 1 portion of the study is completed as of protocol 
amendment 3. 
4.2.4.2 
Safety Data from Cohort 1 of the Phase 1 Portion of the Study 
Seven patients with Ph+ ALL, 3 male patients and 4 female patients, were enrolled and treated in 
cohort 1 of the phase 1 portion of the study. The median age at enrollment was 12.0 years (range, 
9-17 years). Per protocol, up to 6 patients had to be concurrently enrolled into phase 1 cohort 1 to 
determine the RP2D; 1 patient aged >16 years and 6 patients aged ≤16 years were enrolled. 
As of 21 October 2022, 4 patients were on study treatment and 3 patients were receiving 
ponatinib treatment, including 2 patients receiving continuation therapy. 
As of 21 October 2022, all patients presented with TEAEs related to ponatinib and/or related to 
the backbone chemotherapy. 
The most frequently reported TEAEs were anaemia (in 6 patients); ALT increased, AST 
increased, and hypoalbuminaemia (each in 5 patients); blood fibrinogen decreased, 
gamma-glutamyltransferase increased, lymphocyte count decreased, neutrophil count decreased, 
white blood cell count (WBC) decreased, headache, and constipation (each in 4 patients); and 
pyrexia, vomiting, lipase increased, platelet count decreased, and thrombocytopenia (each in 
3 patients). The most frequently reported Grade ≥3 TEAEs were anaemia (in 5 patients); 
lymphocyte count decreased, neutrophil count decreased, and WBC decreased (each in 
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4 patients); and ALT increased, blood fibrinogen increased, platelet count decreased, and 
thrombocytopenia (each in 3 patients). 
Four patients experienced 8 serious TEAEs: ALT increased (2 events), hepatotoxicity, 
hypertriglyceridaemia, and seizures in 1 patient; catheter site haemorrhage and dilatation 
ventricular in 1 patient; and pneumonia in 1 patient. No serious TEAEs related to ponatinib were 
reported. 
Three patients experienced TEAEs leading to ponatinib dose reduction and 4 patients 
experienced TEAEs leading to ponatinib dose discontinuation. 
Two patients experienced dose-limiting toxicities (DLTs) before completing the reinduction 
block and discontinued study treatment. Reported DLTs were Grade 3 skin rash; and Grade 3 
liver toxicity (which included both Grade 3 ALT elevation and Grade 3 direct and total bilirubin 
elevation). Therefore, the available safety data indicate that ponatinib dose level 1 of phase 1 
cohort 1 (ie, 30 mg QD adult exposures) was not adequately tolerated. Per Section 8.1.2 of 
protocol amendment 2, if 2 out of 6 patients experienced DLTs, the treatment regimen was to be 
considered not adequately tolerated and additional cohorts could be enrolled. 
4.2.4.3 
Cohort 2 of the Phase 1 Portion of the Study 
Following review of safety data of phase 1 cohort 1, the dose of ponatinib will be reduced and 
the chemotherapy backbone will remain unchanged for patients enrolled starting phase 1 
cohort 2 per protocol amendment 3 (see Section 4.2.5). 
In adult patients, a ponatinib dose reduction to 15 mg QD is recommended for patients 
experiencing TEAEs at 30 mg QD (Iclusig (ponatinib) 15 and 30 and 45 mg Film-Coated Tablets 
2022; Iclusig (ponatinib) Tablets for Oral Use 2022). 
Thus, dose level 1 of phase 1 cohort 2 will target adult exposures achieved after administration 
of 15 mg QD. Simulations were performed using the allometrically scaled population PK model 
and indicated that ponatinib doses of 15 mg, 10 mg, 7.5 mg, and 5 mg for patients weighing 
≥45 kg, 30 kg to <45 kg, 15 kg to <30 kg, and 5 kg to <15 kg, respectively, are predicted to 
result in systemic exposures that approximately match adult exposures following administration 
of 15 mg (Figure 4.b). Patients experiencing TEAEs that require a dose reduction will have their 
ponatinib dose reduced by 1 dose level (ie, cohort 2 dose level -1 in Table 8.a). 
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Figure 4.b 
Predicted Pediatric Exposures of Ponatinib in Pediatric Patients Compared 
With Adult Exposures at 15 mg 
 
AUC: area under the plasma concentration-time curve; PK: pharmacokinetic(s). 
Circles (error bars) denote the median (5th to 95th percentile) of AUC for pediatric patients in each 5 kg body weight bin. The 
solid (dashed) black line represents the median (range) of AUC for adult patients as estimated from the population PK analysis. 
 
4.2.5 
Rationale for Selection of Chemotherapy Backbone Regimen 
A modified United Kingdom (UK) ALL R3 regimen has been selected as the chemotherapy 
backbone for this study. The UK ALL R3 regimen was used in a study for children with first 
relapse of ALL that compared idarubicin with mitoxantrone in reinduction (Parker et al. 2010). 
This trial reported the best survival results of any relapse regimen to date. However, when this 
reinduction regimen was used in combination with new agents (ie, temsirolimus, decitabine, and 
vorinostat) in recent Therapeutic Advances in Childhood Leukemia & Lymphoma consortium 
and Children’s Oncology Group (COG) protocols, it resulted in severe toxicity, including 
life-threatening infections (Burke et al. 2016; Rheingold et al. 2017). Therefore, for this study, 
the R3 reinduction regimen has been modified by substituting the type of anthracycline while 
keeping the original schedule (Table 8.b). Also, the dexamethasone dose and schedule have been 
changed to a more conventional regimen. This reinduction regimen has been well tolerated when 
used in previous studies (Goulden et al. 2017; Larsen et al. 2016). 
All 3 drugs, asparaginase, methotrexate, and ponatinib, could have contributed to the occurrence 
of liver toxicities observed in most patients in cohort 1, which required ponatinib dose reductions 
and interruptions. In addition, asparaginase has the potential for coagulopathy and pancreatitis as 
does ponatinib, particularly in combination with corticosteroid therapy. 
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4.3 
Age-Appropriate Formulation for Ponatinib 
As of protocol amendment 3, the AAF for ponatinib is available. The AAF is supplied as mini-
tablet–containing capsules, ie minitab capsules, with dose strengths of 2.5 and 5 mg. A previous 
clinical study (Study INCB 84344-103) in healthy adult volunteers assessed the relative 
bioavailability of the AAF capsules administered intact, or the capsule contents sprinkled on 
yogurt or applesauce, versus the tablet formulation. The results of this relative bioavailability 
study indicated that the relative bioavailability (area under the plasma concentration-time curve 
from time 0 to infinity [AUC∞] ratio) and 90% CIs for the AAF versus the tablet formulation 
comparisons were all within 80% to 125%. Therefore, ponatinib tablets, intact minitab capsules, 
and minitab capsules opened and sprinkled in yogurt or applesauce can be used interchangeably 
without dose adjustment. 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objectives 
5.1.1.1 
Phase 1 Primary Objective 
• To determine the RP2D of ponatinib (tablet and age-appropriate formulation [AAF]) in 
combination with chemotherapy. 
5.1.1.2 
Phase 2 Primary Objective 
• To determine the efficacy of ponatinib in combination with chemotherapy as measured by 
the rate of CR at the end of the reinduction block. 
5.1.2 
Secondary Objectives 
5.1.2.1 
Phase 1 Secondary Objectives 
• To define and describe the phase 1 efficacy of ponatinib (tablet and AAF) in combination 
with chemotherapy. 
5.1.2.2 
Phase 2 Secondary Objectives 
• Ph+ ALL only: To describe the proportion of patients who achieved CR at the end of 
consolidation. 
• Ph+ ALL only: To describe the proportion of patients with minimal residual disease (MRD) 
status <0.01% among those who achieved CR at the end of each treatment block. 
• To determine the proportion of patients who relapsed or progressed. 
• To determine EFS, PFS, and OS at 6 months, 1 year, 18 months, 2 years, and 3 years. 
• To determine duration of response (for CR). 
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• To determine the proportion of patients who underwent HSCT following study treatment. 
5.1.2.3 
Phase 1 PK Objective 
• To characterize the PK of ponatinib in combination with chemotherapy. 
5.1.2.4 
Phase 2 PK Objective 
• 
To collect plasma concentration–time data to contribute to population PK and 
exposure-response analyses of ponatinib. 
5.1.2.5 
Phase 1 and Phase 2 Safety Objective 
• To describe the safety profile of ponatinib in combination with chemotherapy for each 
treatment block (ie, reinduction and consolidation). 
5.1.3 
Exploratory Objectives 
• To explore the risk of cardiotoxicity in patients with elevated cardiac troponin and 
N-terminal pro-brain natriuretic peptide (NT-proBNP). 
• Ph+ ALL only: To characterize biomarkers of sensitivity and resistance to ponatinib-
containing therapy, which may include molecular mutations (eg, BCR-ABL1, IKZF1, 
CDKN2A/2B) in samples both prior to and following ponatinib treatment. 
• To assess the acceptability and palatability of the AAF of ponatinib using the palatability 
questionnaire (Appendix E). 
• To determine OS for patients who receive HSCT and patients who do not receive HSCT. 
5.2 
Endpoints 
5.2.1 
Primary Endpoints 
5.2.1.1 
Phase 1 Primary Endpoint 
The phase 1 primary endpoint is the following: 
• RP2D of ponatinib (tablet and AAF) in combination with chemotherapy. 
5.2.1.2 
Phase 2 Primary Endpoint 
The phase 2 primary endpoint is the following: 
• CR at the end of the reinduction block. CR is defined as <5% blasts in BM, normal 
maturation of all cellular components in the BM, no evidence of extramedullary disease, 
absolute neutrophil count (ANC) >1000/µL, and platelet count of >100,000/µL. 
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5.2.2 
Secondary Endpoints 
5.2.2.1 
Phase 1 Secondary Endpoints 
The phase 1 secondary endpoints are the following: 
• CR at the end of the reinduction block. CR is defined as <5% blasts in BM, normal 
maturation of all cellular components in the BM, no evidence of extramedullary disease, 
ANC >1000/µL, and platelet count of >100,000/µL. 
5.2.2.2 
Phase 2 Secondary Endpoints 
The phase 2 secondary endpoints are the following: 
• Ph+ ALL only: Proportion of patients who achieved CR at the end of consolidation. 
• Ph+ ALL: Proportion of patients with MRD-negative status (<0.01%) among those who 
achieved CR at the end of each treatment block. 
• Proportion of patients who relapsed or progressed. 
• EFS, PFS, and OS at 6 months, 1 year, 18 months, 2 years, and 3 years. 
• Duration of response (for CR). 
• Proportion of patients who underwent HSCT following study treatment. 
5.2.2.3 
Phase 1 PK Endpoint 
The phase 1 PK endpoint is the following: 
• Summary statistics of ponatinib PK parameters including maximum observed plasma 
concentration (Cmax), time of first occurrence of Cmax (tmax), and AUC from time 0 to the time 
of the last quantifiable concentration (AUClast). 
5.2.2.4 
Phase 1 and Phase 2 Safety Endpoint 
The phase 1 and phase 2 safety endpoint is the following: 
• AEs, serious adverse events (SAEs), AOEs, venous thrombotic/embolic events (VTEs), and 
any other adverse events of special interest (AESIs). 
5.2.3 
Exploratory Endpoints 
The exploratory endpoints are the following: 
• Change from baseline in laboratory values and cardiovascular outcomes associated with 
elevated cardiac troponin and NT-proBNP. 
• Ph+ ALL only: Biomarkers of potential sensitivity and resistance to ponatinib-containing 
therapy, which may include molecular mutations (eg, BCR-ABL1, IKZF1, CDKN2A/2B) in 
samples both prior and following ponatinib treatment. 
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• Acceptability and palatability of the AAF of ponatinib based on the palatability questionnaire 
administered during reinduction (Appendix E). 
• OS for patients who receive HSCT and patients who do not receive HSCT. 
6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
This is a pivotal phase 1/2, single-arm, open-label, multicenter study designed to evaluate the 
safety, tolerability, PK, and efficacy of ponatinib when administered in combination with 
multiagent chemotherapy in pediatric patients (aged ≥1 year to ≤21 years) with Ph+ ALL, 
Ph+ MPAL, or Ph-like ALL with targetable kinase-activating lesions and either (i) or (ii) as 
follows: 
(i) 
For non-US sites: Patients who have relapsed or are resistant or intolerant to at 
least 1 prior therapy that contained a BCR-ABL1–targeted TKI, OR 
For US sites: Patients who have relapsed or are resistant or intolerant to at least 
1 prior therapy that contained a second-generation BCR-ABL1–targeted TKI; OR 
(ii) 
Have a BCR-ABL1 T315I mutation. 
Patients will undergo screening assessments for up to 10 days to determine eligibility 
(Figure 6.a). In both phase 1 and phase 2, eligible patients will receive two 35-day blocks of 
therapy (reinduction block and consolidation block). Each block will include 29 days of study 
treatment consisting of daily ponatinib and a modified UK ALL R3 chemotherapy backbone 
regimen specified in Table 8.b and a rest period from chemotherapy for a minimum of 6 days 
consisting of daily ponatinib only. Disease assessment will occur at the end of each block. 
Patients will undergo an end of treatment (EOT) visit (EOT1) 25 to 30 days after the last dose of 
study treatment in the consolidation block, or earlier, if the patient is proceeding to alternate 
therapy or optional ponatinib continuation therapy (Appendix A, Table 1). 
Patients completing protocol therapy and the EOT1 visit can proceed to alternate therapies not 
containing ponatinib as off-protocol therapy. Alternatively, eligible patients may receive optional 
ponatinib continuation therapy (either ponatinib monotherapy or combination therapy at the 
investigator’s discretion and with sponsor agreement) after completing the 2 blocks of study 
treatment and the EOT1 visit. Patients who receive optional continuation therapy with 
ponatinib/ponatinib-containing therapy will be followed per the schedule of events (SOE) and 
proceed to a second EOT visit (EOT2) 30 to 40 days after the last dose of ponatinib, or earlier, if 
the patient discontinues ponatinib/ponatinib-containing therapy sooner than 30 days 
(Appendix A, Table 2). Patients who discontinue ponatinib before completing the consolidation 
block will be discontinued from study treatment and proceed to the EOT1 visit. All patients will 
be followed for at least 3 years from EOT1, with primary analysis performed approximately 
6 months after the last patient has been enrolled. 
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Phase 1 of the study (approximately 12 DLT-evaluable patients) is a PK/safety lead-in phase for 
dose confirmation to establish the RP2D of ponatinib administered either as the tablet 
formulation or the AAF (Table 8.a) in combination with the chemotherapy backbone (Table 8.b). 
The initial ponatinib doses evaluated in cohort 1 of the phase 1 portion of the study were selected 
to target systemic exposures comparable to those achieved in adults receiving 30 mg QD based 
on the results of population PK modeling and simulation (see Section 4.2.4.1). 
A staggered enrollment is being applied. Phase 1 cohort 1 was initiated with the tablet 
formulation in patients able to swallow solid oral dosage forms and weighing at least 30 kg as 
the AAF was not available during that enrollment period. As of protocol amendment 3, both the 
tablet formulation and AAF are available for use in phase 1 (see Section 4.3). Additional details 
regarding administration of the AAF are provided in the study/pharmacy manual. 
The PK, safety, and tolerability data from phase 1 will inform selection of the recommended 
dose of ponatinib for confirmatory evaluation of safety and efficacy in the phase 2 portion of the 
study. A rolling 6 design will be followed for all phase 1 cohorts. 
As of cohort 2 of phase 1, patients will be reviewed on an ongoing basis to determine whether 
the patient meets the criteria to be DLT-evaluable. DLT-evaluable patients must have received 
ponatinib doses on at least 70% of the reinduction block days (eg, 25 or more of the 35 days) per 
protocol or experienced a confirmed DLT. 
Ponatinib doses for evaluation in phase 1 cohort 2 will target systemic exposures comparable to 
those achieved in adults receiving 15 mg QD based on the results of population PK modeling and 
simulation (see Section 4.2.4.3). For phase 1 cohort 2, approximately 6 DLT-evaluable patients 
with a body weight of at least 5 kg will be enrolled, with a minimum of 2 patients with a baseline 
body weight <30 kg. No more than 1 DLT-evaluable patient may be >16 years of age in 
cohort 2. 
To determine the RP2D, a minimum of 6 DLT-evaluable patients in cohort 2 must complete the 
reinduction block. If 2 out of 6 patients experience a DLT, the study will be paused to determine 
further tolerability of this combination. All patients enrolled in cohort 2 under protocol 
amendment 3 and those enrolled under protocol amendment 4 will be assessed together in a 
single cohort for determination of DLTs and RP2D as defined in protocol amendment 4. 
Definitions of DLTs are provided in Section 8.2. The DLT observation period for each 
formulation will start on Day 1 and continue until the end of the reinduction block. If patients 
have residual hematologic toxicities at end of the reinduction block, they will be followed for up 
to an additional 7 days for DLT evaluation. 
Cohort enrollment in a rolling 6 design is continuous and will proceed as follows: 
• If ≤1 DLT for the first 3 to 5 patients, subsequent patients (the fourth, fifth, and/or sixth 
patient[s]) may be enrolled. 
• If ≥2 DLTs occur in the first 3 to 5 patients, enrollment will be closed. 
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• If a patient becomes unevaluable for DLT assessment, an additional patient (ie, replacement) 
may be enrolled to ensure a minimum of 6 DLT-evaluable patients. 
Upon review of patients treated in cohort 2, if dose level 1 is determined not to be tolerated or 
fails to achieve the desired target systemic exposures and RP2D is not confirmed with cohort 2, 
then no further cohorts are planned to be tested. 
The RP2D of ponatinib will be determined after evaluating the available safety and PK data from 
the first 6 patients enrolled in phase 1 cohort 2. Up to an additional 6 patients may be enrolled to 
further characterize the safety, PK, and preliminary efficacy of the RP2D of ponatinib before the 
start of phase 2. 
Phase 2 of the study will enroll approximately 68 patients, including DLT-evaluable patients 
enrolled to phase 1 who completed the reinduction block and dosed at the RP2D. 
In phase 2, patients will receive daily ponatinib in combination with the chemotherapy backbone 
at the RP2D determined after review of available data from the phase 1 portion of the study 
(Table 8.b). Phase 2 will evaluate the efficacy and safety of ponatinib at the RP2D in 
combination with chemotherapy in the study population. 
Figure 6.a presents the design schema for the study. 
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Figure 6.a 
Study Design Schema 
 
AAF: age-appropriate formulation; EOT1: end of treatment 1; EOT2: end of treatment 2; RP2D: recommended 
phase 2 dose. 
“equivalent” refers to adult equivalent/target dose. 
a Each block consists of 29 days of study treatment with ponatinib and chemotherapy followed by a chemotherapy 
rest period of a minimum of 6 days consisting of daily ponatinib only. Ponatinib should not be interrupted unless the 
patient has toxicity suspected to be related to ponatinib. 
b Patients will undergo evaluation for disease status at the end of the reinduction block and the consolidation block. 
Patients tolerating treatment at the end of the reinduction block will proceed to the consolidation block regardless of 
their remission status. 
c Patients will have their first EOT visit (EOT1) 25 to 30 days after last dose of ponatinib in the consolidation block, 
or earlier, if the patient is proceeding to alternate therapy or optional ponatinib continuation therapy. 
d Patients who receive optional continuation therapy containing ponatinib will have an additional EOT visit (EOT2) 
30 to 40 days after last dose of ponatinib, or earlier, if the patient is proceeding to alternate therapy. See Table 8.d 
for optional ponatinib continuation therapy regimen. Patients who are receiving clinical benefit from ponatinib 
treatment may continue therapy for a maximum of 12 months. If patients continue deriving clinical benefit after 
12 months of optional continuation therapy, they may remain on ponatinib treatment if the investigator provides the 
evidence of clinical benefits and confirms with the sponsor. 
 
The ponatinib dose may be reduced or discontinued early if a patient experiences study 
treatment–related toxicities. Patients who must discontinue ponatinib due to toxicity before 
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completing the consolidation block will be discontinued from study treatment and proceed to the 
EOT1 visit. Patients may discontinue study treatment at any time. Patients who discontinue study 
treatment will proceed to the EOT1 visit 25 to 30 days after receiving their last dose of ponatinib 
(or earlier, if the patient is proceeding to alternate therapy or optional ponatinib continuation 
therapy) as specified in the SOE (Appendix A, Table 1). Patients who discontinue from optional 
ponatinib continuation therapy will proceed to the EOT2 visit (Appendix A, Table 2). 
Patients will undergo assessments as described in the SOE (Appendix A, Table 1). Key 
assessments for efficacy include BM samples (aspirate and/or biopsy) for CR status and MRD, 
peripheral blood samples to assess hematological and molecular responses and for exploratory 
biomarker assessments. In addition, patients and/or their parents/legal guardians will be 
administered a questionnaire to assess the palatability of the ponatinib AAF (during the 
reinduction block only). Serial blood samples for the measurement of plasma concentrations of 
ponatinib will be obtained at prespecified time points as described in Appendix A, Table 3 and 
Table 4. These data will be used to characterize the PK of ponatinib. 
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) Version 5.0, effective 27 November 2017. 
AEs will be assessed and may include results from laboratory tests, vital signs, and 
electrocardiograms (ECGs) to evaluate the safety and tolerability of ponatinib. 
Development of mutations will be assessed both prior to ponatinib treatment and following study 
treatment. 
6.2 
Number of Patients 
Phase 1 of the study will enroll approximately 12 DLT-evaluable patients; phase 2 of the study 
will enroll approximately 68 patients, including DLT-evaluable patients enrolled to phase 1 who 
completed the reinduction block and are dosed at the RP2D. Approximately 74 study sites in 
approximately 17 countries will enroll patients into the study. 
A patient is considered to be enrolled in the study at the time of initiation of the first dose of 
study drug. Procedures for completion of the enrollment information are described in the site 
operations manual. 
In phase 1, patients who are withdrawn from treatment during the reinduction block for reasons 
other than DLTs and become unevaluable for DLT assessment may be replaced. 
6.3 
Duration of Study 
6.3.1 
Duration of an Individual Patient’s Study Participation 
All patients enrolled will receive two 35-day blocks of therapy (ponatinib in combination with 
chemotherapy for 29 days followed by a rest period from chemotherapy for a minimum of 6 days 
consisting of daily ponatinib only). At the discretion of the treating physician and with sponsor 
agreement, a patient may continue in the optional ponatinib continuation therapy beyond the end 
of the consolidation block and receive ponatinib only or in combination with maintenance-type 
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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 
Patients (aged ≥1 year to ≤21 years and weighing at least 5 kg) with Ph+ ALL, Ph+ MPAL, or 
Ph-like ALL with targetable kinase-activating lesions must have BM involvement and either 
(i) or (ii) as follows:  
(i) 
For non-US sites: patients who have relapsed or are resistant or intolerant to at least 
one prior therapy that contained a BCR-ABL1–targeted TKI; OR 
For US sites: patients who have relapsed or are resistant or intolerant to at least one 
prior therapy that contained a second-generation BCR-ABL1–targeted TKI; OR 
(ii) 
Have a BCR-ABL1 T315I mutation. Referring institutions laboratory results will be 
accepted for enrollment; however, the mutation needs to be confirmed by the central 
laboratory. If the mutational status is not concordant, the patient will be withdrawn 
from the study and excluded from analyses. 
In phase 1 cohort 1, only patients with a body weight of ≥30 kg and able to swallow solid oral 
dosage forms were enrolled because the AAF was not available. As of protocol amendment 3, 
patients weighing at least 5 kg or who are unable to swallow solid oral dosage forms are eligible 
for enrollment as the AAF is available. 
7.1 
Inclusion Criteria 
Phase 1 cohort 1 (enrollment and treatment completed) eligibility criteria at the time of 
enrollment:  
• Patients must have a body weight ≥30 kg.  
• Patients must be able to swallow solid oral dosage forms.  
Phase 1 cohort 2 eligibility criteria at the time of enrollment: 
• Patients must be aged ≥1 year and have a body weight of at least 5 kg. 
Each patient must meet all the following inclusion criteria to be enrolled in the study for phase 1 
and phase 2: 
1. Diagnosis: Patients must have a diagnosis of Ph+ ALL, Ph+ MPAL, or Ph-like ALL with: 
a) Involvement of BM with ALL, including one of the following: 
i. M2 BM (5%-24% lymphoblasts): by morphology with confirmatory testing 
consisting of at least one of the following: flow cytometry lymphoblasts ≥5%, or 
BCR-ABL1 fluorescence in situ hybridization, or ≥10-2 leukemic clone identified by 
immunoglobulin heavy chain–T-cell receptor polymerase chain reaction, OR 
ii. M3 BM (≥25% lymphoblasts): by morphology, OR 
iii. Patients with combined BM (as defined above) and extramedullary disease. 
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b) Evidence of Ph+ ALL, MPAL, or Ph-like ALL:  
i. Definite evidence of BCR-ABL1 fusion (Ph) for Ph+ ALL and MPAL, OR  
ii. Definite evidence of Ph-like ALL with targetable kinase-activating lesions involving 
any of the following kinase genes: ABL1, ABL2, CSF1R, and PDGFRB. 
Ph-like ALL diagnosis requires the identification of specified targetable kinase-
activating lesions preferably by RNA sequencing or by alternative accredited 
method used by the site. Referring institution’s laboratory results will be accepted 
for diagnosis and study enrollment. No confirmation by a sponsor central laboratory 
is required. 
c) Disease status:  
i. For non-US sites: patients who have relapsed (post 0 or 1 HSCT) or are resistant or 
intolerant to at least 1 prior therapy that contained a BCR-ABL1–targeted TKI, OR 
For US sites: patients who have relapsed (post 0 or 1 HSCT) or are resistant or 
intolerant to at least 1 prior therapy that contained a second-generation 
BCR-ABL1-targeted TKI (ie, dasatinib, nilotinib, and bosutinib); OR 
ii. Have a BCR-ABL1 T315I mutation irrespective of relapse, resistance/intolerance, or 
transplant status and irrespective of any prior TKI use. Referring institution’s 
laboratory results will be accepted for study enrollment; however, the mutation needs 
to be confirmed by the central laboratory. If the mutational status is not concordant, 
the patient will be withdrawn from the study and excluded from analyses for RP2D 
and efficacy, but included for safety. 
Notes:  
A patient will be defined as intolerant if they had a Grade ≥3 nonhematologic toxicity or a 
Grade 4 hematologic toxicity considered related to the last TKI and lasting for >2 weeks, and led 
to discontinuation of therapy.  
2. Age and weight: Patients must be ≥1 and ≤21 years of age and weighing at least 5 kg at the 
time of enrollment.  
3. Performance Status: Karnofsky performance status ≥50% for patients ≥16 years of age or 
Lansky Play Scale ≥50% for patients <16 years of age. 
Prior Therapy 
4. Patients must have recovered to less than Grade 2 NCI CTCAE Version 5.0, or to baseline, 
from any nonhematologic toxicities (except alopecia) due to previous therapy. 
5. Patients must meet the following criteria related to prior therapies: 
Cytoreduction with hydroxyurea: Hydroxyurea can be initiated and continued for up to 
24 hours before the start of protocol therapy.  
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Patients who relapsed while receiving cytotoxic therapy: At least 14 days must have 
passed since the completion of the last dose of chemotherapy before the first dose of 
ponatinib can be given except for the following: intrathecal (IT) chemotherapy and/or 
maintenance therapy such as vincristine, mercaptopurine, methotrexate, or glucocorticoids. 
There is no waiting period for those relapsing on maintenance-like therapy. 
HSCT: Patients who have experienced relapse after a HSCT are eligible, provided they have 
no evidence of acute or chronic graft-versus-host disease (GVHD), are not receiving GVHD 
prophylaxis or treatment, and are at least 90 days posttransplant at the time of enrollment. 
Hematopoietic growth factors: Before the first dose of ponatinib, at least 7 days must have 
passed since completion of therapy with granulocyte colony-stimulating factor or other 
growth factors, and at least 14 days must have passed since completion of therapy with 
pegfilgrastim. 
Biologics and targeted therapies: Before the first dose of ponatinib, at least 7 days must 
have passed since the last dose of a biologic agent. For agents that have known AEs 
occurring beyond 7 days after administration, this period must be extended beyond the time 
during which AEs are known to occur. The duration of this interval must be discussed with 
the sponsor’s medical monitor/designee. 
Monoclonal antibodies: After the last dose of monoclonal antibody, at least 3 half-lives of 
the administered antibody must have passed before the first dose of ponatinib. 
Immunotherapy: Before the first dose of ponatinib, at least 30 days must have passed after 
the completion of any type of immunotherapy (eg, tumor vaccines, chimeric antigen receptor 
T-cell [CAR-T-cell]). 
Immunosuppressive therapy: Before the first dose of ponatinib, at least 14 days must have 
passed after the completion of immunosuppressive therapy (including regimens following 
stem cell transplant). 
Radiotherapy: No washout period is necessary for radiation given to any extramedullary site 
other than central nervous system (CNS); ≥90 days must have passed if patient received prior 
total body irradiation or craniospinal or cranial radiotherapy. 
Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m2 of doxorubicin 
equivalents of anthracyclines. 
Organ Function Requirements 
6. Patients must have adequate renal and hepatic function as indicated by the following 
laboratory values: 
a) Adequate renal function defined as: Estimated glomerular filtration rate (eGFR) using 
the Schwartz formula, OR radioisotope glomerular filtration rate (GFR) 
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≥70 mL/min/1.73 m2, OR a normal serum creatinine based on age and sex as in 
Table 7.a: 
Table 7.a 
Maximum Serum Creatinine Value (mg/dL) by Age 
and Sex 
Age (years) 
Male 
Female 
1 to <2 
0.6 
0.6 
2 to <6 
0.8 
0.8 
6 to <10 
1 
1 
10 to <13 
1.2 
1.2 
13 to <16 
1.5 
1.4 
≥16 
1.7 
1.4 
The threshold creatinine values were derived from the Schwartz formula for 
estimating glomerular filtration rate (Schwartz and Gauthier 1985) using child 
length and stature data published by the Centers for Disease Control and Prevention. 
 
Schwartz formula: eGFR (mL/min/1.73 m2) = (k × L) / Pcr  
k: proportional constant (see Table 7.b); L: height (cm); Pcr: plasma creatinine (mg/dL) 
Table 7.b 
Mean Values of k by Age 
Age Group 
k 
(mean value) 
Low birth weight infants ≤1 year 
0.33 
Full-term infants ≤1 year 
0.45 
Children >1-12 years 
0.55 
Females 13-21 years 
0.55 
Males 13-21 years 
0.70 
Source: (Schwartz et al. 1987). 
 
b) Adequate liver function defined as: Direct bilirubin ≤1.5 times the upper limit of 
normal (ULN) for age AND ALT ≤5 times the ULN for age. 
7. No clinical, radiological or laboratory evidence of pancreatitis, including: 
a) Serum lipase must be <2 times the ULN, AND 
b) Serum amylase must be <2 times the ULN. 
8. Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram (ECHO) 
OR left ventricular ejection fraction of ≥50% by ECHO or multigated acquisition scan 
(MUGA). 
9. Normal QT interval with Fridericia correction method (QTcF) on screening ECG, defined as 
QTcF of ≤450 ms. 
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10. Voluntary written informed consent and assent (as dictated by the institutional review board 
(IRB)/independent ethics committee (IEC) and required by applicable local regulations) 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 (if of the age of 
consent) or the patient’s parent or legal guardian at any time without prejudice to future 
medical care. 
Prevention of Pregnancy 
11. Female patients who: 
a) Are surgically sterile, OR 
b) If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time 
of signing the informed consent/assent through at least 6 months after end of therapy, OR 
c) 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.) 
12. 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 at least 6 months after end of therapy, 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 for the female partner], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and male 
condoms should not be used together.) 
7.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. A history or current diagnosis of Burkitt leukemia/lymphoma or mature B-cell leukemia. 
2. A history or current diagnosis of CML. 
3. Diagnosis of ALL, MPAL, or Ph-like ALL with targetable kinase-activating lesions after 
treatment with cytotoxic therapy for another cancer. 
4. Diagnosis of another concurrent primary malignancy. 
5. Clinically significant cardiovascular disease, including but not limited to: 
a) Any history of myocardial infarction (MI) or unstable angina. 
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b) History of or presence of heart block, and/or clinically significant ventricular or atrial 
arrhythmias. 
c) Uncontrolled hypertension, defined as persistent elevation of systolic and/or diastolic 
blood pressures to ≥95th percentile based on age, sex, and height percentiles despite 
appropriate antihypertensive management. 
6. Current systemic use of drug(s) that are known to have a risk of causing prolonged corrected 
QT interval (QTc) or torsades de pointes unless drug(s) can be changed to acceptable 
alternatives (ie, an alternate class of agents that do not affect the cardiac conduction system) 
or the patient can safely discontinue the drug(s). 
7. Uncontrolled hypertriglyceridemia (triglycerides ≥450 mg/dL).  
8. Current systemic use of any medications or herbal supplements that are known to be strong 
inhibitors or strong inducers of CYP3A within 7 days before the first dose of study drug. 
9. Previous treatment with ponatinib. 
10. Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or 
immunotherapy while patient is on study treatment. 
11. Known allergy or contraindications to any of the drugs (active or excipient) used in the study. 
12. Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral 
absorption of ponatinib. 
13. Patients with DNA fragility syndromes, such as Fanconi anemia and Bloom syndrome. 
14. Patients with Down syndrome. 
15. Patients with uncontrolled systemic infection, or known laboratory and/or clinical evidence 
of active infection with HIV, hepatitis B, or hepatitis C. 
16. Patients with pre-existing significant CNS pathology, including history of severe brain 
injury, dementia, cerebellar disease, organic brain syndrome, psychosis, 
coordination/movement disorder, or autoimmune disease with CNS involvement, are not 
eligible.  
17. Patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not 
eligible. (Patients with a history of cerebrovascular ischemia/hemorrhage remain eligible 
provided all neurologic deficits and causative factor(s) have resolved.) 
18. Uncontrolled seizure disorder. (Patients with seizure disorders that do not require 
antiepileptic drugs or are well controlled with stable doses of antiepileptic drugs are eligible.) 
19. History of severe coagulopathy or cardiovascular or peripheral vascular events. 
20. Any condition or illness that, in the opinion of the investigator or sponsor, would 
compromise patient safety or interfere with the evaluation of the safety or efficacy of 
ponatinib. 
21. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse. 
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22. Pregnancy and breastfeeding exclusions: 
a) Female patients who are pregnant are excluded since fetal toxicities and teratogenic 
effects have been noted for several of the study treatments. A pregnancy test is required 
for female patients of childbearing potential. 
b) Lactating women who plan to breastfeed their infants. 
23. Treatment with live attenuated vaccinations within 30 days prior to initiation of study 
treatment regimen. 
8.0 
STUDY TREATMENT 
Investigational therapy: Ponatinib 
Chemotherapy backbone (see Table 8.b) 
Treatment blocks (ponatinib plus chemotherapy backbone): 
• Reinduction phase: One 35-day cycle (29 days study treatment, 6 days rest consisting of 
daily ponatinib only). 
• Consolidation phase: One 35-day cycle (29 days study treatment, 6 days rest consisting of 
daily ponatinib only). Consolidation can start on or after Day 36 when peripheral counts 
recover and the patient has recovered from chemotherapy-related toxicities. Ponatinib 
therapy will not be interrupted during this period unless the patient has toxicity suspected to 
be related to ponatinib. 
Optional continuation therapy (see Table 8.d). 
8.1 
Study Treatment Administration 
8.1.1 
Investigational Therapy: Ponatinib 
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). 
Prior to protocol amendment 3, ponatinib was available as immediate-release tablets at dosage 
strengths of 10 mg, 15 mg, and 30 mg. To match adult exposures at the phase 1 cohort 1 starting 
dose (30 mg adult exposures) and to allow for dose reductions (15 mg adult exposures), the 
tablet strengths were sufficient only for patients weighing ≥30 kg (Section 8.1.1.1). Upon 
implementation of protocol amendment 3, an AAF of ponatinib minitab capsules is available to 
enable administration of ponatinib to pediatric patients weighing <30 kg or unable to swallow 
solid oral dosage forms. 
In phase 1 cohort 1, only patients weighing ≥30 kg and able to swallow the tablets were enrolled 
as the AAF was not available. At the time of protocol amendment 3, the AAF is available at dose 
strengths of 2.5 mg and 5 mg. In phase 1 cohort 2, ponatinib treatment will be assigned at the 
starting dose (15 mg adult exposures) and dose reductions will be allowed according to the dose 
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levels defined in Table 8.a. Additional details regarding administration of the AAF are provided 
in the study/pharmacy manual. 
If the patient is not hospitalized, ponatinib will be administered by the patient’s parent or legal 
guardian or will be self-administered by the patient on a daily schedule at the assigned dose level 
in phase 1 or at the RP2D in phase 2 by mouth (PO) QD. Each 35-day dosing period is referred 
to as one block. Each block consists of 29 days of study treatment (ponatinib in combination 
with chemotherapy) followed by a rest period from chemotherapy for a minimum of 6 days. 
Ponatinib will be administered QD during the treatment block including the rest period. Any 
change with the schedule should be discussed with the sponsor’s medical monitor/designee. 
Each patient or the patient’s parent or legal guardian will be provided a diary or equivalent where 
the date and time of each administration will be recorded; complete instructions will be provided 
with the site operations manual. 
Patients should receive ponatinib at approximately the same time each day. Patients who fail to 
take their daily ponatinib dose within 6 hours of when it is due should not make up the missed 
dose. Any missing doses should be recorded, and subsequent training of the patient or patient’s 
parent or legal guardian 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. 
8.1.1.1 
Tablet Formulation 
For eligible patients assigned to ≥10 mg doses and who are able to swallow solid oral dosage 
forms, ponatinib will be supplied by the sponsor as 10 mg (oval-shaped) and 15 mg and 30 mg 
(round-shaped), white, film-coated tablets. 
Patients and their parents or legal guardians should be instructed to take/administer 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. 
8.1.1.2 
Age-Appropriate Formulation 
For eligible patients who are unable to swallow solid oral dosage forms or require doses <10 mg, 
an AAF of ponatinib will be provided by the sponsor as round-shaped, film-coated mini-tablets 
filled into an opaque white capsule as 2.5 and 5 mg capsules (ie, minitab capsules). 
Patients and their parents or legal guardians should be instructed to take/administer the 
prescribed number of minitab capsules at approximately the same time each day, continuously 
throughout the study, and not to take more than the prescribed dose at any time. Minitab capsules 
should be taken/administered either swallowed whole with water, with or without food, or, if 
needed, the capsule contents sprinkled in applesauce or yogurt and swallowed. Additional details 
regarding administration of the AAF are provided in the study/pharmacy manual. 
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Patients and/or their parents/legal guardians will be administered a questionnaire to assess the 
palatability of the ponatinib AAF (during the reinduction block only). 
8.1.2 
Study Treatment Regimen 
Phase 1 will determine the RP2D of ponatinib. A rolling 6 design (Skolnik et al. 2008) will be 
followed for both phase 1 cohort 1 and phase 1 cohort 2 (details are provided in Section 6.1). 
In phase 1 cohort 1, pediatric patients received fixed doses of ponatinib based on body weight 
ranges (tablet formulation only) with chemotherapy (Table 8.b). 
In phase 1 cohort 2, patients will also receive fixed doses of ponatinib based on body weight 
ranges provided in Table 8.a (both tablet formulation or AAF) with chemotherapy (Table 8.b). 
Throughout each block of therapy (ie, reinduction, consolidation, and monthly optional 
continuation) patients should receive the weight-based dose of ponatinib as assigned based on 
body weight at Day 1 of each block. 
Table 8.a 
Phase 1 Cohort 2 Ponatinib Doses 
 
Body Weight 
≥45 kg 
30 kg to <45 kg 
15 kg to <30 kg 
5 kg to <15 kg 
Cohort 2 Dose Level 1 
15 mg 
10 mg 
7.5 mg 
5 mg 
Cohort 2 Dose Level -1 
10 mg 
7.5 mg 
5 mg 
2.5 mg 
 
The following chemotherapy treatment regimen is adapted from the ALL R3 study (Parker et al. 
2010) with a modified reinduction block by the replacement of mitoxantrone/idarubicin with 
daunorubicin, use of conventional dexamethasone regimen, and the addition of daily ponatinib to 
both treatment blocks (Table 8.b). Additional details are provided in Table 8.c. 
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Table 8.b 
Phase 1 and Phase 2 Treatment Regimen for the Reinduction and 
Consolidation Blocks 
 
Dose 
Days/Frequency 
Reinduction Block (Weeks 1-4) 
Ponatinib PO 
See Table 8.a (cohort 2) for 
phase 1 dose; RP2D in phase 2 
Daily (Days 1-35) 
Vincristine IV 
1.5 mg/m2 
1, 8, 15, 22 
Dexamethasone PO/IV a 
10 mg/m2 
1-15 
PEG-asparaginase IV/IM b 
2500 IU/m² 
2 
Daunorubicin IV 
30 mg/m2 
1, 2 
Initial IT chemotherapy c 
See Table 8.c 
1 
CNS-1/2: IT methotrexate chemotherapy d 
See Table 8.c 
15 and 29 
CNS-3: ITT chemotherapy e 
See Table 8.c 
8, 15, 22, and 29 
Consolidation Block (Weeks 5-8) f 
Ponatinib PO 
See Table 8.a (cohort 2) for 
phase 1 dose; RP2D in phase 2 
Daily (Days 1-35) 
Dexamethasone PO/IV a 
6 mg/m2 
1-5  
Vincristine IV 
1.5 mg/m2 
3 
Methotrexate IV g 
1000 mg/m2 
8 
PEG-asparaginase IV/IM b 
2500 IU/m² 
9 
Cyclophosphamide IV 
440 mg/m2 
15-19 
Etoposide IV 
100 mg/m2 
15-19 
CNS-1/2: IT methotrexate chemotherapy d 
See Table 8.c 
8 
CNS-3: ITT chemotherapy e 
See Table 8.c 
8 
ALT: alanine aminotransferase; ANC: absolute neutrophil count; CNS: central nervous system; 
IM: intramuscularly; IT: intrathecal; ITT: triple intrathecal; IU: international units; IV: intravenously; PEG: 
polyethylene glycol; PO: by mouth (orally); RP2D: recommended phase 2 dose. 
See Table 8.c or Table 5 for additional administration details. 
Note: 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 Dexamethasone will be given as 2 divided doses with a maximum daily dose of 40 mg. 
b In cases where PEG-asparaginase is not available or where patients are allergic to PEG-asparaginase, 
Erwinia-asparaginase can be used as an alternative. If there are supply issues with PEG-asparaginase at the site, 
the dosing of PEG-asparaginase can occur over a range of ± 4 days. 
c May include IT methotrexate or ITT chemotherapy. Omit initial IT chemotherapy on Day 1 if patient received 
IT chemotherapy within 7 days before study enrollment as part of diagnostic lumbar puncture procedure. 
d IT methotrexate is for CNS-1/2 patients only. Dose is defined by age; see Table 8.c. 
e ITT chemotherapy is for CNS-3 patients only. Dose is defined by age; see Table 8.c. 
f To start the consolidation block, the following criteria must be met: ANC ≥750/µL, platelets ≥50,000/µL 
(untransfused) (van Veen et al. 2010), and toxicity considered to be related to treatment with ponatinib must have 
resolved to Grade 1 or baseline or to a level considered acceptable by the physician. 
g Intermediate-dose methotrexate administered IV over 36 hours. The 1000 mg/m2/dose should be given as a 
100 mg/m2 bolus over 30 minutes followed by 900 mg/m2 over 35.5 hours. Note: Be certain that the methotrexate 
infusion is completed in the 36-hour period. See Table 8.c for IV hydration and leucovorin rescue therapy. 
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Table 8.c 
Details of Phase 1 and Phase 2 Treatment Regimens for the Reinduction 
and Consolidation Blocks 
Reinduction Block (Weeks 1-4) 
Ponatinib:  
PO on Days 1-35, dose assigned per protocol 
Vincristine: 
IV push over 1 minute or infusion via minibag as per institutional policy 
Days: 1, 8, 15, and 22 
Dose: 1.5 mg/m2/dose (max 2 mg) 
Dexamethasone:  
PO or IV 
Days: 1 through 15 
Dose: 10 mg/m2/day, divided BID, ie, 5 mg/m2/dose BID 
PEG-asparaginase: 
IV over 1 to 2 hours, or IM 
Day: 2  
Dose: 2,500 IU/m2/dose 
Patients with an allergic reaction to PEG-asparaginase can be given Erwinia asparaginase IM/IV 
25,000 IU/m2/dose on Monday/Wednesday/Friday (or every other day per institutional standard) × up to 6 doses 
for each dose. 
Erwinia asparaginase: for patients with an allergic reaction to PEG-asparaginase or in cases where 
PEG-asparaginase is not available 
IM/IV 
Dose: 25,000 IU/m2/dose 
Daunorubicin: 
IV over 15 minutes 
Days: 1 and 2 
Dose: 30 mg/m2 
Initial IT chemotherapy:  
Day 1; may include methotrexate (CNS-1/2), or triple IT (ITT) chemotherapy (CNS-3) (see Appendix G for 
definitions) 
IT methotrexate: for CNS-1/2 patients only 
Days: 15 and 29 
Omit IT methotrexate on Day 1 if patient received IT chemotherapy within 7 days before study enrollment as part 
of diagnostic lumbar puncture procedure. 
Dose: Defined by age: 
 Age 1 through 1.99 years: 8 mg 
 Age 2 through 2.99 years: 10 mg 
 Age 3 through 8.99 years: 12 mg 
 Age ≥9 years: 15 mg 
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Table 8.c 
Details of Phase 1 and Phase 2 Treatment Regimens for the Reinduction 
and Consolidation Blocks 
ITT chemotherapy: for CNS-3 patients only 
Days: 8, 15, 22, and 29 
Dose: Defined by age in the following table: 
 
Age (years) 
Methotrexate 
Hydrocortisone 
Cytarabine 
 
1 – 1.99 
8 mg 
8 mg 
16 mg 
 
2 – 2.99 
10 mg 
10 mg 
20 mg 
 
3 – 8.99 
12 mg 
12 mg 
24 mg 
 
≥9 
15 mg 
15 mg 
30 mg 
Consolidation Block (Weeks 5-8) a 
Ponatinib:  
PO on Days 1-35, dose assigned per protocol 
Dexamethasone:  
PO or IV 
Days: 1 through 5 
Dose: 6 mg/m2/day, divided BID, ie, 3 mg/m2/dose BID 
Vincristine: 
IV push over 1 minute or infusion via minibag as per institutional policy 
Day: 3 
Dose: 1.5 mg/m2/dose (max 2 mg) 
Intermediate-dose methotrexate: 
IV over 36 hours.  
Day: 8 
Dose: 1000 mg/m2/dose, given as a 100 mg/m2 bolus over 30 minutes followed by 900 mg/m2 over 35.5 hrs. 
Note: Be certain that the methotrexate infusion is completed in the 36-hour period. 
Suggested hydration and alkalinization:  
Start hydration at least 6 hours prior to the start of methotrexate. Hydrate with 5% dextrose in water 1/4 normal 
saline with 30 mEq NaHCO3/L at 125 mL/m2/h to achieve a urine specific gravity ≤1.010 and pH between 7 and 
8. Ringers lactate maybe used as initial fluid if a bicarbonate-containing solution is unavailable. Adjust fluid 
volume and sodium bicarbonate to maintain urine specific gravity and pH at above parameters. A bicarbonate 
bolus (25 mEq/m2 over 15 min) may be given to raise the urine pH relatively quickly. A normal saline bolus may 
also be helpful in facilitating hydration. Continue hydration and alkalinization throughout methotrexate infusion 
after its completion until the last dose of leucovorin has been given. 
Leucovorin: 
PO/IV 
Days: 10 and 11 
Dose: 15 mg/m2/dose every 6 hours beginning 48 hours after the START of methotrexate infusion. 
If 48-hour methotrexate level is ≤0.5 µM, do not give more than 2 doses of leucovorin (48 and 54 hours). 
If methotrexate level at 48 hours is >0.5 µM, then continue hydration and leucovorin rescue at 15 mg/m2/dose 
PO/IV every 6 hours until methotrexate level is <0.1 µM. 
Hold trimethoprim/sulfamethoxazole, any nonsteroidal anti-inflammatory medications, penicillins, proton pump 
inhibitors, or aspirin-containing medications on the day of intermediate-dose methotrexate infusion and for at 
least 72 hours after the start of the intermediate-dose methotrexate infusion and until the methotrexate level is 
≤0.5 μM. 
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Table 8.c 
Details of Phase 1 and Phase 2 Treatment Regimens for the Reinduction 
and Consolidation Blocks 
PEG-asparaginase: 
IV over 1 to 2 hours, or IM 
Day: 9 or 10, administer 4 hours after completion of Day 8 IV methotrexate 
Dose: 2,500 IU/m2/dose 
Patients with an allergic reaction to PEG-asparaginase can be given Erwinia asparaginase IM/IV 
25,000 IU/m2/dose on Monday/Wednesday/Friday (or every other day per institutional standard) × up to 6 doses 
for each dose. 
Erwinia asparaginase: in case of unavailability of PEG-asparaginase or for patients with an allergic 
reaction to PEG-asparaginase 
IM/IV 
Dose: 25,000 IU/m2/dose 
Cyclophosphamide: 
IV over 15-30 minutes.  
Days: 15 through 19 
Dose: 440 mg/m2/dose 
Etoposide: 
IV over 1-2 hours.  
Days: 15 through 19 
Dose: 100 mg/m2/dose 
IT methotrexate: for CNS-1/2 patients only 
Day: 8 
Dose: Defined by age: 
 Age 1 through 1.99 years: 8 mg 
 Age 2 through 2.99 years: 10 mg 
 Age 3 through 8.99 years: 12 mg 
 Age ≥9 years: 15 mg 
ITT chemotherapy: for CNS-3 patients only 
Day: 8 
Dose: Defined by age in the following table: 
 
Age (years) 
Methotrexate 
Hydrocortisone 
Cytarabine 
 
1 – 1.99 
8 mg 
8 mg 
16 mg 
 
2 – 2.99 
10 mg 
10 mg 
20 mg 
 
3 – 8.99 
12 mg 
12 mg 
24 mg 
 
≥9 
15 mg 
15 mg 
30 mg 
BID: twice daily; CNS: central nervous system; IM: intramuscularly; IT: intrathecal; ITT: triple intrathecal; 
IU: international units; IV: intravenously; PEG: polyethylene glycol; PO: by mouth (orally); ULN: upper limit of 
normal. 
Note: 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 To start the consolidation block, the following criteria must be met: ANC ≥750/µL, platelets ≥50,000/µL 
(untransfused) (van Veen et al. 2010), and toxicity considered to be related to treatment with ponatinib must have 
resolved to Grade 1 or baseline or to a level considered acceptable by the physician. 
 
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Ponatinib will be administered QD as part of the study treatment regimen (Table 8.b). For 
phase 1 cohort 1, dose level 1 targeted adult exposures achieved at 30 mg QD as determined by 
simulations from an allometrically scaled adult population PK model. For phase 1 cohort 2, dose 
level 1 is expected to achieve systemic exposures that approximately match adult exposures after 
administration of 15 mg QD. Pediatric patients received fixed doses of ponatinib based on 
weight ranges for phase 1 cohort 1 and will receive fixed doses of ponatinib based on the weight 
ranges provided in Table 8.a for phase 1 cohort 2. Patients experiencing TEAEs that require a 
dose reduction will have their ponatinib dose reduced as per Table 8.a. 
Patients achieving documented clinical benefit have the option to continue to receive ponatinib 
monotherapy or ponatinib in combination with maintenance-type chemotherapy regimen 
(Table 8.d) on investigator decision and with agreement by the sponsor, with the intent to avoid 
further intensive multiagent chemotherapy in combination with ponatinib. Also, no experimental 
agent is allowed to be incorporated in the optional continuation ponatinib/ponatinib-containing 
therapy. If electing the optional continuation therapy, the patient will continue on the same dose 
he/she was on and tolerated during the consolidation block. If the patient had a dose reduction 
during consolidation block, subsequent dose re-escalation may only occur to the reintroduction 
dose if criteria stated in Section 8.4.2.4 are met. Once the RP2D dose is known, and if it is 
different from the dose the patient is receiving, it will be at the discretion of the investigator to 
alter the dose of ponatinib. This optional treatment is to allow patients to continue ponatinib 
therapy until they are able to receive HSCT or other alternative therapy(ies). Once patients 
discontinue the optional ponatinib/ponatinib-containing therapy, they will have to complete the 
EOT2 evaluation. At this time, patients may receive further therapy(ies) at the discretion of the 
investigator. 
Patients who complete protocol therapy (reinduction and consolidation block) and EOT1 
evaluation, and do not proceed to an optional continuation ponatinib-containing therapy, are 
considered to have completed protocol therapy. At this time, patients may receive further 
therapy(ies) at the discretion of the investigator. 
Patients who discontinue ponatinib early in the reinduction block or consolidation block will be 
discontinued from study treatment and proceed to the EOT1 visit. At this time, patients may 
receive further therapy(ies) at the discretion of the investigator. 
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Table 8.d 
Optional Continuation Therapy With Ponatinib: Recommended 
Combination Regimen Following Consolidation 
Therapeutic Agent 
Days/Frequency 
Ponatinib 
Daily 
Vincristine 
Every 4 weeks 
Dexamethasone or prednisone 
5 days every 4 weeks 
Mercaptopurine 
Daily 
Methotrexate (PO) 
Once a week 
Methotrexate (IT) 
Once every 3 months 
IT: intrathecal; PO: by mouth (orally). 
Note: 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. 
 
8.2 
Definitions of Dose-limiting Toxicities 
DLTs will be graded according to NCI CTCAE Version 5.0 and the causality will be assigned by 
the investigator. The DLT observation period for each formulation will be up to the first 35 days 
on treatment in phase 1 unless there are residual hematologic toxicities on Day 35, in which case 
the patient will be followed for up to an additional 7 days for DLT evaluation. 
Events considered DLTs will be defined as any of the following phase 1 events occurring during 
the first 35 days on treatment (reinduction block) that are assessed by the investigator as 
possibly, probably, or definitely related to ponatinib and must be reported as related: 
• Any Grade ≥3 nonhematologic toxicity that occurs after the first dose of ponatinib and is 
possibly, probably, or definitely related to ponatinib, with the following exceptions: 
– Fever or infection with or without hospitalization. 
– Fatigue and gastrointestinal symptoms (anorexia, vomiting, dehydration, mucositis). 
– Hypofibrinogenemia. 
– Metabolic/laboratory abnormalities, including ALT, that resolve to ≤Grade 2 within 
7 days. 
• Grade ≥3 elevation of ALT concurrent with an elevation of direct bilirubin >2 × ULN. 
• Any Grade 4 pancreatitis, or Grade 3 pancreatitis which does not resolve within 7 days. 
• Any Grade 4 skin rash, or Grade 3 skin rash which does not resolve within 7 days. 
• Hematologic toxicities: Failure to recover a peripheral ANC ≥0.5 × 109/L and a platelet count 
≥50 × 109/L due to documented BM hypoplasia (cellularity <10% to 20%) within 42 days 
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after the beginning of systemic chemotherapy without evidence of active disease by BM 
evaluation or active infection. 
• Any delay or interruption of therapy of ≥4 weeks due to suspected treatment-related toxicity 
unless otherwise specified. 
Patients will be evaluated for DLTs in phase 1 during the reinduction block. Patients who meet 
DLT criteria will discontinue study treatment and proceed to the EOT1 visit. 
When there is ambiguity about whether an AE is related to the underlying disease or the 
chemotherapy backbone, as opposed to ponatinib, the most conservative approach will be taken 
and the AE will be considered as study drug–related. 
8.3 
Criteria for Beginning a Consolidation Block or Optional Continuation Therapy 
Treatment with ponatinib will use a block length of 35 days (29 days of study treatment followed 
by a rest period from chemotherapy for a minimum of 6 days). Ponatinib will be administered 
QD during the treatment block including the rest period. For a new treatment block to begin, the 
patient must meet the following criteria: 
• ANC must be ≥750/µL. 
• Platelet count must be ≥50,000/µL (van Veen et al. 2010). 
• For therapy to resume, toxicity considered to be related to treatment with ponatinib must 
have resolved to Grade 1 or baseline or to a level considered acceptable by the physician. 
The physician may consult with the sponsor’s medical monitor to determine levels that are 
acceptable based on the overall clinical status of the patient to continue therapy. 
If the patient does not meet the above-cited criteria for retreatment, initiation of the next 
treatment block should be delayed for 1 week. During a period of treatment delay, patients 
should be closely monitored for recovery and resumption of treatment. Should the start of 
consolidation need to be delayed for more than 3 weeks because of incomplete recovery from 
treatment-related toxicity, the dose will be reduced by 1 dose level when treatment resumes. If 
further treatment is delayed for more than 3 weeks at the reduced dose level and further 
reductions are not permitted per the guidelines (see Section 8.4) then the patient will discontinue 
study treatment and proceed to the EOT1 visit. 
8.4 
Dose Modification Guidelines for Safety 
8.4.1 
Early Safety Stopping Rules 
Due to concerns regarding vaso-occlusive events and pancreatitis resulting from the combination 
of ponatinib with the multiagent chemotherapy backbone, the sponsor may suspend enrollment 
for the following events: 
• If ≥4 patients in the first 15 patients accrued develop Grade ≥3 veno-occlusive event 
regardless of the presence or absence of a central vascular access device. 
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• Any major adverse cardiac event (MACE) including but not limited to: 
– Any grade arteriothrombotic event. 
– Any grade cardiovascular event. 
• If ≥3 patients in the first 15 patients accrued develop Grade ≥3 pancreatitis. 
A recommendation to reopen enrollment might be made if causes other than therapy are thought 
to be the primary cause of the event(s). Any decision to restart enrollment after the stopping rules 
have been met will require prior approval of a substantial amendment by the applicable Health 
Authorities, such as the Medicines and Healthcare products Regulatory Agency (MHRA). 
The sponsor may suspend further enrollment if more than one patient dies for reasons other than 
disease progression. 
8.4.2 
Dose Reduction for Treatment-related Toxicity 
8.4.2.1 
Nonhematologic Treatment-Related Toxicity: Ponatinib 
Dose reduction guidelines for ponatinib are summarized in Table 8.e, and AEs should be graded 
according to NCI CTCAE Version 5.0. 
These guidelines should be followed by clinical investigators; however, for an individual patient, 
dose interruptions, reductions, and treatment discontinuation can also be based on the clinical 
circumstance. Variation from these guidelines must be communicated with the medical 
monitor/designee, ideally prior to implementation but no later than 72 hours, and resulting 
agreements should be recorded in source documents. When the observed toxicity has resolved to 
Grade ≤1 or returned to baseline, the investigator may resume dosing if clinically indicated. 
Guidance for re-escalation after resolution of adverse drug reactions is provided in 
Section 8.4.2.4. 
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 from the toxicity or toxicities in question to 
Grade 1 or to baseline values. 
Doses may be interrupted for study drug–related toxicities for up to 3 weeks; longer interruptions 
need to be discussed with the sponsor’s medical monitor/designee. 
See Section 8.4.2.4 for dose re-escalation guidelines after the resolution of adverse drug 
reactions. 
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Table 8.e 
Dose Modifications for Nonhematologic Treatment-Related Toxicity: 
Ponatinib 
General Toxicities 
Modification 
Grade 1 or transient Grade 2 
No dose modification 
Grade 2 
Dose modification per investigator’s discretion 
Grade 3 or 4 
Occurrence a at initial dose: 
Hold until event is Grade 1, or has returned to baseline 
Resume at dose level -1 
Occurrence a at dose level -1: 
Discontinue ponatinib 
Pancreatitis and Elevation of Lipase 
Modification c 
Serum lipase >1 to 1.5 × ULN 
Consider interrupting ponatinib until resolution, then 
resume at same dose 
Serum lipase >1.5 to 2 × ULN, asymptomatic serum 
lipase 2 to 5 × ULN, or asymptomatic radiologic 
pancreatitis 
Interrupt ponatinib until Grade 1 (<1.5 × ULN) or 
baseline, then resume at next lower dose 
Symptomatic serum lipase >2 to 5 × ULN, 
symptomatic Grade 3 pancreatitis, or asymptomatic 
serum lipase >5 × ULN 
Interrupt ponatinib until complete resolution of 
symptoms and after recovery of lipase elevation to 
Grade 1 or baseline, then resume at next lower dose 
Symptomatic pancreatitis and serum lipase >5 × ULN 
Discontinue ponatinib 
Hepatic Toxicity 
Modification 
Grade ≥3 elevation of ALT  
Occurrence a at initial dose: 
Hold until event is Grade 1, or has returned to baseline 
Resume at dose level -1 
Occurrence a at dose level -1: 
Hold until event is Grade 1, or has returned to baseline: 
Discontinue ponatinib 
Grade ≥3 elevation of ALT concurrent with an 
elevation of direct bilirubin >2 mg/dL 
Discontinue ponatinib 
Direct bilirubin >2 mg/dL 
Hold until <1.5 × ULN 
Resume at dose level 1 (full dose) 
Occurrence a at dose level 1: 
Wait until <1.5 × ULN 
Resume at dose level -1 
Occurrence a at level -1: 
Discontinue ponatinib 
LVEF/CHF d 
Modification 
Grade 1 
No dose adjustment 
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 dose level -1 
Occurrence a at dose level -1: 
Discontinue ponatinib 
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Table 8.e 
Dose Modifications for Nonhematologic Treatment-Related Toxicity: 
Ponatinib 
Grade 3 
Discontinue ponatinib 
Grade 4 
Discontinue ponatinib 
Skin Rash 
Modification 
Grade 1 
No dose modification 
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 previous dose: 
Hold until event is Grade 1, or has returned to baseline 
Resume at dose level -1 
Occurrence b at dose level -1: 
Discontinue ponatinib 
Skin Rash 
Modification 
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 dose level -1 
Occurrence a at dose level -1: 
Discontinue ponatinib 
Grade 4 
Discontinue ponatinib 
AE: adverse event; ALT: alanine aminotransferase; CHF: congestive heart failure; ECHO: echocardiogram; 
LVEF: left ventricular ejection fraction; NCI CTCAE: National Cancer Institute Common Terminology Criteria 
for Adverse Events; 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 Also see asparaginase guidance in Section 8.4.3.1; if a patient has pancreatitis, discontinue asparaginase. 
d See Section 8.4.3.2 for dose modification guidance for daunorubicin-related cardiac toxicity. 
Note: NCI CTCAE Version 5.0 criteria should be used to interrupt or discontinue study drug for Grades 2, 3, or 4 
events considered to be study drug–related. 
 
Patients discontinuing ponatinib will discontinue study treatment and proceed to the EOT visit. 
8.4.2.1.1 
Peripheral Neuropathy 
Peripheral neuropathy will be closely monitored during reinduction and toxicities graded. A 
complete neurologic examination should be documented before the start of therapy, including a 
minimum assessment of cranial nerve function; deep tendon reflexes of the brachioradialis, 
patellar, and Achilles tendons; balance; gait; and general sensation. All dose modifications 
should be based on the worst preceding toxicity. 
Since vincristine can also cause peripheral neuropathy, dose modification will be performed as 
follows in Table 8.f. Modifications should be made any time peripheral neuropathy is noted. 
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Table 8.f 
Dose Modifications for Peripheral Neuropathy and Neuropathic Pain Per 
Modified “Balis” Pediatric Scale 
Grade 1 with pain a or Grade 2 
Hold ponatinib and vincristine until neuropathy has resolved to Grade 1. 
When symptoms subside, restart ponatinib and vincristine at full dose. 
Grade 2 with pain a or Grade 3  
Hold ponatinib and vincristine until neuropathy has resolved to ≤Grade 2. 
When symptoms subside, restart ponatinib at dose level -1 and vincristine at 
full dose.  
Grade 4 
Discontinue ponatinib and vincristine. 
a Pain uncontrolled by nonsteroidal anti-inflammatory drugs or narcotics. 
See text below for Modified “Balis” Pediatric Scale. 
 
Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies 
Peripheral Motor Neuropathy 
• Grade 1: Subjective weakness, but no deficits detected on neurological exam, other than 
abnormal deep tendon reflexes. 
• Grade 2: Weakness that alters fine motor skills (buttoning shirt, coloring, writing or drawing, 
using eating utensils) or gait without abrogating ability to perform these tasks. 
• Grade 3: Unable to perform fine motor tasks (buttoning shirt, coloring, writing or drawing, 
using eating utensils) or unable to ambulate without assistance. 
• Grade 4: Paralysis. 
Peripheral Sensory Neuropathy 
• Grade 1: Paresthesias, pain, or numbness that do not require treatment or interfere with 
extremity function. 
• Grade 2: Paresthesias, pain, or numbness that are controlled by non-narcotic medications 
(without causing loss of function), or alteration of fine motor skills (buttoning shirt, writing 
or drawing, using eating utensils) or gait, without abrogating ability to perform these tasks. 
• Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with extremity 
function (gait, fine motor skills as outlined above), or quality of life (loss of sleep, ability to 
perform normal activities severely impaired). 
8.4.2.2 
Dose Modifications for Arterial Occlusive Events and Venous Thrombotic/Embolic 
Events: Ponatinib 
If an AOE or VTE occurs, treatment should be interrupted or discontinued. Ponatinib should not 
be re-administered to patients with arterial or venous occlusive events unless the investigator 
assesses that the potential benefit outweighs the risk of continued therapy. 
AOEs and VTEs include a broad range of nonspecific terms that could meet the criteria for 
diagnosis of this type of event. Investigators should use their clinical judgment and medical 
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knowledge of the specific terms in describing these 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 
these criteria. 
Investigator’s discretion should be used to judge the event as a vascular pathology when 
applying these dose-modifying schemes. 
8.4.2.2.1 
Arterial Occlusive Events 
In patients suspected of developing any serious or clinically significant AOE requiring urgent 
intervention or hospitalization AOE, ponatinib should be immediately interrupted, and may be 
discontinued at the discretion of the treating physician. 
Patients should be discontinued from ponatinib in the event of MI, unstable angina, 
cerebrovascular accident, transient ischemic attack (TIA), or revascularization procedures. For 
all other AOEs, dose modification guidelines are outlined in Table 8.g. 
Table 8.g 
Dose Modifications for Arterial Occlusive Events: 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 initial dose: 
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: 
Discontinue ponatinib 
Grade 3 
Discontinue ponatinib 
Grade 4 
Discontinue ponatinib 
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. 
 
8.4.2.2.2 
Venous Thrombotic/Embolic Events 
Patients should be discontinued from ponatinib in the event of life-threatening pulmonary 
embolism or retinal vein thrombosis. 
For all other VTEs, dose modification guidelines are outlined in Table 8.h. 
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Table 8.h 
Dose Modifications for Venous Thrombotic/Embolic Events: Ponatinib 
VTEs 
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 dose level -1 
Occurrence a at dose level -1: 
Discontinue ponatinib 
Grade 3 
Occurrence a at any dose level: 
Discontinue ponatinib 
Grade 4 
Discontinue ponatinib 
VTE: venous thrombotic/embolic event. 
a “Occurrence” means the first time a VTE is encountered by a patient at a given dose level. 
 
8.4.2.3 
Hypothyroidism 
If a patient develops evidence of hypothyroidism, a consultation with a pediatric endocrinologist 
should be initiated for thorough evaluation, follow-up plan and assessment for replacement 
therapy.  
8.4.2.4 
Dose Re-escalation After Resolution of Adverse Drug Reactions 
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 the following criteria is met: 
• All Grade ≥2 and Grade 3 nonhematologic toxicities have recovered to Grade 1 or baseline. 
Patients may receive a dose escalation up to the starting dose level if the above criteria continue 
to be met. In no circumstances should a patient receive a ponatinib dose higher than their starting 
dose level. 
Note: Patients with Grade ≥3 left ventricular dysfunction, congestive heart failure (CHF), arterial 
occlusion, and Grade ≥2 pancreatitis are not eligible for dose re-escalation after resolution of 
their symptoms. 
8.4.2.5 
Criteria for Discontinuation of Ponatinib 
Grade 4 nonhematologic toxicities will in general require that treatment with ponatinib be 
permanently discontinued. If, in the opinion of the investigator and the project clinician, it is in 
the patient’s best interest to continue treatment with ponatinib, then the dose of ponatinib should 
be reduced to dose level -1 if the patient is receiving the first dose level after recovery of the 
toxicity or toxicities in question to Grade 1 or to baseline values. 
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8.4.3 
Chemotherapy Backbone 
It is the investigator’s responsibility to refer to the study/pharmacy manual or the most current 
individual package insert (local approved label or relevant summary(ies) of product 
characteristics [SmPC]) for specific information related to the chemotherapy backbone side 
effects, preparation, reconstitution, dispensation, storage, and handling. Local approved labels or 
Section 4.8 of the relevant SmPC will serve as the reference safety information (RSI) for 
determining expectedness of serious adverse reactions (SARs) that occur with these 
chemotherapy agents. The following are general practice guidelines. 
8.4.3.1 
Asparaginase (Polyethylene Glycol-Asparaginase or Erwinia Asparaginase)-Related 
Toxicities) 
8.4.3.1.1 
For Allergy 
Local allergic reactions (inflammation at injection site or swelling): Continue asparaginase 
administration in the presence of Grade 1 allergy (transient flushing or rash; drug fever <38ºC). 
Note: These recommendations only apply when asparaginase is administered intramuscularly 
(IM). 
Systemic allergic reactions: Discontinuation may be considered for severe Grade 2 or higher 
allergic reactions as defined by NCI CTCAE version 5.0. 
Note: Premedication with antihistamines to decrease the risk of overt allergy symptoms is 
strongly discouraged since antihistamine use may mask the appearance of systemic allergy. 
Systemic allergy is frequently associated with the presence of asparaginase-neutralizing 
antibodies, which render asparaginase therapy ineffective. In the event of severe systemic or 
recurrent local allergic reaction, Erwinia asparaginase should be substituted. 
Anaphylaxis: Discontinue polyethylene glycol (PEG)-asparaginase if the patient develops 
Grade 3 anaphylaxis as defined by NCI CTCAE version 5.0 (symptomatic bronchospasm, with 
or without urticaria, parenteral intervention indicated; allergy-related edema/angioedema; 
hypotension). If this occurs, Erwinia asparaginase should be substituted. 
The FDA initially approved Erwinia asparaginase for use following allergy to PEG-asparaginase, 
at a dose of Erwinia asparaginase 25,000 IU/m2 × 6 doses IM on a Monday/Wednesday/Friday 
schedule substituted for a single dose of PEG-asparaginase. In December 2014, the FDA 
expanded its approval to include intravenous (IV) as well as IM administration. 
If a patient develops a Grade 3 or higher anaphylaxis to Erwinia asparaginase, discontinue future 
asparaginase therapy. Consider discontinuation for severe Grade 2 or higher allergic reactions. 
In the event that a PEG-asparaginase infusion is discontinued for an allergic reaction, regardless 
of amount received, substitution with Erwinia asparaginase should begin approximately 48 hours 
after PEG-asparaginase has been discontinued and preferably to coincide with the recommended 
Monday/Wednesday/Friday administration schedule previously detailed in patients who are 
clinically stable. Up to 6 doses of Erwinia asparaginase may be administered, as tolerated, to 
replace the incomplete IV PEG-asparaginase dose. Of note, Erwinia asparaginase is 
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recommended only for PEG-asparaginase hypersensitivity reactions and not for pancreatitis, 
hepatitis, coagulation abnormalities, or other nonhypersensitivity toxicities associated with 
PEG-asparaginase. To best suit the needs of each individual patient, additional modifications to 
these recommendations may be made at the discretion of the treating physician. 
Treating physicians may elect to discontinue PEG-asparaginase and switch to Erwinia 
asparaginase, at their discretion, on the basis of laboratory evidence of silent inactivation of 
asparaginase activity in the absence of clinical symptoms of hypersensitivity. 
8.4.3.1.2 
For Coagulopathy 
If the patient is symptomatic, hold asparaginase until symptoms resolve, then resume with the 
next scheduled dose. Consider factor replacement (with fresh frozen plasma, cryoprecipitate, or 
factor VIIa). Do not withhold dose for abnormal laboratory findings without clinical symptoms. 
8.4.3.1.3 
For Hyperbilirubinemia 
Asparaginase may need to be withheld in patients with elevated direct bilirubin, since 
asparaginase has been associated with hepatic toxicity. No specific guidelines are available. 
8.4.3.1.4 
For Hyperglycemia 
Do not modify dose. Treat hyperglycemia as medically indicated. 
8.4.3.1.5 
For Hyperlipidemia 
Do not modify dose. Treat hyperlipidemia as medically indicated. 
8.4.3.1.6 
For Ketoacidosis 
Hold asparaginase until the blood glucose level is regulated with insulin. 
8.4.3.1.7 
For Pancreatitis 
Discontinue asparaginase in the presence of Grade 3 or 4 pancreatitis. In the case of 
asymptomatic Grade 2 pancreatitis (enzyme elevation or radiologic findings only), asparaginase 
should be held until symptoms and signs subside and amylase/lipase levels return to normal and 
then resumed. Grade 3 or 4 pancreatitis is a contraindication to additional asparaginase 
administration. 
8.4.3.1.8 
For Thrombosis 
Withhold asparaginase until resolved, and treat with appropriate antithrombotic therapy, as 
indicated. Upon resolution of symptoms, consider resuming asparaginase while continuing 
low-molecular-weight heparin or antithrombotic therapy. 
Do not withhold dose for abnormal laboratory findings without a clinical correlate. For 
significant thrombosis, not central line–related, consider evaluation for inherited predisposition 
to thrombosis. 
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8.4.3.1.9 
For Central Nervous System Events 
For CNS events (bleed, thrombosis, or infarction): Hold asparaginase. Treat with fresh frozen 
plasma, factors, or anticoagulation therapy as appropriate. Resume at full dose when all 
symptoms have resolved (and there is evidence of recanalization, in the case of thrombosis by 
computerized tomography [CT]/ magnetic resonance imaging [MRI]). Consider evaluation for 
inherited predisposition to thrombosis. 
8.4.3.2 
Daunorubicin (Anthracycline)-Related Toxicities 
8.4.3.2.1 
For Cardiac Toxicity 
Discontinue for clinical or echocardiographic evidence of cardiomyopathy (shortening fraction 
<27% or ejection fraction <50%) or Grade 3 or 4 left ventricular systolic dysfunction per 
NCI CTCAE Version 5.0. 
8.4.3.2.2 
For Hyperbilirubinemia 
The recommended doxorubicin dose reduction algorithm for hyperbilirubinemia is presented in 
Table 8.i. 
Table 8.i 
Daunorubicin Dose Reduction Algorithm for Hyperbilirubinemia 
Direct Bilirubin  
% Dose Reduction 
<1.2 mg/dL 
0% (full dose) 
1.2-3.0 mg/dL 
50%  
3.1-5.0 mg/dL 
75%  
>5.0 mg/dL 
Withhold dose and administer next scheduled dose if toxicity has resolved 
 
8.4.3.2.3 
For Extravasation 
In the event of an extravasation, discontinue the IV administration of the drug and institute 
appropriate measures to prevent further extravasation and damage according to institutional 
guidelines. 
8.4.3.3 
Intrathecal Methotrexate/Triple Intrathecal Chemotherapy-Related Toxicities 
8.4.3.3.1 
For Systemic Toxicity 
The dosage for IT methotrexate will not be reduced for systemic toxicity (eg, myelosuppression, 
mucositis). Instead, leucovorin may be used at a dose of 5 mg/m2/dose every 12 hours × 2 doses, 
beginning 48 hours after the IT chemotherapy has been delivered. This may reduce the risk of 
worsening already existent myelosuppression (ANC <0.5 × 109/L) or mucositis. Do not 
administer leucovorin solely to prevent myelosuppression. 
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8.4.3.3.2 
For Acute Neurotoxicity 
Neurotoxicity has extremely protean manifestations, ranging from transient events, seizures or 
episodes of acute hemiparesis, to severe necrotizing encephalopathies. These toxicities are 
poorly understood, and currently it is impossible to predict who will suffer these complications. 
In addition, there are no data clearly linking the occurrence of an acute neurotoxic event with an 
increased risk of long-term neurocognitive dysfunction, nor do the changes present on MRI at 
the time of an acute event clearly correlate with or predict outcome. 
The following guidelines are offered for consideration following an acute event, but it must be 
recognized that there are little data to support these approaches or any others. Thus, the treating 
physician must evaluate the patient and, with the family, make the best possible decision with 
respect to the relative risk and benefit of continued therapy. 
Following an acute neurotoxic event, a history and physical examination should guide the 
differential diagnosis. A neurology consult may be of value and should be considered. Seizures 
and other transient events may be linked to fever, infection, encephalitis, meningitis, 
hypertension, electrolyte disturbance, hypoglycemia, trauma, intracranial hemorrhage or 
thrombosis, narcotic withdrawal, illicit drug use, or other causes in addition to the direct side 
effects of chemotherapy. Appropriate laboratory studies may include, but are not limited to, 
blood cultures, a complete blood cell count, electrolytes (eg, calcium, magnesium, and 
phosphorus), glucose levels, renal and liver function studies, and/or an examination of the 
cerebrospinal fluid (CSF). Imaging studies may include a CT scan and/or an MRI. The CT is 
commonly normal in the absence of stroke, but if calcifications are present, this finding may be 
indicative of a more severe mineralizing leukoencephalopathy. MRI abnormalities may be 
pronounced but transient. Posterior reversible encephalopathy may be present on MRI with 
extensive diffusion abnormalities, but these do not appear to correlate with subsequent 
demyelination or gliosis. Additional studies, including magnetic resonance angiography and/or 
venogram should be considered, if clinically indicated (eg, if there are focal deficits). 
Many acute events, seizures or episodes of transient hemiparesis, are temporally related to the 
administration of IT chemotherapy, commonly occurring 9 to 11 days postadministration. For 
patients who return to their “pre-event” status, without residual deficits of physical or neurologic 
examination, there are few data to support or guide therapeutic interventions. It is reasonable to 
hold the next dose of IT chemotherapy, or, substitute IT cytarabine for 1 dose of IT 
methotrexate, or triple IT chemotherapy. It is also reasonable to include leucovorin rescue at a 
dose of 5 mg/m2 every 12 hours × 2 doses beginning 48 hours after the lumbar puncture. This 
pattern of rescue was associated with a clear diminution in the incidence of acute neurotoxicity 
in 1 case series. There have been questions about potential interference of leucovorin with the 
efficacy of the IT methotrexate, but there are little data to support or refute this position. 
Moreover, the administration 48 hours later would minimize any potential interference. If the 
event does not recur, resumption of standard therapy should be considered, following 1 modified 
or omitted IT dose. In the face of multiple recurrent events, or evidence of progressive 
encephalopathy, another evaluation is warranted, and the treating physician may consider a more 
prolonged or definitive change in therapy. These decisions are extremely difficult and may hinge 
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on an individual’s view of the importance of quality of life versus an increase in the risk of 
relapse. Since the greatest impact of CNS prophylaxis occurs early in therapy, the timing of these 
events may also influence clinical decisions. Cranial radiation has been suggested as an 
alternative to continued IT chemotherapy though much of the literature on long-term 
neurocognitive dysfunction supports a more deleterious effect from cranial radiation therapy than 
IT chemotherapy. Cranial radiation is not allowed during protocol therapy. 
The use of dextromethorphan has been suggested as a neuroprotectant, capable of preventing 
N-methyl-d-aspartate (NMDA)-mediated neurotoxicity without prohibitive toxicity. Low-dose 
therapy has been recommended, in part, based on data suggesting that dextromethorphan is 
concentrated in brain relative to serum. However, the literature on the use of dextromethorphan 
supports a tight dose-response relationship, with the likelihood of sparing an initially unaffected 
area, following ischemic damage, linked to dose, in both clinical trials and animal models of 
CNS ischemia. At doses thought to be therapeutic, side effects have included nystagmus, nausea 
and vomiting, distorted vision, ataxia, and dizziness. In addition, Hollander et al have raised 
concerns about the potential deleterious effects of long-term NMDA receptor blockade on 
memory because hippocampal long-term potentiation is dependent on the activation of the 
NMDA receptor (Hollander et al. 1994). Thus, in the absence of a clinical trial there are few data 
to support the addition of dextromethorphan. 
8.4.3.3.3 
For Hydrocephalus, Microcephaly, or Known Abnormality of Cerebrospinal Fluid 
Flow Precluding Intrathecal Chemotherapy via Lumbar Puncture 
Intraventricular chemotherapy via Ommaya catheter may be used in place of IT chemotherapy 
delivered by lumbar puncture. IT chemotherapy should be given according to the same schedule, 
but at 50% of the corresponding age-based doses that would be given by lumbar puncture. 
NOTE: Obstruction to CSF flow may be a contraindication to IT and/or intraventricular therapy. 
8.4.3.3.4 
For Viral, Bacterial, or Fungal Meningitis 
Omit until resolved. 
8.4.3.4 
Dexamethasone-Related Toxicities 
8.4.3.4.1 
For Hypertension 
Dose should not be reduced. Sodium restriction and antihypertensives should be employed in an 
effort to control hypertension. Avoid calcium channel blockers due to their potential 
prohemorrhagic effect. 
8.4.3.4.2 
For Hyperglycemia 
Dose should not be reduced for hyperglycemia. Rather, insulin therapy should be employed to 
control the blood glucose level. 
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8.4.3.4.3 
For Pancreatitis 
Do not modify dose for asymptomatic elevations of amylase and/or lipase. Discontinue steroids, 
except for stress doses, in the presence of hemorrhagic pancreatitis or severe pancreatitis. 
8.4.3.4.4 
For Osteonecrosis 
Do not modify corticosteroid therapy for osteonecrosis (NCI CTCAE Version 5.0 term: 
avascular necrosis). 
8.4.3.4.5 
For Varicella 
Steroids should be held during active infection unless being taken as per protocol therapy 
guidelines. Do not hold during incubation period following exposure. 
8.4.3.4.6 
For Severe Infection 
Do not hold or discontinue steroids without serious consideration, as this is a critical period in 
the treatment of ALL. 
8.4.3.4.7 
For Severe Psychosis 
Dexamethasone dose may be reduced by 50% for severe psychosis. If symptoms persist, switch 
to prednisone. 
8.4.3.5 
Vincristine-Related Toxicities 
In this protocol, it may be difficult to determine if peripheral neuropathy is due to vincristine or 
ponatinib. Both agents can cause peripheral neuropathy, and there is some overlap in their 
presentation. Ponatinib is commonly associated with painful sensory peripheral neuropathy. 
Vincristine neuropathy, in contrast, is commonly associated with motor or mixed neuropathy, 
including distal extremity weakness. 
8.4.3.5.1 
For Severe Neuropathic Pain (Grade 3 or Greater) 
Please use “Balis” Scale for grading neuropathy (see Section 8.4.2.1.1). 
Hold dose(s). When symptoms subside, resume at 50% previous calculated vincristine dose 
(maximum dose: 1 mg), then escalate to full dose as tolerated. Note: Neuropathic pain can be not 
only severe but also difficult to treat. However, because vincristine is an important component of 
curative therapy and most neuropathies are ultimately reversible, vincristine therapy may be 
given at full dose at investigator’s discretion. Severe peripheral neuropathies, with or without a 
family history, might suggest the need for a molecular diagnostic evaluation to rule out 
Charcot-Marie-Tooth disease (CMT), type 1A or hereditary neuropathy with liability to pressure 
palsies. Drugs such as gabapentin may be of value. 
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8.4.3.5.2 
For Vocal Cord Paralysis 
Hold dose(s). When symptoms subside, resume at 50% previous calculated dose (maximum 
dose: 1 mg), then escalate to full dose as tolerated. See above for comment on CMT. 
8.4.3.5.3 
For Foot Drop or Paresis 
Should be ≥Grade 3 to consider holding or decreasing dose. These toxicities are largely 
reversible but over months to years. Accordingly, holding doses of vincristine and/or lowering 
the dose may not result in rapid resolution of symptoms and may compromise cure. See above 
for comment on CMT. Physical therapy may be beneficial to maintain range of motion and 
provide ankle foot orthosis and other forms of support. Drugs such as gabapentin may be of 
value. 
8.4.3.5.4 
For Jaw Pain 
Treat with analgesics; do not modify vincristine dose. 
8.4.3.5.5 
For Hyperbilirubinemia 
The recommended vincristine dose reduction algorithm for hyperbilirubinemia is presented in 
Table 8.j. See also Table 8.e for modifications of ponatinib for hepatic toxicity. 
Table 8.j 
Vincristine Dose Reduction Algorithm for Hyperbilirubinemia 
Direct Bilirubin 
Dose Reduction  
<3.1 mg/dL  
Full dose (maximum dose: 2 mg) 
3.1-5.0 mg/dL  
50% of calculated dose (maximum dose: 1 mg) 
5.1-6.0 mg/dL  
75% of calculated dose (maximum dose: 0.5 mg) 
>6.0 mg/dL  
Withhold dose and administer next scheduled dose if toxicity has resolved. Do not make 
up missed doses.  
 
8.4.3.5.6 
For Constipation, Ileus (≥Grade 3), or Typhlitis 
Hold dose(s); institute aggressive regimen to treat constipation if present. When symptoms abate, 
resume at 50% of calculated dose (maximum dose: 1 mg) and escalate to full dose as tolerated. 
8.4.3.5.7 
For Extravasation 
In the event of an extravasation, discontinue the IV administration of the drug and institute 
appropriate measures to prevent further extravasation and damage according to institutional 
guidelines. 
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8.4.3.6 
Etoposide (VP-16) 
8.4.3.6.1 
For Allergic Reaction 
Premedicate with diphenhydramine (1-2 mg/kg slow IV push, maximum dose is 50 mg). If 
symptoms persist, add hydrocortisone 100-300 mg/m2. Continue to use premedication before 
etoposide in future. Also consider substituting an equimolar amount of etoposide phosphate, in 
the face of significant allergy and/or hypotension. Etoposide phosphate is a water-soluble 
prodrug that does not contain polysorbate 80 and PEG, the solubilizing agent in etoposide that 
may induce allergic reactions and hypotension. Etoposide phosphate is rapidly converted to 
etoposide in vivo and provides total drug exposure that is statistically indistinguishable from that 
measured for etoposide at equimolar doses. 
8.4.3.6.2 
For Hypotension 
If diastolic or systolic blood pressure falls 20 mm Hg during infusion, reduce infusion rate by 
50%. Start a simultaneous infusion of normal saline (NS) 10 mL/kg if blood pressure fails to 
recover or falls further. Stop infusion if blood pressure does not recover, continue NS. If the 
patient has had any episode of hypotension, prehydrate with 0.9% sodium chloride at 10 mL/kg/h 
for 2 hours prior to any subsequent infusion. 
8.4.3.6.3 
For Renal Insufficiency 
If renal function decreases, adjust etoposide as follows: creatinine clearance (CrCl) 
10-50 mL/min/1.73 m2, decrease dose by 25%; if CrCl <10 mL/min/1.73 m2, decrease dose by 
50%. 
8.4.3.6.4 
For Hyperbilirubinemia 
If direct bilirubin is >2 mg/dL, decrease dose by 50%. If direct bilirubin is >5 mg/dL, hold 
etoposide. 
8.4.3.7 
Intermediate-Dose Methotrexate Infusion Guidelines and Dose Modifications for 
Toxicity 
When IT therapy and intermediate-dose methotrexate are scheduled for the same day, it is 
strongly recommended to deliver the IT therapy within 6 hours of beginning of the IV 
methotrexate infusion (hour -6 to +6, with 0 being the start of the methotrexate bolus). 
Hold trimethoprim/sulfamethoxazole, any nonsteroidal anti-inflammatory medications, 
penicillins, proton pump inhibitors or aspirin-containing medications on the day of intermediate-
dose methotrexate infusion and for at least 72 hours after the start of the intermediate-dose 
methotrexate infusion and until the methotrexate level is less than 0.5 μM for intermediate-dose 
methotrexate. In the presence of delayed clearance continue to hold these medications until 
methotrexate level is less than 0.1 μM. 
Recommended prehydration: to start at least 6 hours prior to commencement of IV 
methotrexate. Fluid: 5% dextrose in water 1/4 NS with 30 to 50 mEq NaHCO3/L at 
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125 mL/m2/hour. Ringers lactate may be used as the initial fluid if a bicarbonate-containing 
solution is unavailable. Adjust fluid volume and sodium bicarbonate to maintain urine specific 
gravity ≤1.010 and pH between 7 and 8. A bicarbonate bolus (25 mEq/m2 over 15 min) may be 
given to raise the urine pH relatively quickly; a NS bolus may also be helpful in facilitating 
hydration. 
Hour 0: Methotrexate 100 mg/m2 IV infused over 30 minutes. This is followed, immediately, by 
methotrexate 900 mg/m2 given by continuous IV infusion over 35.5 hours. Be certain that the 
intermediate-dose methotrexate infusion is completed in the 36-hour period. Note, even if the 
infusion is not complete at this time point, it must be stopped. 
Recommended posthydration: Continue hydration using 5% dextrose in water 1/4 NS with 
30-50 mEq NaHCO3/L at 125 mL/m2/hour (3 L/m2/day) throughout intermediate-dose 
methotrexate infusion until the last dose of leucovorin has been given. In patients with delayed 
methotrexate clearance, continue hydration until the plasma methotrexate concentration is below 
0.1 μM. 
Leucovorin rescue: 15 mg/m2 PO/IV at 48 and 54 hours after the start of the methotrexate 
infusion. If 48-hour methotrexate level is ≤0.5 μM, then only 2 doses of leucovorin are 
administered (at 48 and 54 hours). If methotrexate level at 48 hours is >0.5 μM, then continue 
hydration and leucovorin rescue at 15 mg/m2/dose PO/IV every 6 hours until methotrexate levels 
are <0.1 μM. 
Hour 48: Check plasma methotrexate level at 48 hours after start of the methotrexate infusion. If 
the level is ≤0.5 μM, then do not give more than 2 doses of leucovorin (48 and 54 hours). If 
methotrexate level at 48 hours is >0.5 μM, then continue hydration and leucovorin rescue at 
15 mg/m2/dose PO/IV every 6 hours until methotrexate levels are <0.1 μM. 
For methotrexate levels that exceed these expected values, modify the rescue regimen as noted 
below and increase hydration to 200 mL/m2/h. Monitor urine pH to assure a value ≥7.0 and 
monitor urine output to determine if volume is ≥80% of the fluid intake, measured every 4 hours. 
If serum creatinine rises significantly, at any time point (>100% in 24 hours), assure appropriate 
urine pH and urine volume as above and consider glucarpidase. If urine output fails to continue 
at 80% of the fluid intake, consider furosemide or acetazolamide. Regardless of urine output, 
also consider glucarpidase (carboxypeptidase G2) (Table 8.k). 
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Table 8.k 
Methotrexate Dose Reduction Algorithm for Toxicity 
48 h methotrexate 
level  
Leucovorin Rescue  
≤0.5 μM  
Continue 15 mg/m2 IV/PO q 6 hours for 2 doses.  
0.5 – 1 μM  
Increase to 15 mg/m2 q 6 hours until methotrexate level <0.1 μM (draw q 6-24 hours).  
1 – 5 μM  
Increase to 15 mg/m2 q 3 hours until methotrexate level <0.1 μM (draw q 6-24 hours).  
5 – 10 μM  
Increase to 100 mg/m2 q 6 hours until methotrexate level <0.1 μM (draw q 6-24 hours).  
>10 μM  
Increase to 1000 mg/m2 q 6 hours until methotrexate level <0.1 μM (draw q 6-24 hours). 
Consider glucarpidase.  
IV: intravenous; PO: by mouth (orally); q: every. 
 
8.4.3.7.1 
For Nephrotoxicity 
Postpone course if pretreatment (methotrexate) serum creatinine is >1.5 × baseline or GFR CrCl 
<65 mL/minute/1.73m2. If there is a rising creatinine (>100% in 24 hours) or the 48-hour 
methotrexate level is >10 μ/L consider using glucarpidase. If renal function does not recover, 
omit methotrexate. Do not give intermediate-dose methotrexate to a patient with this degree or 
renal impairment, assuming that prolonged excretion can be managed with glucarpidase. 
NOTE: For patients who have markedly delayed methotrexate clearance secondary to renal 
dysfunction, consider using glucarpidase (carboxypeptidase G2, Voraxaze). To obtain supplies 
of glucarpidase in the US contact the Voraxaze 24-hour Customer Service line at 855-786-7292. 
Additional information can be found at btgplc.com/products/specialty-pharmaceuticals/voraxaze 
regarding product availability through ASD Healthcare, Cardinal, and McKesson. Canadian sites 
should contact McKesson at (877) 384-7425 for further information. Sites in Australia and New 
Zealand should contact Hospira at 1300-046-774 (local) or 
medicalinformationAUS@hospira.com. Patients requiring glucarpidase rescue will remain on 
study. 
Stop leucovorin 2 hours before administering glucarpidase as it is a competitive substrate and 
may compete with methotrexate for glucarpidase binding sites. 
Dose of glucarpidase: 50 units/kg administered by IV bolus over 5 minutes. Reconstitute each 
vial with 1 mL sodium chloride 0.9% (do not further dilute). Each vial contains 1000 units/mL 
(after reconstitution) and round dose up to vial size. No further dose is required. 
Maintaining alkalinization of urine with sodium bicarbonate is essential to maintain urinary 
pH >7. 
It is essential that patients are NOT co-prescribed the following medicines which reduce 
methotrexate excretion: nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, ciprofloxacin, 
co-trimoxazole, penicillin, probenecid, omeprazole. 
Two hours after administration of glucarpidase, leucovorin should be administered at a dose of 
250 mg/m2 every 6 hours by IV bolus (maximum rate: 160 mg/min) for up to 48 hours and then 
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decreased based on plasma methotrexate concentrations to 15 mg/m2 IV or PO every 6 hours 
until the plasma methotrexate concentration is <0.2 μM. 
8.4.3.7.2 
For Liver dysfunction 
Samples for the determination of ALT value must be drawn within 72 hours, PRIOR to a course 
of IV methotrexate. Blood samples for ALT should not be drawn following the start of 
methotrexate infusions as methotrexate causes significant short-term elevation in ALT levels. 
Hold IV methotrexate for direct hyperbilirubinemia of >2.0 mg/dL. 
8.4.3.7.3 
For Mucositis 
For Grade 3-4 mucositis, withhold IV methotrexate until resolved. 
8.4.3.8 
Cyclophosphamide 
8.4.3.8.1 
For Hematuria 
Omit in the presence of macroscopic hematuria. If there is a history of previous significant 
hematuria, hydrate before cyclophosphamide until specific gravity is <1.010 and hydrate at 
125 mL/m2/h for 24 hours after dose. Monitor for adequate urine output as per institution 
guidelines. Give IV mesna at a total dose that is 60% of the cyclophosphamide dose divided to 
3 doses (eg, if the cyclophosphamide dose is 1000 mg/m2, the total mesna dose is 600 mg/m2 or 
200 mg/m2/dose). Give the first mesna dose 15 minutes before or at the same time as the 
cyclophosphamide dose and repeat 4 and 8 hours after the start of cyclophosphamide. This total 
daily dose of mesna can also be administered as IV continuous infusion. The continuous infusion 
should be started 15-30 minutes before or at the same time as cyclophosphamide and finished no 
sooner than 8 hours after the end of cyclophosphamide infusion. 
8.4.3.8.2 
For Renal Dysfunction 
If CrCl or radioisotope GFR is <10 mL/min/1.73m2, reduce dose of cyclophosphamide by 50%. 
Prior to dose adjustment of cyclophosphamide, the CrCl should be repeated with good hydration. 
8.4.4 
Supportive Care 
Best supportive care and treatment will be given as appropriate to each patient (antiemetics, 
antibiotics, transfusions, oxygen therapy, nutritional support, palliative treatment for pain or 
cough, etc.). Patients may experience profound myelosuppression and immune suppression 
during this time. Parents/legal guardians must also be made aware that patients may experience 
very rapid clinical deterioration. This suggests the need for a supportive care network that can 
recognize and respond to sudden changes in a patient’s condition. 
Hospitalization is strongly recommended until the absolute phagocyte count (sum of the 
neutrophils, bands, and monocytes) is rising for 2 successive days, and the patient is afebrile and 
clinically stable. An additional discharge criterion of an ANC of at least 200/μL is also 
suggested. 
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Aggressive supportive care improves outcome. The following guidelines are intended to give 
general health direction for optimal patient care and to encourage uniformity in the treatment of 
this patient population. Notify the study clinician (or designee) of any unexpected or unusually 
severe complications. 
8.4.4.1 
Concurrent Therapy 
8.4.4.1.1 
Chemotherapy or Investigational Therapy 
Patients must not receive any non-protocol chemotherapy, investigational therapy, or immune 
modulating agents. 
8.4.4.1.2 
Cranial Irradiation for Central Nervous System Disease 
Cranial irradiation for CNS disease is NOT allowed during protocol therapy. 
8.4.4.1.3 
Radiotherapy to Chloroma 
Radiotherapy for chloroma is NOT allowed. 
8.4.4.1.4 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes, and general supportive 
care are to be used as necessary. 
8.4.4.1.5 
Hydroxyurea 
Patients may have received hydroxyurea to keep WBC count below 50,000/μL prior to beginning 
protocol therapy, but hydroxyurea must be discontinued 24 hours prior to starting systemic 
protocol therapy. 
8.4.4.1.6 
Cardiac Protectants 
Patients can receive cardiac protectants such as dexrazoxane while treated on this protocol per 
treating physician’s decision. 
8.4.4.1.7 
Alternative Medication 
Use of alternative medications (eg, herbal or botanical for anticancer purposes) is not permitted 
during the entire study period. 
8.4.4.2 
Blood Products 
Investigators should follow institutional guidelines regarding the administration of blood 
products. 
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8.4.4.3 
Infection Control 
8.4.4.3.1 
Pneumocystis Prophylaxis 
All patients are to receive prophylaxis with trimethoprim/sulfamethoxazole for pneumocystis for 
2 sequential days each week at a dose of 2.5 mg/kg/dose trimethoprim/sulfamethoxazole 
(maximum dose of 160 mg) twice daily (BID) or according to institutional policy, unless they 
have a documented sulfa allergy. Patients with sulfa allergy should receive dapsone 2 mg/kg PO 
QD with a maximum dose of 100 mg/day, or monthly pentamidine (IV or aerosolized). 
Pneumocystis prophylaxis should be continued throughout the entire study period. 
8.4.4.3.2 
Bacterial, Fungal, and Viral Prophylaxis 
Secondary to the high risk of serious invasive bacterial and fungal infection in patients with 
relapsed ALL, prophylaxis for bacterial and fungal infections is MANDATED on this protocol. 
Patients should receive levofloxacin at a dose based on each institution’s formulary (but as a 
recommendation, levofloxacin could be dosed at 10 mg/kg/dose [maximum 750 mg/dose] IV or 
PO BID if <5 years old and at 10 mg/kg/dose [maximum 750 mg/dose] IV or PO QD if ≥5 years 
old). 
All patients MUST receive antifungal prophylaxis during each course of therapy. Antifungal 
prophylaxis may be given per each institution’s standards. It is strongly encouraged to use a drug 
with antimold activity such as caspofungin or micafungin. The doses used should be in the 
treatment range more so than prophylactic as that is when colonization and infection may occur 
in patients at high risk for fungal infection. 
For patients with a history of documented or suspected herpes simplex virus or varicella zoster 
virus infection, it is recommended for them to receive prophylactic acyclovir at 750 mg/m2/day 
divided BID. 
It is strongly recommended that patients have quantitative immunoglobulins checked per 
institutional policy. Those with quantitative immunoglobulin G level below the normal range for 
age should receive IV immunoglobulin monthly. 
Bacterial, fungal, and viral prophylaxis should be initiated on Day 8 of reinduction and continued 
at least until the post-nadir ANC is >500/µL. 
8.4.4.3.3 
Fever and Neutropenia 
All patients with a fever >38.5°C on a single occasion, or >38°C on 2 occasions within 12 hours, 
and an ANC <500/µL are to be hospitalized and treated immediately with IV broad-spectrum 
antibiotics after obtaining appropriate cultures. The specific choice of antibiotics to be used in 
empiric treatment of febrile neutropenia is dependent on each institution’s experience regarding 
the type of infecting organisms, and their antibiotic sensitivity patterns. Duration of therapy 
should be determined by site of infection, culture results, and response to treatment. Antifungal 
treatment is to be considered for the persistence of fever, or emergence of a new fever in 
neutropenic patients after 3 days of broad-spectrum antibiotic coverage. Radiographic imaging 
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surveillance for sites of infection should also be performed as clinically indicated. When severe 
mucositis or a sepsis syndrome is present in patients with febrile neutropenia, or a patient has a 
history of prior alpha hemolytic sepsis, consider inclusion of vancomycin in the empiric 
antibiotic regimen. 
8.4.4.3.4 
Empiric Management of Pulmonary Infiltrates 
Pulmonary infiltrates should be evaluated in the context of the patient’s clinical and laboratory 
profile as well as institutional infection patterns. If the patient is not neutropenic, and the 
pulmonary lesions on CT scan are not particularly suggestive of a fungal infection (Aspergillus, 
mucor), consider using broad-spectrum antibiotics. If the patient develops progressively 
worsening clinical or laboratory features, or if, the pulmonary lesions on CT scan are suggestive 
of a fungal infection (Aspergillus, mucor), then more aggressive diagnostic measures should be 
undertaken. Pulmonary infiltrates may be evaluated with bronchoscopy and biopsy, lavage, or 
open lung biopsy. If a procedure cannot be tolerated, and/or if there is high clinical suspicion 
consider beginning empiric treatment with amphotericin B given the high likelihood of fungal 
disease. It is advisable to seek an infectious disease consult under these circumstances. Empiric 
coverage may include treatment of gram-negative and positive bacteria, Legionella 
(erythromycin), Pneumocystis (trimethoprim/sulfamethoxazole), and fungi (amphotericin) 
pending culture results. 
If fungal pulmonary disease is documented, surveillance radiographic imaging studies of the 
sinuses, abdomen/pelvis are indicated. Surgical excision of pulmonary lesions should be 
considered at the discretion of the treating physician. Treatment of fungal infections with 
amphotericin B and/or other antifungal agents will be at the discretion of the treating physician. 
8.4.4.3.5 
Management of Mucositis/Perirectal Cellulitis 
Mucositis should be managed with IV hydration and hyperalimentation (if indicated), effective 
analgesia, broad-spectrum gram-positive and gram-negative antibiotic therapy, and empiric 
antiviral and antifungal therapy, as indicated. Management of perirectal cellulitis should include 
broad-spectrum antibiotic therapy with dual gram-negative coverage as well as anaerobic 
coverage (ie, ceftazidime + aminoglycoside + metronidazole; or piperacillin-tazobactam + 
aminoglycoside), sitz baths, a strong barrier technique, and effective analgesia. 
8.4.4.3.6 
Use of Granulocyte Colony-Stimulating Factor 
The routine use of granulocyte colony-stimulating factor or other hematopoietic growth factors 
are not generally recommended but may be used at the discretion of the investigator in situations 
such as serious infection with neutropenia. 
8.4.4.4 
Safety Monitoring for Cardiac Toxicity 
Elevation of cardiac biomarkers in the first 3 months of anthracycline therapy suggests possible 
pathological left ventricular remodeling and the need for long-term follow-up. Dexrazoxane 
therapy has been associated with lower elevation of these biomarkers (Lipshultz et al. 2012). 
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Additionally, cardiotoxicity has been observed with ponatinib in adult studies but the effects in 
pediatric population is not known. Please refer to section 8.4.2.2 for guidance on ponatinib dose 
modifications for these events. 
Cardiac function and biomarkers will be followed in all patients enrolled on study, according to 
the following schedule: 
1. Biomarkers of cardiotoxicity 
a) Cardiac troponin T or I. 
b) NT-proBNP. 
Both will be assessed prior to first dose of ponatinib and daunorubicin and 2 weeks, 1 month, 
2 months, and 3 months from the second daunorubicin dose. 
2. Cardiac function 
ECHO or MUGA will be performed in the following schedule: 
a) Baseline - prior to initiating therapy. 
b) At the end of reinduction block. 
c) At the end of consolidation block. 
d) At EOT1. 
e) Yearly until end of study follow-up. 
8.5 
Excluded Concomitant Medications and Procedures 
Systemic treatment with any of the following drug-metabolizing enzyme inhibitors or inducers 
should be avoided during the study: 
• Strong CYP3A inhibitors: boceprevir, clarithromycin, cobicistat, conivaptan, grapefruit-
containing products including grapefruit juice, idelalisib, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, and voriconazole. 
• Strong CYP3A inducers: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, 
primidone, rifampin, rifapentine, rifabutin, and St. John’s wort. 
Because the above lists are not exhaustive, the investigator should consult the package insert for 
any medication under consideration for use to assess if it is a strong CYP3A inhibitor or strong 
CYP3A inducer. 
Medications that prolong the QT interval but are not associated with a known risk of torsades de 
pointes 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 
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ECG monitoring should be performed and documented. Discuss with the medical monitor a 
possibility of study drug discontinuation if any possible cardiac changes are noted. 
The investigator should refer to the most current package insert for the agents in the 
chemotherapy backbone for their drug-drug interaction information (Table 8.b and Table 8.c). 
The following concurrent medications and treatments are also prohibited: 
• Other anticancer therapies. 
• Chemotherapy, radiation therapy, another investigational agent, or immunotherapy. 
• Herbal preparations or related over-the-counter preparations containing herbal ingredients. 
• All live vaccines during the study treatment period and for at least 6 months after the last 
dose of the study treatment regimen. 
8.6 
Permitted Concomitant Medications and Procedures 
All treatments/therapies received within 30 days before the first dose of study drug will be 
recorded as prior treatments. 
All concomitant medications administered from the time of informed consent signature through 
the EOT1 visit (or EOT2 visit, for patients who receive optional ponatinib continuation therapy) 
(either the last dose of ponatinib 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 of childbearing potential (ie, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile; a postmenopausal state 
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is defined as no menses for 12 months without an alternative medical cause) 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. 
Given the preclinical findings of phototoxicity in rats (see current version of the investigator’s 
brochure), particularly with regard to eye sensitivity, it is recommended that patients minimize 
exposure to direct sunlight and take precautions, such as using sunscreen, sunglasses with 100% 
UV protection, or wearing a broad-brimmed hat along with the sunglasses, when outdoors. 
Smoking/e-cigarettes/vaping are strongly discouraged due to unknown effects of smoking on 
cardiovascular disease. 
8.8 
Management of Clinical Events 
Although the study excludes patients with active hepatitis B at the time of screening, ponatinib 
and chemotherapeutic agents 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 a high tumor burden such as WBC count ≥100,000/µL 
or diffuse organ involvement are considered high risk. Pre-existing uremia or hyperuricemia, 
decreased urinary flow or acidic urine, dehydration, 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, CHF, 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. 
Refer to the current local ponatinib package insert for details on management of patients who 
have or who develop the following conditions: AOEs, VTEs, hypertension, 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, TLS, posterior reversible encephalopathy syndrome, 
compromised wound healing, or gastrointestinal perforation. 
For all other therapies to be administered per this protocol, investigators should refer to the 
current local package insert for specific drugs for management of clinical events. See also 
Section 8.4.3 and Section 8.4.4. 
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8.9 
Blinding and Unblinding 
This is an open-label, unblinded study. 
8.10 
Description of Investigational Agents 
The tablet formulation of the ponatinib investigational drug product is supplied as white, oval or 
round, film-coated tablets for oral administration. Each tablet contains 10, 15, 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 PEG, talc, polyvinyl alcohol, and titanium dioxide. 
An AAF of ponatinib (minitab capsules) was developed for pediatric patients unable to swallow 
solid oral dosage forms and for patients requiring doses less than 10 mg. Ponatinib minitab size 2 
opaque white hydroxypropyl methylcellulose (HPMC) capsules are filled with 2-mm, round, 
film-coated mini-tablets. The formulation of the core mini-tablets contains ponatinib HCl, 
lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal silicon 
dioxide, and magnesium stearate. The 5 and 2.5 mg strengths capsules contain 10 and 5 minitabs 
(0.5 mg), respectively. These mini-tablets are coated with an aqueous film coating composed of 
PEG, talc, polyvinyl alcohol, and titanium dioxide. The coated mini-tablets are then encapsulated 
in a capsule containing HPMC and titanium dioxide. 
8.11 
Preparation, Reconstitution, and Dispensation 
Ponatinib tablets should be swallowed whole with water and should not be crushed or dissolved 
in liquid (Iclusig (ponatinib) Tablets for Oral Use 2022). 
Ponatinib minitab capsules should be either swallowed whole with water, or the capsule contents 
sprinkled in applesauce or yogurt and swallowed. 
Additional details regarding administration of the AAF are provided in the study/pharmacy 
manual. 
8.12 
Packaging and Labeling 
Upon receipt of drug supply, contents must be verified promptly, and the proper contacts notified 
of any discrepancies or damages as described in the study/pharmacy manual. 
8.12.1 
Ponatinib Tablets 
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 (only provided for phase 1 cohort 1): 30 count in white HDPE bottles with foil 
induction seal and cap. 
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Bottle labels for ponatinib tablets 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 
Ponatinib Age-Appropriate Formulation (AAF) 
The ponatinib AAF (mini-tablet filled into capsules, ie minitab capsules) will be supplied as 
follows: 
• 2.5 mg capsules: 35 count in white HDPE bottles with induction seal and cap. 
• 5 mg capsules: 35 count in white HDPE bottles with induction seal and cap. 
Bottle labels for ponatinib AAF 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 minitab capsules, and lot number. 
8.12.3 
Chemotherapy Backbone 
The chemotherapy backbone may be sourced by the clinical study sites when local regulations 
allow. 
8.13 
Storage, Handling, and Accountability 
8.13.1 
Storage 
All investigational supplies are to be kept in a secure area with controlled access. 
Ponatinib should be stored as described on the study drug labels. 
The chemotherapy backbone should be stored and handled as described in the study/pharmacy 
manual or, if locally sourced, the most current drug label (eg, US Package Insert, EU Summary 
of Product Characteristics), as applicable. 
8.13.2 
Handling and Accountability 
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/minitab capsule strength, the 
number of tablets/minitab capsules 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. 
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During the coronavirus disease 2019 (COVID-19) public health emergency, alternative study 
drug delivery to trial participants may be necessary to avoid unnecessary patient visits to sites 
while providing needed study drug. Additional study drug may be dispensed during a scheduled 
study visit or study drug may be shipped directly from investigative sites to participants’ 
residences by a contracted logistics provider or distributor (direct-to-patient [DTP] shipment) in 
compliance with national laws or temporary national emergency measures and Takeda processes. 
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 trial 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 trial, 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 site (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 
Refer to the pharmacy manual for any other protocol-specified materials to be used in the study. 
9.0 
STUDY CONDUCT 
This trial 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 for this study, the central laboratory, 
any additional clinical 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 IRB/IEC and Takeda (or designee). 
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9.3 
Study Procedures 
Refer to the SOEs (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. 
All possible measures should be taken to reduce pain and discomfort (eg, use of local anesthesia 
before venipunctures, noninvasive measure should be preferred and timing coordinated with 
daily activities as far as possible). Physical pain and discomfort intensity must be assessed and 
regularly monitored and treated according to local appropriate guidance (eg, ethical 
considerations for clinical studies on medicinal products conducted with minors), particularly in 
neonates and children who cannot express it verbally. In order to minimize pain, discomfort, and 
fear, facilities should be appropriate to childcare, and the personnel should be trained to look 
after children and supervised by experienced health care professionals. The investigative site’s 
staff should be trained to communicate with both the parents or legal guardian and the children. 
The degree of burden and risk threshold will be constantly monitored by the investigator. 
9.3.1 
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 enrollment, patients must continue to 
maintain laboratory values within eligibility parameters. Any patient who is rescreened 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. See the SOE in Appendix A, 
Table 1 for all screening procedures. 
For patients diagnosed with Ph-like ALL the site must provide the methodology used and the 
accredited laboratory performing the test for diagnosis (eg, RNA sequencing, fluorescence in situ 
hybridization [FISH]) and document in the eCRF.  
Patients who discontinued from screening or run-in period due to COVID-19–related factors but 
were otherwise qualified to participate in the study may be rescreened if the sponsor’s medical 
monitor agrees. 
9.3.2 
Informed Consent/Assent 
Each patient or patient’s parent or legal guardian must provide written informed consent/assent 
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 and, if 
applicable, the patient’s parent or legal guardian of all elements of informed consent. Adequate 
time must be allowed for questions and for the patient to make a voluntary decision. 
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9.3.3 
Demographics and Medical/Surgical History 
During the screening period, demographic data and a complete medical history will be compiled 
for each patient. The history will emphasize the background and progress of the patient’s 
malignancy and include a description of prior therapies for it. In addition, concomitant 
medications will be recorded as specified in Section 9.3.10. 
9.3.4 
Physical Examination and Vital Signs 
A complete physical examination (including height and weight) will be completed as specified in 
the SOEs (Appendix A, Table 1 and Table 2). 
Sites should calculate body surface area (BSA) from the weight and height measured at baseline 
and prior to each block of therapy as specified in the SOEs. 
Vital sign measurements will include systolic and diastolic blood pressure, heart rate, respiratory 
rate, and body temperature. Vital sign measurements will be assessed as specified in the SOEs. 
9.3.5 
Growth and Development 
Growth will be assessed using growth charts. Developments will be assessed with Tanner 
staging. Growth and development will be assessed as indicated in the SOEs (Appendix A, 
Table 1 and Table 2). 
9.3.6 
Performance Status 
The Karnofsky performance status scale (patients ≥16 years of age) or Lansky Play Scale 
performance status (patients <16 years of age) should be evaluated during each complete 
physical examination, as specified in the SOEs (Appendix A, Table 1 and Table 2). These 
performance score scales are available in Appendix D (Karnofsky and Burchenal 1949; Lansky 
et al. 1987). Patients must have a Karnofsky or Lansky Play Scale performance status ≥50% to 
be eligible for this study. Additional details on assessing performance status are provided in the 
site operations manual. 
9.3.7 
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 pregnancy testing (urine 
or serum) will be performed according to local standard of care while patient is on ponatinib 
continuation therapy (Appendix A, 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. 
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9.3.8 
Cardiovascular Risk Assessments 
9.3.8.1 
12-Lead Electrocardiogram 
All ECGs must be 12-lead ECGs, performed as specified in the SOEs (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 blood draw coincides with the timing of an ECG, the ECG should be performed 
first, followed by the blood draw. 
9.3.8.2 
Echocardiogram or Multigated Acquisition Scan 
An ECHO or MUGA for assessment of left ventricular ejection fraction must be performed as 
specified in the SOEs (Appendix A, Table 1 and Table 2). 
9.3.9 
Ophthalmological Examination 
An ophthalmological examination will be performed to screen for corneal and retinal vascular 
pathology at the time points outlined in the SOE (Appendix A, Table 1). 
9.3.10 
Concomitant Medications and Procedures 
All relevant medications/therapies and therapeutic procedures used/completed by the patient 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 informed consent form (ICF) 
until the EOT1 visit (or the EOT2 visit, for patients who receive optional ponatinib continuation 
therapy) will be recorded in the eCRF as concomitant medications, as specified in the SOEs 
(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. 
9.3.11 
Adverse Events 
Monitoring of AEs will be conducted throughout the study, starting on the date of signed ICF, 
and continuing until the EOT1 visit (or the EOT2 visit, for patients who receive optional 
ponatinib continuation therapy) as specified in the SOE (Appendix A, Table 1 and Table 2). 
Monitoring of SAEs will be conducted throughout the study, starting on the date of signed ICF, 
and continuing through 30 days after administration of the last dose of ponatinib.  
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 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. 
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9.3.12 
Enrollment 
A patient is considered to be enrolled in the study at the time of initiation of the first dose of 
study drug. Procedures for completion of the enrollment information are described in the site 
operations manual. 
9.3.13 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed as specified in the SOEs (Appendix A, Table 1 
and Table 2). Local laboratory test results should be assessed before dosing.  
9.3.13.1 
Hematology and Chemistry  
Blood samples for complete blood cell count with differential will be obtained as specified in the 
SOEs (Appendix A, Table 1 and Table 2) including on Day 35 of the reinduction block and 
consolidation block for disease assessment, or more frequently as clinically indicated. The full 
chemistry panel must be obtained as specified in the SOE, or more frequently as clinically 
indicated. 
9.3.13.2 
Coagulation 
A blood sample for a coagulation panel will be obtained as specified in the SOE (Appendix A, 
Table 1). 
9.3.13.3 
Troponin and NT-proBNP 
Assessment can be performed with either troponin T or troponin I, but ensure the same type of 
testing is used throughout the study. A blood sample for troponin testing (either troponin T or I) 
and another sample for NT-proBNP will be obtained as specified in the SOE (Appendix A, 
Table 1). 
9.3.13.4 
Free T4 and Thyroid Stimulating Hormone 
Blood samples for free T4 and thyroid stimulating hormone will be obtained as specified in the 
SOEs (Appendix A, Table 1 and Table 2).  
9.3.13.5 
Hepatitis B and C 
At the time of screening, hepatitis is testing is mandatory in countries with regulatory 
requirements and is optional in countries without regulatory requirements for testing. Blood is to 
be tested for hepatitis B and C surface antigen, hepatitis B and C core antibody, and hepatitis B 
and C surface antibody, at minimum, as specified in the SOE (Appendix A, Table 1). 
9.3.13.6 
HIV 
At the time of screening, HIV testing is mandatory in countries with regulatory requirements, 
and clinical assessment with HIV testing is optional in countries without regulatory requirements 
for testing (Appendix A, Table 1). 
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9.3.14 
Disease Assessment 
9.3.14.1 
Evaluation of CR 
BM samples (aspirate and/or biopsy) and complete blood cell count will be needed to assess CR 
status at the time points indicated in the SOE (Appendix A, Table 1). CR status will be 
confirmed by the investigator upon review of blasts in the BM morphology report from the local 
laboratory, extramedullary disease, neutrophil, and platelet recovery as well as blasts in 
peripheral blood, if applicable. 
After EOT1, complete blood cell count and BM evaluation for CR assessment may be performed 
at other times when clinically indicated. Results from the local laboratory testing of any BM 
sample (aspirate and/or biopsy), whether scheduled or unscheduled, must be recorded in the 
patient’s eCRF. 
If a BM sample (aspirate and/or biopsy) is used for the diagnosis of recurrence, a complete blood 
cell count should also be performed. If relapse from CR is confirmed, results of the assessments 
used to confirm the relapse, including peripheral blood, BM, CSF, or radiologic assessment, and 
their dates must be provided in the electronic data capture (EDC). If relapse from CR is 
confirmed, a peripheral blood sample must be collected for molecular mutation analysis. 
9.3.14.2 
Cerebrospinal Fluid 
CSF will be needed to assess CR status at the time points indicated in the SOEs (Appendix A, 
Table 1 and Table 2). CR status will be assessed by CSF for cell count and cytospin cytology. 
9.3.15 
Biomarkers and Pharmacokinetic Measurements 
Table 9.a includes information on the primary specimens to be collected for this study. Blood, 
BM, and plasma samples will be collected at the time points detailed in Appendix A, Table 1. 
Details on sample handling, storage, shipment, and analysis are provided in the laboratory 
manual. 
MRD will be evaluated once CR assessment is performed and only for patients with CR status 
reported by the investigator by the end of the consolidation block. 
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Table 9.a 
Primary Specimen Collection 
# 
Specimen Name 
Primary 
Specimen 
Primary 
Specimen 
Derivative 1 
Description of 
Intended Use 
Sample 
Collection 
1 
Fresh BM aspirate sample for MRD 
(Ph+ ALL only) 
BM 
DNA 
RNA 
MRD 
measurements 
Mandatory 
2 
Peripheral blood sample for MRD 
(Ph+ ALL only) 
Blood 
DNA 
RNA 
MRD 
measurements 
Mandatory if 
BM sample 
cannot be 
obtained a 
3 
Blood samples for molecular 
mutations (Ph+ ALL only) 
Blood 
RNA 
Confirm T315I 
mutation/ 
potential 
sensitivity/ 
resistance 
mutation 
Mandatory 
4 
Plasma sample for ponatinib PK 
Plasma 
 
PK measurements 
Mandatory 
ALL: acute lymphoblastic leukemia; BCR-ABL1: breakpoint cluster region Abelson 1; BM: bone marrow; MRD: 
minimal residual disease; Ph+: Philadelphia chromosome positive; PK: pharmacokinetic(s); WBC: white blood 
cell. 
a For initial screening, if a BM aspirate cannot be obtained, peripheral blood may be substituted to send for MRD 
probe development as long as there are at least 1000 circulating blasts/μL (ie, a WBC count of 10,000/μL with 
10% blasts or a WBC count of 5000/μL with 20% blasts). 
 
9.3.15.1 
Bone Marrow Samples for MRD Assessment 
MRD will be evaluated (only in patients with Ph+ ALL and only those who achieve CR by end 
of consolidation as reported by the investigator) as specified in the SOE (Appendix A, Table 1). 
The optimal sample for MRD assessment is the first pull or early pull of the BM aspirate. BM 
aspirate samples for MRD evaluation will be sent to a central laboratory. 
For initial screening, if a BM aspirate cannot be obtained, peripheral blood may be substituted to 
send for MRD probe development as long as there are at least 1000 circulating blasts/μL (ie, a 
WBC count of 10,000/μL with 10% blasts or a WBC count of 5000/μL with 20% blasts). 
For MRD assessment, BM evaluation 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. 
9.3.15.2 
Peripheral Blood Samples for Molecular Mutations 
Peripheral blood samples will be collected only from Ph+ ALL patients as specified in the SOEs 
(Appendix A, Table 1 and Table 2). Baseline samples will be tested immediately to confirm 
T315I mutation for patients requiring enrollment eligibility confirmation and communicated to 
the investigator. All other enrolled patients will have baseline samples tested to identify T315I 
mutation along with the other screening of molecular mutations to be conducted by sponsor for 
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exploratory analysis and will not be communicated to the investigator. Other samples both prior 
and following ponatinib treatment will be tested to characterize biomarkers of sensitivity and 
resistance to ponatinib-containing therapy (eg, BCR-ABL1, IKZF1, CDKN2A/2B) (Table 9.a). 
Peripheral blood samples for molecular mutations analysis will be sent to a central laboratory. 
9.3.15.3 
PK Measurements 
Blood samples for the measurement of plasma concentrations of ponatinib will be collected from 
all patients at multiple time points as specified in Appendix A, Table 3 and Table 4. These data 
will be used to characterize the PK of ponatinib. A sparser sampling scheme will be used for 
patients weighing <20 kg because of potential blood volume loss limitations. 
The exact date and time of each PK sample collection should be recorded in the eCRF. In 
addition, the exact date and time of dosing for the 2 preceding doses of ponatinib before all PK 
sample collections, and on the day of PK sample collection, should be recorded (at a minimum) 
in the eCRF. 
Details regarding the preparation, handling, and shipping of the PK samples are provided in the 
site operations manual. 
9.3.16 
Palatability and Acceptability of Ponatinib Age-Appropriate Formulation 
Patient acceptance of medication (acceptability) can be defined as the overall ability of the 
patient to use the medicine as intended. Acceptability of an oral medication is an important 
consideration in patients, particularly children, since it has a significant impact on patient 
compliance (Mistry et al. 2017; Van Riet-Nales et al. 2017). Palatability tests have been 
performed for several pediatric medications using different measurement scales (Davies and 
Tuleu 2008). This study will incorporate a questionnaire with questions related to the taste and 
smell using a 5-point facial hedonic scale. This scale allows for indication of preference by 
pointing at a pictorial scale of facial expressions that has been commonly used in palatability 
studies (Davies and Tuleu 2008; Mulla et al. 2016). 
After each dose of ponatinib on Days 1, 8, 15, and 22 during reinduction, a questionnaire will be 
provided to the patient and parent/legal guardian. At the investigator’s/designee’s discretion, if 
the patient is too young to complete the survey, only the parent/legal guardian will be surveyed. 
In each case, a nurse or research staff member will record the verbal responses to the questions. 
When facial hedonic scale is used, the child or parent/legal guardian will be asked to indicate 
their preference by circling the pictorial scale of facial expression. The palatability study 
questionnaire is provided in Appendix E. 
9.3.17 
Follow-up Assessments 
All patients will be followed for survival, recurrence, progression, growth and development, and 
subsequent treatments for at least 3 years from EOT1. Any disease assessments completed as 
clinically indicated need to be recorded in the EDC as indicated in Section 9.3.14. 
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Patients will be evaluated for alternative therapy, safety, and survival after EOT1 at 6 months, 
1 year, 18 months, 2 years, and every year thereafter for a total of at least 3 years after EOT1. 
If a patient refuses to return to the clinic for scheduled long-term follow-up study visits, 
information can be collected via telephone contact reports at the time of the regularly scheduled 
study visits; however, this is not preferred. If any concerns relating to study treatment are 
identified by the investigator during this telephone consultation with the patient, the investigator 
should request that the patient attend an in-person clinic visit to complete the assessments 
outlined in the SOEs (Appendix A, Table 1 and Table 2) for the long-term follow-up visits, or 
alternatively, have the patient visit their personal physician/other medical care provider for 
appropriate follow-up. Any results generated outside of the investigative site must be obtained by 
the investigator and recorded in the eCRF. 
Efforts will be made to avoid any patient being lost to follow-up during the conduct of the study. 
Before patients are considered lost to follow-up, a minimum of 2 documented telephone contact 
attempts must be made, and 1 certified letter must be sent within 6 weeks of the most recent 
planned study visit in an effort to contact patients. 
If a patient has been documented as lost to follow-up or if the site staff becomes aware of a 
patient’s death between scheduled visits, then the date of death must also be obtained and 
recorded in the eCRF. 
9.3.18 
Changes to Study Procedures Due to COVID-19 Public Health Emergency 
The following information provides guidance regarding changes to the study procedures that 
could be implemented for patients or study sites affected by the COVID-19 public health 
emergency. 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 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 principal investigator in consultation with the 
study team and the medical team as needed, while maintaining patient safety and confidentiality 
as the priority. 
Procedural changes due to COVID-19 public health emergency may include the following: 
• Informed consent procedure: If necessary, informed consent from a potential or current 
patient may be obtained via electronic informed consent (eIC) capabilities, or an electronic 
face-to-face consent interview when these patients are unable to travel to the site.  
• All patient visits from screening/baseline through to and including the EOT1 visit must be 
done with the patient present at the investigative site. This includes, but is not limited to, 
visits containing PK assessments, lumbar punctures, BM evaluations, or chemotherapy 
dosing. The optional continuation therapy visits should be done at the investigative site. 
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Every effort should be made to conduct patient visits at the investigative site. However, 
follow-up visits may be conducted by home health care visits in cases where flexibility is 
needed due to the COVID-19 public health emergency. Home health care visits will be 
documented in the study records and eCRF. 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). 
• 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 site 
staff who can visit the patient’s residence. 
• Missed clinic visits or patient withdrawals due to COVID-19 must be recorded on the eCRF. 
(Section 9.6). 
• 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. 
• Allow transfer of patients to investigative sites away from risk zones or closer to their home 
to sites already participating in the study or new ones. 
• Deviations from the protocol-specified procedures (eg, not collecting a protocol-specified 
specimen, such as postdose blood work) will be recorded as related to COVID-19 
(Section 14.2). 
• Alternative study drug deliveries may include dispensing additional ponatinib at clinic visits 
or DTP delivery of ponatinib from the investigative site to patients in compliance with 
national laws or temporary national emergency measures (Section 8.13.2). 
• Alternative monitoring approaches may include remote source data verification or remote 
source data review (Section 14.1). 
9.4 
Completion of Study Treatment 
All patients will be considered to have completed study treatment when they have completed the 
reinduction and consolidation blocks and the EOT1 visit and did not discontinue study treatment 
early or meet any of the criteria listed in Section 9.5, and if the patients received optional 
continuation therapy then after completing the EOT2 visit. 
9.5 
Reasons for Discontinuation of Treatment 
Discontinuation of treatment with study drug is to be reviewed and confirmed by the sponsor’s 
medical monitor or designee. 
Study drug must be immediately discontinued for patients who become pregnant. Depending on 
the outcome of the pregnancy (spontaneous or elective abortion), the sponsor/investigator may 
decide the patient can continue in the study. 
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Treatment with study drug may also be discontinued for any of the following reasons: 
• AE. 
• Protocol deviation and noncompliance. 
• Progressive disease. 
• Symptomatic deterioration. 
• Initiation of non-protocol therapy. 
• Study terminated by sponsor. 
• Withdrawal by patient or, if applicable, patient’s parent or legal guardian. 
• Lost to follow-up. 
• Other. 
Once study drug has been discontinued, all study procedures outlined for the EOT1 visit will be 
completed as specified in the SOE (Appendix A, Table 1). The primary reason for study drug 
discontinuation will be recorded on the eCRF including unavoidable circumstances such as the 
COVID-19 public health emergency. 
In the case of study termination by the sponsor, eligible patients may have continued access to 
ponatinib as described in Section 6.3.5. 
9.6 
Withdrawal of Patients From Study 
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 or, if applicable, patient’s parent or legal guardian. 
• Lost to follow-up. 
• Other. 
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. 
9.7 
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. 
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Patients will be provided a diary or equivalent where the date and time of ponatinib 
administration will be recorded; complete instructions will be provided with the site operations 
manual. 
9.8 
Criteria for Premature Termination or Suspension of the Study 
Study participation by individual sites or the entire study may be prematurely terminated if 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. 
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study: 
• New information or other evaluation regarding the safety or efficacy of ponatinib that 
indicates a change in the known safety profile such that the benefit-risk is no longer 
acceptable for patients participating in this study. 
• The independent data monitoring committee (IDMC) recommends that the study should be 
suspended or terminated.  
• Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety. 
• Study-specific criteria for terminating the study (eg, study meets predefined rule for futility 
or benefit).  
• Emergence of events that meet the criteria for early safety stopping rules as in Section 8.4.1. 
• Insufficient recruitment rate. 
10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
Pretreatment Event Definition 
A 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 
Adverse Event Definition 
AE 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 
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frequency since the administration of study drug. AE relationship should be assessed as related 
(includes attribution of possibly, probably, or definitely) or not related. 
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 
Serious Adverse Event Definition 
SAE 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). 
• 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, 
on the basis of appropriate medical judgment, it may jeopardize the patient, require medical 
or surgical intervention to prevent one 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 considered an AE, will 
be determined using the NCI CTCAE Version 5.0. Clarification should be made between an SAE 
and an AE that is considered severe in intensity (Grade 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 (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a WBC 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. 
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10.1.4 
Adverse Events of Special Interest Definitions 
AOEs and VTEs have been identified as AESIs for ponatinib. These include arterial and VTE 
and occlusive AEs that meet the criteria for SAEs, as defined in Section 10.1.3. 
The sponsor has determined that the events in the following list should be considered AESIs: 
• MI: The Third Universal Definition of Myocardial Infarction (Thygesen et al. 2012) is used 
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) with at least 
1 value above the 99th percentile upper reference limit (URL) and with at least 1 of the 
following: 
• Symptoms of ischemia. 
• 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 
cardiac troponin values (>5 × 99th percentile URL) in patients with normal baseline 
values (≤99th percentile URL) or a rise of cardiac troponin 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 cardiac 
troponin 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). 
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• Coronary artery disease (CAD) (newly diagnosed or worsening of existing CAD) or 
symptoms that may reflect cardiovascular disease (Thygesen et al. 2012). 
• 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 (Easton et al. 2009). 
• 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. 
• 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 these criteria. Dose modification 
guidelines for AOEs/VTEs are presented in Section 8.4.2.2. 
10.2 
Procedures for Recording and Reporting Adverse Events and Serious Adverse 
Events 
All AEs spontaneously reported by the patient or parent/legal guardian 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. This 
will be done by transmitting an EDC SAE report. If transmission of an EDC SAE report is not 
feasible, then a facsimile of the completed Takeda paper-based SAE form will be sent. A sample 
of the paper-based SAE form and processing directions are in the Study Manual. Information in 
the SAE report or form must be consistent with the data provided on the eCRF. 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 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. 
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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). 
10.3 
Monitoring of Adverse Events 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 the EOT visit (EOT1 or EOT2, as 
applicable) 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 progressive disease 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 
ponatinib 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). 
The safety and response data from phase 1 will be continuously reviewed by the sponsor and the 
medical monitor. At the cohort review meeting, the safety and response data will be reviewed by 
the sponsor together with participating investigators and a decision will be made either to 
proceed to the next phase of the study, evaluate a lower dose, or terminate the study. 
Prior to proceeding with the phase 2 enrollment for each formulation (tablet and AAF), an end of 
phase 1 meeting will be conducted and all factors impacting safety, including protocol deviations 
will be evaluated. These data and decisions will be provided to the IDMC for their review and 
feedback and an end of phase 1 summary will be sent to all participating sites. After the 
determination of the RP2D and commencing phase 2 enrollment at the RP2D, the sponsor’s team 
will continue to monitor all available safety data and hold safety review meetings on a regular 
basis. At any time, if the IDMC raises any important safety concerns, these will be 
communicated to the sites and when appropriate, the informed consents may be amended. 
Further details on the IDMC are provided in Section 11.2. 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a patient becomes pregnant or suspects pregnancy while participating in this study, the patient 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by sending a completed pregnancy form to the Takeda 
Global Pharmacovigilance department or designee. The pregnancy must be followed for the final 
pregnancy outcome. 
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If a patient impregnates a partner during participation in this study, the sponsor must also be 
contacted immediately by sending a completed pregnancy form to the Takeda Global 
Pharmacovigilance department or designee. Every effort should be made to follow the pregnancy 
for the final pregnancy outcome. 
Reporting details and contact information are provided in the site operations manual. 
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 address provided in the site operations manual. 
A medication error is a preventable event that involves an identifiable patient and 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 address provided in the site operations 
manual. 
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. 
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 EU EMA, 
investigators, and IRBs and 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 expedited reports 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 trial. The investigative site also will forward a copy of all expedited 
reports to its IRB or IEC in accordance with national regulations. 
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11.0 
STUDY-SPECIFIC COMMITTEES 
11.1 
Sponsor Liaison Team 
The Sponsor Liaison Team (SLT) or their respective delegates consists of key representatives 
from the ponatinib development team who have knowledge of the day-to-day activities of the 
study. The SLT should consist of, at a minimum, the following individuals: 
• Ponatinib global clinical lead. 
• Project clinician. 
• Lead project statistician. 
• Ponatinib global safety lead. 
The team will attend the open meeting sessions to answer any questions proposed by the IDMC 
relevant to study/program scientific and clinical issues. The SLT may request that the IDMC 
addresses specific issues related to the study. The committee will also liaise with the pediatric 
consortia study committees regarding important issues and developments related to the study. 
11.2 
IDMC 
An IDMC comprised of a pediatric oncologist, pediatric hematologist, and a statistician will 
review safety and efficacy data at the planned primary analysis and at regular intervals outlined 
in the charter. The IDMC will review study data according to the IDMC charter. 
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 Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC), Preferred Term 
(PT), 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. Additionally, the 
IDMC will receive regular listing updates on all SAEs and immediate notification of any deaths. 
Details of the IDMC (scope of functions and schedule) will be captured in its charter before the 
start of the study. Further details will be provided in the IDMC charter. 
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A cardiovascular endpoint adjudication process may be implemented at any time throughout the 
study to determine if an AOE meets the definition for a MACE. 
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 
MedDRA. Drugs will be coded using the World Health Organization (WHO) Drug Dictionary 
(01 March 2018). 
12.1 
eCRFs 
Completed eCRFs are required for each patient who signs, or whose parent or legal guardian 
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, contract 
research organization (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 the change. 
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. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor (or 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 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, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copies of eCRFs including the 
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audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities and the sponsor (or 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 or electronic medical record to ensure long-term legibility. Furthermore, 
ICH E6 (GCP) 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 for record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents. 
13.0 
STATISTICAL METHODS 
13.1 
Statistical Analysis Plans 
A SAP will be prepared and finalized before database lock. This document will provide further 
details regarding the definition of analysis variables and analysis methodology to address all 
study objectives. 
A data review will be conducted before database lock. This review will assess the accuracy and 
completeness of the study database, patient evaluability, and appropriateness of the planned 
statistical methods. 
In general, summary tabulations will be presented by study phase and dose cohort 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 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 database lock for the interim 
analysis as defined in Section 13.2. Deviations from the statistical analyses outlined in this 
protocol will be indicated in the SAP; any further modifications will be noted in the final CSR. 
13.1.1 
Analysis Sets 
The populations used for analysis will include the following: 
• Safety population: Patients who receive at least 1 dose of ponatinib. The safety population 
will be used for all safety analyses. 
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• PK analysis population: Patients in the phase 1 portion of the study who have sufficient 
ponatinib dosing data and concentration–time data to permit the calculation of ponatinib PK 
parameters. 
• DLT-evaluable population: Patients in the phase 1 portion of the study who receive at least 
1 dose of ponatinib in the reinduction block; to confirm no DLT was observed, the patient 
must have received at least 70% of the planned ponatinib dosing. The DLT-evaluable 
population will be used to determine the maximum tolerated dose. 
Patients who are withdrawn from treatment during the reinduction block for reasons other 
than DLTs will be replaced. 
• Response-evaluable population: Ph+ ALL patients at RP2D who receive at least 1 dose of 
ponatinib and complete at least 1 postbaseline disease assessment will be used for efficacy 
analyses. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized, including sex, age, race, ethnicity, 
weight, height, BSA, primary diagnosis, and other parameters as appropriate. 
13.1.3 
Efficacy Analysis 
Patients with Ph-like ALL and Ph+ MPAL will not be included in efficacy analyses. These 
patients will be included in safety and other descriptive analyses. 
13.1.3.1 
Primary Efficacy Endpoint Assessment 
Primary efficacy endpoint will be analyzed in the phase 2 portion of the study. Primary data 
analysis for this study will be conducted when all patients have been assessed for their primary 
endpoint and been on study for approximately 6 months after the last patient has been enrolled. 
The response-evaluable population will be assessed for the phase 2 primary endpoint. The 
phase 2 primary endpoint is CR at the end of the reinduction block. The estimate of the primary 
endpoint will be presented with 2-sided 90% Wilson Score CI. 
13.1.3.2 
Secondary Efficacy Endpoint Assessment 
Secondary efficacy endpoints will be summarized descriptively, with 2-sided 95% CIs provided. 
Time-to-event analysis will be conducted to obtain point estimates and 95% CIs for duration of 
response and the EFS, PFS, and OS rates at 6 months, 1 year, 18 months, 2 years, and 3 years. 
13.1.3.3 
Definitions of Response Criteria 
Definitions of response criteria for the purpose of efficacy analyses are provided in Table 13.a. 
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Table 13.a 
Definitions of Efficacy Response Criteria 
Term 
Definition 
CR 
CR meeting all the following (ie, no recurrence): 
• 
No circulating blasts and <5% blasts in the BM. 
• 
Normal maturation of all cellular components in the BM. 
• 
No extramedullary disease. 
• 
ANC >1000/µL (or >1.0 × 109/L). 
• 
Platelets >100,000/µL (or >100 × 109/L). 
Duration of response 
The interval between the first assessment at which the criteria for CR 
are met until the time at which relapse from CR occurs. 
EFS 
From date of enrollment until one of the following: 
• 
Death due to any cause. 
• 
Refractory to treatment, defined as failure to achieve CR by end of 
the consolidation block. 
• 
Relapse from CR. 
MRD negative (Ph+ ALL only) 
MRD status <0.01% 
OS 
The interval between the first dose date of study drug and death due to 
any cause. 
PFS 
From date of enrollment until one of the following: 
• 
Death related to disease under study. 
• 
Disease progression, defined as an increase of at least 25% in the 
absolute number of circulating or BM blasts or development of 
new extramedullary disease. 
• 
Relapse from CR. 
Relapse from CR a 
Reappearance of blasts in the blood or BM (≥5%) or in any 
extramedullary site after a CR. 
ALL: acute lymphoblastic leukemia; ANC: absolute neutrophil count; BM: bone marrow; CR: complete 
remission; EFS: event-free survival; MRD: minimal residual disease; OS: overall survival; Ph+: Philadelphia 
chromosome positive; PFS: progression-free survival. 
a If a bone marrow sample (aspirate and/or biopsy) is used for the diagnosis of recurrence, a complete blood cell 
count should also be performed. 
 
13.1.4 
Exploratory Analyses 
Exploratory endpoints will be summarized descriptively, with 95% CIs provided where 
appropriate. 
13.1.5 
PK Analysis 
Ponatinib PK parameters will be calculated, as permitted by the data, for individual phase 1 
patients in the PK analysis population using the ponatinib plasma concentration–time data. The 
calculated parameters will include ponatinib Cmax, tmax, and AUClast. PK parameters will be 
summarized using descriptive statistics. Individual ponatinib plasma concentration–time data and 
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individual PK parameters will be presented in listings. Individual and mean ponatinib plasma 
concentration–time profiles will be plotted. 
The sparse PK data collected in the phase 2 portion of the study will be listed and summarized by 
time point. The PK data collected in both phase 1 and phase 2 of the study will contribute to 
population PK and exposure-response analyses of ponatinib in the pediatric patient population. 
These analyses may include data collected in other ponatinib studies. The analysis plan for the 
population PK and exposure-response analyses will be separately defined, and the results of 
these analyses will be reported separately. 
13.1.6 
Safety Analysis 
The safety analysis will cover short-term AE, SAE, and AESI rates and changes from baseline in 
laboratory values. 
AEs will be summarized using the safety population. The DLT-evaluable population will be used 
for the analysis of DLT. 
All AEs will be coded using the MedDRA. Data will be summarized using PT and primary SOC. 
The safety analysis will be carried out at interim, primary and final analyses. 
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. TEAEs will be tabulated by primary SOC, High Level 
Term (HLT), and 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. 
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters. In 
addition, urinalysis results will be listed. 
A summary of ECG abnormalities will be presented by visit. ECG parameters (QT, QTc, PR, 
and QRS intervals and ventricular rate) will be summarized at each scheduled time point, along 
with the mean change from baseline to each posttreatment time point. Shift tables for laboratory 
parameters will be generated based on changes in NCI CTCAE Version 5.0 grade from baseline 
to the worst postbaseline value. Graphical displays of key safety parameters, such as scatter plots 
of baseline versus worst postbaseline values, may be used to understand the ponatinib safety 
profile. 
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All concomitant medications collected from screening through the study period will be classified 
to PTs according to the WHO Drug Dictionary (01 March 2018). 
13.2 
Interim Analysis and Criteria for Early Termination 
There will be 1 interim analysis performed when 20 patients at the RP2D have completed 
reinduction. Enrollment will not be stopped while the interim analysis data is reviewed by the 
IDMC (Section 11.2). Following the interim analysis results and application of the prespecified 
rules, the IDMC may recommend stopping the trial for futility or recommend continuing the trial 
with or without modifications. The sponsor’s Executive Committee will make final decisions 
based on the IDMC’s recommendations. The analysis will be performed as defined in 
Section 13.1.3.1. 
13.3 
Determination of Sample Size and Justification of Control Rate Assumption 
The Wilson Score CI approach will be used for the sample size determination. The Wilson Score 
interval is an improvement over the normal approximation interval in that the actual coverage 
probability is closer to the nominal value. Based on the Wilson Score CI approach and assuming 
N = 68 patients to reject the null hypothesis of a 67% CR rate, a 2-sided type I error of 0.1, and 
that under the alternative hypothesis the ponatinib CR rate is 80% based on simulations with 
1,000,000 iterations, the power of the trial equals 81.5%. This simulation also demonstrated that 
under the null hypothesis, the type I error is controlled at a nominal level of 0.1 (2-sided). 
The null hypothesis of a 67% CR rate is based on the following justification from 2 studies. In 
the first study, 87 adult patients with Ph+ ALL were treated with imatinib plus chemotherapy 
(Lim 2017). Of the 87 patients, 44 experienced a relapse, and of those, 19 (43.2%) achieved a 
second CR (CR2). Based on these results, we assume that the prior distribution control rate 
follows β(a, b), mean = a/(a + b) = 19/(19 + 25) = 0.432. The outcomes of imatinib plus 
chemotherapy were also evaluated in a study of 92 pediatric patients with Ph+ ALL (Schultz et 
al. 2014). Among those who relapsed, follow-up data were available on 34 patients, of which 
24 (70.6%) achieved a CR2 (personal communication, 11 June 2019). Based on those results, we 
assume that a CR2 event, x, follows a binomial (n, p) distribution, where x = 24, n = 34, and the 
estimated rate p = 24/34 = 0.71. The CR2 posterior distribution follows β(a + x, n – x + b). 
Thus, the mean CR2 rate from the posterior distribution = (a + x)/(n + a + b) = 0.5513. The 95% 
credible interval of the CR2 rate = (0.44, 0.66) = (44%, 66%). 
Because our prior distribution control rate uses adult data, we take a conservative approach and 
assume that the control rate is no less than the 95% upper credible limit, ie, 67%. 
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. 
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The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee including, but not limited to, the investigator’s site file, 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. 
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 public health 
emergency, 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. Such alternative approaches must adhere to any applicable 
local laws and guidances. 
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. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
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 EC, 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 the primary 
study assessment. 
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 investigator should document each protocol deviation and report to the IRB/IEC each 
deviation that the IRB/IEC requires to be reported. For COVID-19–related protocol deviations, 
the specific protocol deviation and the reason for the deviation should be documented. 
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 US FDA, the UK MHRA, and the EU EMA). If 
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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 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 Harmonised Tripartite 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 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 because of privacy and conflict of interest concerns should instead 
provide a Federalwide 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 advertisements and other 
documents required by all applicable laws and regulations must be submitted to a central and/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 its exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. If required by country or regional regulations or procedures, approval from the 
competent regulatory authority will be obtained before commencement of the study or 
implementation of a substantial amendment. 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 the 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 patients, 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 
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approvals and relevant documentation for these items must be provided to the sponsor 
(or designee). 
Patient incentives should not exert undue influence for participation. Payments to patients 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 guideline for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, assent form (if applicable), subject authorization form 
(if applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal health information for purposes of 
conducting the study. The ICF further explains the nature of the study, its objectives, and 
potential risks and benefits, and 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 
and, if applicable, the subject authorization form. The ICF, assent form (if applicable), subject 
authorization form (if applicable), and subject information sheet (if applicable) must be approved 
by both the IRB or IEC and the sponsor before use. 
The ICF, assent form (if applicable), subject authorization form (if applicable), and subject 
information sheet (if applicable) must be written in a language fully comprehensible to the 
prospective subject’s parent or legal guardian (or the prospective subject, if the subject is of the 
age of consent). It is the responsibility of the investigator to explain the detailed elements of the 
ICF, assent form (if applicable), subject authorization form (if applicable), and subject 
information sheet (if applicable) to the subject or the subject’s parent or legal guardian. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. If the subject is not capable of rendering adequate 
written informed consent, then the subject’s parent or legal guardian may provide such consent 
for the subject in accordance with applicable laws and regulations. 
The subject, or the subject’s parent or legal guardian, must be given ample opportunity to 
(1) inquire about details of the study and (2) decide whether to participate in the study. If the 
subject, or the subject's parent or legal guardian, determines that he or she will participate in the 
study, then the ICF and assent form (if applicable) must be signed and dated at the time of 
consent and before the subject enters into the study. The subject or the subject’s parent or legal 
guardian should be instructed to sign using their legal names, not nicknames, using a ballpoint 
pen with either blue or black ink. The investigator must also sign and date the ICF, assent form 
(if applicable), and subject authorization (if applicable) 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, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
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the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed assent form (if applicable), the signed subject authorization form (if 
applicable), and the subject information sheet (if applicable) shall be given to the subject. 
All revised ICFs and assent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s parent or legal guardian 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. 
During the COVID-19 public health emergency, informed consent and assent from a potential or 
current trial participant and parent/legal guardian may be obtained via eIC capabilities, or an 
electronic face-to-face consent/assent interview when these individuals are unable to travel to the 
site. 
For patients who would have to travel long distances to the study site, remote consenting and 
assenting is allowed if permitted by local regulations (eg, IRB or IEC). 
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 be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
subject initials, may be used to verify the subject’s identity and accuracy of the subject’s unique 
identification number. 
To comply with ICH guideline 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), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical 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 
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disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and 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 by Takeda policy/standards. 
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 in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/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 
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, clinicaltrialsregister.eu, and 
other publicly accessible websites (including the Takeda corporate site) and registries, as 
required by Takeda policy/standards, applicable laws, and/or regulations. 
15.4.4 
Data Sharing 
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. 
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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. 
16.0 
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Short, N., Kantarjian, H., Ravandi, F., Daver, N., Pemmaraju, N., Thomas, D., et al. 2017. 
Frontline hyper-CVAD plus ponatinib for patients with Philadelphia chromosome-
positive acute lymphoblastic leukemia: updated results of a phase II study. Poster No. 5-
28.  ASCO, 2017. 
Skolnik, J. M., Barrett, J. S., Jayaraman, B., Patel, D. and Adamson, P. C. 2008. Shortening the 
timeline of pediatric phase I trials: the rolling six design. Journal of Clinical Oncology, 
26(2), 190-5. 
Soverini, S., De Benedittis, C., Papayannidis, C., Paolini, S., Venturi, C., Iacobucci, I., et al. 
2014. Drug resistance and BCR-ABL kinase domain mutations in Philadelphia 
chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-
generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, 
but not in the frequency of mutation involvement. Cancer, 120, 1002–9. 
Tamai, M., Inukai, T., Kojika, S., Abe, M., Kagami, K., Harama, D., et al. 2018. T315I mutation 
of BCR-ABL1 into human Philadelphia chromosome-positive leukemia cell lines by 
homologous recombination using the CRISPR/Cas9 system. Scientific Reports, 8(1), 
9966. 
Thygesen, K., Alpert, J. S., Jaffe, A. S., Simoons, M. L., Chaitman, B. R., White, H. D., et al. 
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Upreti, V. V. and Wahlstrom, J. L. 2016. Meta-analysis of hepatic cytochrome P450 ontogeny to 
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CONFIDENTIAL 
Van Riet-Nales, D. A., Kozarewicz, P., Aylward, B., de Vries, R., Egberts, T. C., Rademaker, C. 
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Haematol, 148(1), 15-25. 
Watanabe, K., Minami, Y., Ozawa, Y., Miyamura, K. and Naoe, T. 2012. T315I mutation in Ph-
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Weinberg, O. K. and Arber, D. A. 2010. Mixed-phenotype acute leukemia: historical overview 
and a new definition. Leukemia, 24(11), 1844-51. 
Zabriskie, M. S., Eide, C. A., Tantravahi, S. K., Vellore, N. A., Estrada, J., Nicolini, F. E., et al. 
2014. BCR-ABL1 compound mutations combining key kinase domain positions confer 
clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell, 26(3), 
428-42. 
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Quantitative analysis of minimal residual disease predicts relapse in children with B-
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110(5), 1607-11. 
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CONFIDENTIAL 
Appendix A Schedules of Events 
Table 1 
Schedule of Events 
 
35-Day Cycles 
Screening/ 
Baseline a 
Reinduction Block 
Consolidation Block 
EOT1 b 
Follow-up c 
Cycle Days 
1 
8 
15 
22 
29 
35 
1 
8 
15 
22 
29 
35 
25-30 Days After 
Last Dose 
 
Window (days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
±14 
Study Procedures 
Informed consent/pediatric assent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and chemistry d 
X d 
X d 
X 
X 
X 
X 
X z 
X 
X 
X 
X 
X 
X z 
X 
X e 
Hepatitis B and C testing f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV testing g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel h 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Troponin and NT-proBNP i 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Free T4, TSH 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X  
Pregnancy test j 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Vitals, including height, weight, BSA k 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X  
Physical examination including neurological 
assessment l  
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Growth and development assessment m 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Performance status (Karnofsky/Lansky 
score, Appendix D) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
12-lead ECG n 
X 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
ECHO or MUGA 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X o 
Concomitant medications and procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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CONFIDENTIAL 
Table 1 
Schedule of Events 
 
35-Day Cycles 
Screening/ 
Baseline a 
Reinduction Block 
Consolidation Block 
EOT1 b 
Follow-up c 
Cycle Days 
1 
8 
15 
22 
29 
35 
1 
8 
15 
22 
29 
35 
25-30 Days After 
Last Dose 
 
Window (days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
±14 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lumbar puncture p 
X 
X 
X q 
X 
X q 
X 
 
 
X 
 
 
X 
 
 
 
Bone marrow aspirate assessed locally 
and/or biopsy for morphology, cytogenetics, 
and flow cytometry r  
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Fresh bone marrow aspirate sample assessed 
centrally for MRD s, t, v 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Peripheral blood samples for molecular 
mutations u, v 
X aa 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
(relapse only)  
Administration of study treatment w 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Palatability questionnaire of ponatinib x 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Ophthalmological examination y 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Plasma sample for ponatinib PK 
See Table 3 for phase 1 and Table 4 for phase 2 PK sampling schedules. 
Investigator’s assessment of disease 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X bb 
Alternative therapy (anticancer therapy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE: adverse event; ALL: acute lymphoblastic leukemia; BCR-ABL1: breakpoint cluster region Abelson 1; BSA: body surface area; CNS: central nervous system; COVID-19: 
coronavirus disease 2019; ECG: electrocardiogram; ECHO: echocardiogram; EOT: end of treatment; IT: intrathecal; MPAL: mixed phenotype acute leukemia; MRD: minimal 
residual disease; MUGA: multigated acquisition scan; NT-proBNP: N-terminal pro-brain natriuretic peptide; Ph-like: Philadelphia chromosome-like; PK: pharmacokinetic; PT: 
prothrombin time; QTcF: QT interval corrected per Fridericia method; TSH: thyroid stimulating hormone; WBC: white blood cell. 
Note: Other studies or more frequent monitoring may be indicated for good clinical care. Initial IT chemotherapy: Day 1; may include methotrexate for CNS-1/2 patients, 
or triple IT chemotherapy for CNS-3 patients. All patient visits from screening/baseline through to and including the EOT1 visit must be done with the patient present at the 
investigative site. Every effort should be made to conduct patient visits at the investigative site. However, follow-up visits may be conducted by home health care visits in cases 
where flexibility is needed due to the COVID-19 public health emergency. 
a The screening visit must occur within 10 days before the day of the first dose of study drug (Day -10 to Day 0). 
b All patients will proceed to EOT (EOT1) 25 to 30 days after last dose of study treatment in the consolidation block or earlier, if the patient is proceeding to alternate therapy or 
optional ponatinib continuation therapy; EOT1 should be completed before alternative anticancer therapy(ies) are given. For patients with an early EOT1, the ECHO or MUGA 
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02 November 2023 
 
CONFIDENTIAL 
Table 1 
Schedule of Events 
 
35-Day Cycles 
Screening/ 
Baseline a 
Reinduction Block 
Consolidation Block 
EOT1 b 
Follow-up c 
Cycle Days 
1 
8 
15 
22 
29 
35 
1 
8 
15 
22 
29 
35 
25-30 Days After 
Last Dose 
 
Window (days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
±14 
does not need to be repeated if done within 25 days and the ECG does not need to be repeated if done within 7 days prior to the visit. Only patients who receive optional 
continuation therapy containing ponatinib will undergo a second EOT visit (EOT2). See Table 2. Patients who discontinue ponatinib early in the reinduction block or 
consolidation block will be discontinued from study treatment and proceed to the EOT1 visit. 
c Each patient will be followed for a minimum of 36 months after the EOT1 visit or until patient withdrawal from study, whichever occurs first. Follow-up visits will occur after 
EOT1 at 6 months, 1 year, 18 months, 2 years, and then annually until the end of the study. If a patient refuses to return to the clinic for the scheduled long-term follow-up visits, 
information can be collected via telephone contact reports; however, this is not preferred (see Section 9.3.17). 
d The hematology and chemistry blood samples for Day 1 may be collected within 4 days before dosing to ensure patient eligibility on study Day 1. If screening clinical 
laboratory testing was performed within 4 days before the Day 1 dose, it need not be repeated on Day 1. Hematology includes complete blood cell count with differential 
consisting of the following: hemoglobin, hematocrit, leukocytes (WBCs), differential WBC count, and platelets. Machine counts are acceptable. The chemistry panel consists of 
the following: sodium, potassium, carbon dioxide, chloride, blood urea nitrogen or urea, creatinine, direct bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, lactate dehydrogenase, gamma-glutamyl transferase, triglycerides, lipase, amylase, albumin, glucose, urate, calcium, phosphate, and magnesium. 
e To follow organ function and detect relapse. 
f Hepatitis testing is mandatory in countries with regulatory requirements and is optional in countries without regulatory requirements for testing. 
g HIV testing is mandatory in countries with regulatory requirements, and clinical assessment with HIV testing is optional in countries without regulatory requirements for testing. 
h Coagulation panel includes platelets [with hematology], activated partial thromboplastin time and PT, fibrinogen degradation products or D-dimer, factor FVII, and 
antithrombin level. 
i Troponin testing can be performed with either troponin T or troponin I, but ensure the same type of testing is used throughout the study. Blood sample can be collected either at 
the screening visit or on Day 1 before ponatinib and daunorubicin dosing. Additional evaluations may be done if clinically indicated. 
j A pregnancy test will be performed only for female patients of childbearing potential according to local standard of care. At screening, the results must be negative within 3 days 
before the first dose of ponatinib is administered. Monthly pregnancy testing (urine or serum) will be performed according to local standard of care while patient is receiving 
ponatinib. 
k Height and weight needed to assess growth. 
l The neurological assessment can be performed by the pediatric oncologist and includes the Modified “Balis” Pediatric Scale for peripheral neuropathy. 
m Growth charts and Tanner staging will be used for growth and development assessments. Other tests may be needed as clinically indicated. 
n ECGs must all be 12-lead ECGs. The baseline ECG should be performed at screening/baseline, or on Day 1, before ponatinib dosing. On Day 1, and thereafter as per the 
schedule in the reinduction and consolidation period, the ECG should be performed 4-6 hours after ponatinib administration. 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. On days when both an ECG and a blood draw is performed, the 
ECG should be done before the blood draw. 
o During follow-up, ECHO or MUGA will be performed yearly until end of study follow-up. 
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02 November 2023 
 
CONFIDENTIAL 
Table 1 
Schedule of Events 
 
35-Day Cycles 
Screening/ 
Baseline a 
Reinduction Block 
Consolidation Block 
EOT1 b 
Follow-up c 
Cycle Days 
1 
8 
15 
22 
29 
35 
1 
8 
15 
22 
29 
35 
25-30 Days After 
Last Dose 
 
Window (days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
±14 
p Lumbar puncture for cell count and cytospin cytology will be performed with every IT therapy and when clinically indicated. 
q For CNS-3 patients only. 
r For initial screening, if a bone marrow aspirate cannot be obtained, peripheral blood may be substituted for initial diagnosis as long as there are at least 1000 circulating 
blasts/μL (ie, a WBC count of 10,000/μL with 10% blasts or a WBC count of 5000/μL with 20% blasts). Flow cytometry, cytogenetics, fluorescence in situ hybridization, or 
molecular studies can be used to confirm the type and subtype of acute leukemia. If a bone marrow sample (aspirate and/or biopsy) is used for the diagnosis of recurrence, a 
complete blood cell count should also be performed. 
s At screening, at the end of each treatment block and when clinically indicated. Bone marrow aspirate for MRD evaluation will be performed by a central laboratory (not 
applicable for patients with Ph-like ALL and MPAL). 
t For initial screening, if a bone marrow aspirate cannot be obtained, peripheral blood may be substituted to send for MRD probe development as long as there are at least 1000 
circulating blasts/μL (ie, a WBC count of 10,000/μL with 10% blasts or a WBC count of 5000/μL with 20% blasts). 
u Submission of peripheral blood samples to central laboratory to assess molecular mutations (eg, BCR-ABL1, IKZF1, CDKN2A/2B). Only 1 evaluation is needed before starting 
therapy: blood sample can be taken either at the screening/baseline visit or on Reinduction Block Day 1 prior to dosing, but not both. Blood samples should be taken post-protocol 
treatment at EOT1 before alternative therapy(ies) are given. For patients with Ph+ ALL for whom the investigator reports a relapse from complete remission, a peripheral blood 
sample should also be taken before alternative therapy(ies) are given and submitted to central laboratory to assess molecular mutations. 
v Not applicable for patients with Ph-like ALL and MPAL. 
w Administration of study treatment will also include diary review and study treatment verification. Ponatinib will be administered once daily throughout each 35-day block 
(Days 1-35). See Table 5 for details of study treatment administration. 
x Age-appropriate formulation only: After each dose of ponatinib taken on Days 1, 8, 15, and 22 of the reinduction block, a questionnaire will be provided to patient and 
parent/legal guardian. If the patient is too young to complete the survey, only the parent/legal guardian will be surveyed. In each case, site staff will record the verbal responses to 
the questions. 
y Ophthalmological examination to screen for corneal and retinal vascular pathology. 
z Hematology at Day 35 (±3 days) includes platelets and neutrophils to complete the investigator’s disease assessment for determination of complete remission prior to initiation 
of the consolidation block. (This assessment may be used as the same assessment for Day 1 of the consolidation block). Chemistry assessment at Day 35 is not required.  
aa Baseline samples will be tested immediately to confirm T315I mutation for patients requiring enrollment eligibility confirmation and communicated to the investigator. 
bb If relapse from complete remission is confirmed, results of the assessments used to confirm the relapse, including bone marrow assessment, and their date must be provided in 
the electronic data capture. 
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CONFIDENTIAL 
 
Table 2 
Schedule of Events for Ponatinib 
28-Day Cycles 
Optional Continuation Regimen 
EOT2 a 
Follow-up b 
Cycle Days 
1 c 
Every 3 Months 
30-40 Days After 
Last Dose 
 
Window (days) 
±3 
±7 
 
±14 
Hematology and chemistry d 
X 
 
X 
X e 
Pregnancy test f 
X 
 
X 
 
Vitals, including height, weight, BSA g 
X 
 
X 
X  
Physical examination and neurological assessment h,i 
X 
 
X 
X 
Growth and development assessment j 
 
 
X 
X  
Performance status (Karnofsky/Lansky score, Appendix D) 
X 
 
X 
X 
12-lead ECG k 
 
X 
X 
X 
ECHO or MUGA l 
 
X 
X 
X 
Free T4, TSH 
X 
 
 
X 
Concomitant medications and procedures 
X 
 
X 
 
AE reporting 
X 
 
X 
 
Lumbar puncture m 
 
X m 
 
 
Peripheral blood samples for molecular mutations n 
Only required if relapse occurs. 
(Not applicable for Ph-like ALL and MPAL). 
Administration of study treatment o 
X 
 
 
 
Investigator’s assessment of disease 
 
 
X 
X p 
Alternative therapy (anticancer therapy) 
 
 
 
X 
AE: adverse event; BCR-ABL1: breakpoint cluster region Abelson 1; BSA: body surface area; COVID-19: coronavirus disease 2019; ECG: electrocardiogram; 
ECHO: echocardiogram; EOT: end of treatment; MUGA: multigated acquisition scan; TSH: thyroid stimulating hormone; WBC: white blood cell. 
Note: Other studies or more frequent monitoring may be indicated for good clinical care. The optional continuation therapy should be done at the 
investigative site. Every effort should be made to conduct patient visits at the investigative site. However, follow-up visits may be conducted by home health 
care visits in cases where flexibility is needed due to the COVID-19 public health emergency. 
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Table 2 
Schedule of Events for Ponatinib 
28-Day Cycles 
Optional Continuation Regimen 
EOT2 a 
Follow-up b 
Cycle Days 
1 c 
Every 3 Months 
30-40 Days After 
Last Dose 
 
Window (days) 
±3 
±7 
 
±14 
a EOT2 is 30 to 40 days after the last dose of ponatinib, or earlier, if the patient is proceeding to alternate therapy; EOT2 should be completed before alternative 
anticancer therapy(ies) are given. 
b Each patient will be followed for a minimum of 36 months after EOT1 visit or until patient withdrawal from study, whichever occurs first. For patients eligible 
to receive optional ponatinib continuation treatment, follow-up visits after EOT2 will occur at 6 months, 1 year, 18 months, 2 years, and then annually. If a 
patient refuses to return to the clinic for the scheduled long-term follow-up visits, information can be collected via telephone contact reports; however, this is not 
preferred (see Section 9.3.17). 
c For the first cycle of optional ponatinib continuation therapy only: Day 1 assessments need to be performed ONLY if 10 days or more have elapsed since the 
EOT1 visit. 
d The hematology and chemistry blood samples will be collected on Day 1 as well as at EOT2 and Follow-up. Hematology includes complete blood cell count 
with differential consisting of the following: hemoglobin, hematocrit, leukocytes (WBCs), differential WBC count, and platelets. Machine counts are 
acceptable. The chemistry panel consists of the following: sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, creatinine, direct bilirubin, alkaline 
phosphatase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, gamma-glutamyl transferase, triglycerides, lipase, amylase, albumin, 
glucose, urate, calcium, phosphate, and magnesium. A local bone marrow aspirate and biopsy for morphology, cytogenetics, and flow cytometry should be done 
if clinically indicated. 
e To follow organ function and detect relapse. 
f A pregnancy test will be performed only for female patients of childbearing potential according to local standard of care. At initiation of therapy, the results 
must be negative within 3 days before the first dose of ponatinib is administered. Monthly pregnancy testing (urine or serum) will be performed according to 
local standard of care while patient is on ponatinib continuation therapy. 
g Height and weight needed to assess growth. 
h The neurological assessment can be performed by the pediatric oncologist and includes the Modified “Balis” Pediatric Scale for peripheral neuropathy. 
i The neurological assessment should be performed once a month during continuation therapy. 
j Growth charts and Tanner staging will be used for growth and development assessments. Other tests may be needed as clinically indicated. 
k ECGs must all be 12-lead ECGs. 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. On days when both an ECG and a blood draw is performed, the ECG should be done before the blood draw. During 
the optional ponatinib continuation therapy, ECGs may be performed more frequently if clinically indicated. During follow-up, ECGs will be performed yearly 
until the end of study follow-up. 
l During the optional continuation therapy, ECHOs or MUGAs may be performed more frequently if clinically indicated. During follow-up, ECHO or MUGA 
will be performed yearly until the end of study follow-up. 
m Lumbar puncture for cell count and cytospin cytology to be performed every 3 months while the patient is receiving optional continuation combination 
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Table 2 
Schedule of Events for Ponatinib 
28-Day Cycles 
Optional Continuation Regimen 
EOT2 a 
Follow-up b 
Cycle Days 
1 c 
Every 3 Months 
30-40 Days After 
Last Dose 
 
Window (days) 
±3 
±7 
 
±14 
therapy with intrathecal chemotherapy. 
n Submission of peripheral blood samples to central laboratory to assess molecular mutations including T315I (eg, BCR-ABL1, IKZF1, CDKN2A/2B) if relapse 
from complete remission is reported by the investigator. 
o Administration of study treatment will also include diary review and study treatment verification. Ponatinib will be administered once daily. See Table 6 for 
details of recommended combination regimen for optional ponatinib continuation therapy. Patients may receive ponatinib as monotherapy or in combination 
with maintenance-type chemotherapy until more definitive therapy is initiated. 
p Bone marrow and other pertinent investigations are to be performed as clinically indicated. If relapse from complete remission is confirmed, results of the 
assessments used to confirm the relapse, including bone marrow assessment, and their date must be provided in the electronic data capture. 
 
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CONFIDENTIAL 
Table 3 
Phase 1 PK Sampling Schedule 
Blood samples will be collected from all patients for the measurement of plasma concentrations of ponatinib. A sparser PK sampling 
schedule will be used for patients weighing <20 kg because of potential blood volume loss limitations. The exact date and time of each 
PK sample collection should be recorded in the eCRF. 
Note: If ponatinib is not administered on Day 22 of the reinduction block, then the Day 22 and Day 23 PK samples should be collected 
on the next ponatinib dosing day. 
Time Point 
Reinduction Block 
Day 1 
Reinduction Block 
Day 2 
Reinduction Block 
Day 22 
Reinduction Block 
Day 23 
For Patients <20 kg 
Predose (within 1 hour prior to dosing) 
 
 
X 
 
2 hours postdose (±15 minutes) 
 
 
X 
 
4 hours postdose (±15 minutes) 
X 
 
 
 
6 hours postdose (±15 minutes) 
 
 
X 
 
24 hours postdose (±1 hour) 
 
X a 
 
X a 
For Patients ≥20 kg 
Predose (within 1 hour prior to dosing) 
 
 
X 
 
1 hour postdose (±10 minutes) 
X 
 
X 
 
2 hours postdose (±15 minutes) 
X 
 
X 
 
4 hours postdose (±15 minutes) 
X 
 
X 
 
6 hours postdose (±15 minutes) 
X 
 
X 
 
8 hours postdose (±30 minutes) 
X 
 
X 
 
24 hours postdose (±1 hour) 
 
X a 
 
X a 
PK: pharmacokinetic. 
a The 24 hours postdose sample should be collected prior to the Day 2 or Day 23 dose of ponatinib. 
 
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CONFIDENTIAL 
Table 4 
Phase 2 PK Sampling Schedule 
Blood samples will be collected from all patients for the measurement of plasma concentrations of ponatinib. A sparser PK sampling 
schedule will be used for patients weighing <20 kg because of potential blood volume loss limitations. The exact date and time of each 
PK sample collection should be recorded in the eCRF. 
Note: If ponatinib is not administered on Day 22 of the reinduction block, then the Day 22 PK samples should be collected on the next 
ponatinib dosing day. 
Time Point 
Reinduction Block 
Day 1 
Reinduction Block 
Day 2 
Reinduction Block 
Day 22 
For Patients <20 kg 
Predose (within 1 hour prior to dosing) 
 
 
X 
1 to 2 hours postdose 
X 
 
 
3 to 4 hours postdose 
 
 
X 
6 to 8 hours postdose 
X 
 
X 
24 hours postdose (±1 hour) 
 
X a 
 
For Patients ≥20 kg 
Predose (within 1 hour prior to dosing) 
 
 
X 
1 to 2 hours postdose 
X 
 
X 
3 to 4 hours postdose 
X 
 
X 
6 to 8 hours postdose 
X 
 
X 
24 hours postdose (±1 hour) 
 
X a 
 
PK: pharmacokinetic. 
a The 24 hours postdose sample should be collected prior to the Day 2 dose of ponatinib. 
 
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CONFIDENTIAL 
 
Table 5 
Schedule of Drugs 
Days 
1 
2 
3 
5 
8 
9 
15 
19 
22 
29 
35 
Reinduction Block 
 
 
 
 
 
 
 
 
 
 
Ponatinib PO a 
 
 
 
 
 
 
 
 
 
 
 
Vincristine IV (1.5 mg/m2) b 
X 
 
 
 
X 
 
X 
 
X 
Bone 
marrow 
 
Dexamethasone PO/IV (10 mg/m2) c 
 
 
 
 
 
 
 
 
 
 
PEG-asparaginase IV/IM (2500 IU/m2) d 
 
X 
 
 
 
 
 
 
 
 
Daunorubicin IV (30 mg/m2) e 
X 
X 
 
 
 
 
 
 
 
 
CNS-1/2: IT methotrexate chemotherapy g 
X f 
 
 
 
 
 
X 
 
 
X 
 
CNS-3: ITT chemotherapy h 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Consolidation Block i 
 
 
 
 
 
 
 
 
 
 
Ponatinib PO a 
 
 
 
 
 
 
 
 
 
 
 
Dexamethasone PO/IV (6 mg/m2) j 
 
 
 
 
 
 
 
 
 
Bone 
marrow 
 
Vincristine IV (1.5 mg/m2) b 
 
 
X 
 
 
 
 
 
 
 
Methotrexate IV (1000 mg/m2) k 
 
 
 
 
X 
 
 
 
 
 
PEG-asparaginase IV/IM (2500 IU/m2) l 
 
 
 
 
 
X 
 
 
 
 
Cyclophosphamide IV (440 mg/m2) m 
 
 
 
 
 
 
 
 
 
 
Etoposide IV (100 mg/m2) n 
 
 
 
 
 
 
 
 
 
 
CNS-1/2: IT methotrexate chemotherapy g 
 
 
 
 
X 
 
 
 
 
 
 
CNS-3: ITT chemotherapy h 
 
 
 
 
X 
 
 
 
 
 
 
ANC: absolute neutrophil count; BID: twice daily; CNS: central nervous system; IM: intramuscularly; IT: intrathecal (therapy); ITT: triple intrathecal 
(therapy); IU: international units; IV: intravenous(ly); PEG: polyethylene glycol; PO: orally (by mouth); RP2D: recommended phase 2 dose. 
a Dose assigned per protocol: In phase 1, dose is as described in Table 8.a; in phase 2, dose is RP2D. 
b IV push over 1 minute or infusion via minibag as per institutional policy. Maximum dose is 2 mg. 
c 10 mg/m2/day divided BID, ie, 5 mg/m2/dose BID. 
d IV over 1 to 2 hours or IM. In cases where PEG-asparaginase is not available or where patients are allergic to PEG-asparaginase, Erwinia-asparaginase can 
be used as an alternative. If there are supply issues with PEG-asparaginase at the site, the dosing of PEG-asparaginase can occur within 4 days of due date. 
e IV over 15 minutes. 
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Table 5 
Schedule of Drugs 
f May omit initial IT chemotherapy on Day 1 if patient received IT chemotherapy within 7 days before study enrollment as part of diagnostic lumbar puncture 
procedure. 
g IT methotrexate is for CNS-1/2 patients only. Dose is defined by age as follows: age 1 through 1.99 years: 8 mg; age 2 through 2.99 years: 10 mg; age 3 
through 8.99 years: 12 mg; age ≥9 years: 15 mg. 
h ITT chemotherapy is for CNS-3 patients only. Dose is defined by age in the following table: 
 
Age (years) 
Methotrexate 
Hydrocortisone 
Cytarabine 
 
1 – 1.99 
8 mg 
8 mg 
16 mg 
 
2 – 2.99 
10 mg 
10 mg 
20 mg 
 
3 – 8.99 
12 mg 
12 mg 
24 mg 
 
≥9 
15 mg 
15 mg 
30 mg 
i To start the consolidation block, the following criteria must be met: ANC ≥750/µL, platelets ≥50,000/µL (untransfused) (van Veen et al. 2010), and toxicity 
considered to be related to treatment with ponatinib must have resolved to Grade 1 or baseline or to a level considered acceptable by the physician. 
j 6 mg/m2/day divided BID, ie, 3 mg/m2/dose BID. 
k Intermediate-dose methotrexate administered IV over 36 hours. The 1000 mg/m2/dose should be given as a 100 mg/m2 bolus over 30 minutes followed by 
900 mg/m2 over 35.5 hours. Note: Be certain that the methotrexate infusion is completed in the 36-hour period. See Table 8.c for IV hydration and leucovorin 
rescue therapy. 
l IV over 1 to 2 hours or IM on Day 9 or 10; administer 4 hours after completion of Day 8 IV methotrexate. In cases where PEG-asparaginase is not available 
or where patients are allergic to PEG-asparaginase, Erwinia-asparaginase may be given IM/IV on Monday/Wednesday/Friday (or every other day per 
institutional standard) × up to 6 doses for each dose of PEG-asparaginase at 25,000 IU/m2/dose.  
m IV over 15-30 minutes. 
n IV over 1-2 hours. 
 
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Table 6 
Optional Continuation Therapy With Ponatinib: Recommended Combination Regimen Following Consolidation 
Therapeutic Agent 
Days/Frequency 
Ponatinib 
Daily 
Vincristine 
Every 4 weeks 
Dexamethasone or prednisone 
5 days every 4 weeks 
Mercaptopurine 
Daily 
Methotrexate (PO) 
Once a week 
Methotrexate (IT) 
Once every 3 months 
IT: intrathecal; PO: by mouth (orally). 
 
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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 investigator agrees to assume the following responsibilities: 
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 (nonroutine/nonstandard 
panel) screening assessments, are NOT performed on potential patients 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 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 patients. 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 ICH and local regulations, are 
met. 
9. Obtain valid informed consent from each patient who participates in the study, and document 
the date of consent in the patient’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 patient’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 patient or the patient’s parent or legal guardian. 
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 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
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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. 
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 the 
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. 
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Appendix E Acceptability and Palatability Questionnaire for the Ponatinib AAF 
(Reinduction Only) 
Acceptability/Palatability Questionnaire for Ponatinib AAF (Reinduction only) 
Patient ID #: _______________ 
Date: __________________ 
Dose Day: Day 1____ Day 8____ Day 15____ Day 22____ 
Who completed the form? Parent/Guardian____ Child____ 
1. How was ponatinib AAF administered?  
____ Whole minitablet capsule(s) with water 
____ Opened capsule with minitablets sprinkled on applesauce 
____ Opened capsule with minitablets sprinkled on yogurt 
2. Did you (or your child) swallow the dose? Yes____ No____ 
3. What do you think of the smell? 
 
1 
2 
3 
4 
5 
4. What do you think of the taste?  
 
1 
2 
3 
4 
5 
5. Any aftertaste?  Yes____ No____ 
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6. How easy is it for you (your child) to take ponatinib? 
 
1 
2 
3 
4 
5 
7. How easy is it to take other oral medications? 
 
1 
2 
3 
4 
5 
 
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Appendix F Tanner Scale 
Criteria for Distinguishing Tanner Stages 1 to 5 During Female Pubertal Maturation 
Stage 
Breast 
Pubic Hair 
1 (prepubertal) 
No palpable glandular tissue or pigmentation of areola; 
elevation of areola only 
No pubic hair; short, fine vellus hair 
only 
2 
Glandular tissue palpable with elevation of breast and 
areola together as a small mound; areolar diameter 
increased 
Sparse, long, pigmented terminal 
hair chiefly along the labia majora 
3 
Further enlargement without separation of breast and 
areola; although more darkly pigmented, areola still pale 
and immature; nipple generally at or above midplane of 
breast tissue when individual is seated upright 
Dark, coarse, curly hair, extending 
sparsely over mons 
4 
Secondary mound of areola and papilla above breast 
Adult-type hair, abundant but 
limited to mons and labia 
5 (adult) 
Recession of areola to contour of breast; development of 
Montgomery’s glands and ducts on areola; further 
pigmentation of areola; nipple generally below midplane 
of breast tissue when individual is seated upright; 
maturation independent of breast size 
Adult-type hair in quantity and 
distribution; spread to inner aspects 
of the thighs in most racial groups 
Source: Data from Ross GT: Disorders of the ovary and female reproductive tract. In Wilson JD, Foster DW (eds): 
Textbook of Endocrinology, 7th ed. Philadelphia, WB Saunders, 1985, p 206. 
 
Criteria for Distinguishing Tanner Stages 1 to 5 During Pubertal Stages in Boys 
Stage 
Pubic Hair 
Genital 
1 
Absence of pubic hair 
Childlike penis, testes, and scrotum (testes 2 mL) 
2 
Sparse, lightly pigmented hair mainly at the 
base of the penis 
Scrotum enlarged with early rugation and pigmentation; 
testes begin to enlarge (3–5 mL) 
3 
Hair becomes coarse, darker, and more curled 
and more extensive 
Penis has grown in length and diameter; testes now 8–10 
mL; scrotum more rugated 
4 
Hair adult in quality, but distribution does not 
include medial aspect of thighs 
Penis further enlarged with development of the glans; 
scrotum and testes (10–13 mL) further enlarged 
5 
Hair is adult and extends to thighs 
Penis and scrotum fully adult; testes 15 mL and greater 
Source: Modified from Marshall WA, Tanner JM: Variation in pattern of pubertal changes in boys. Arch Dis Child 
1970;45:13–23. 
 
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Appendix G Definition of CNS- 1/2/3 in CSF  
CNS-1: In CSF, absence of blasts on cytospin preparation, regardless of the number of WBCs.  
CNS-2: In CSF, presence <5/µL WBCs and cytospin positive for blasts, or ≥5/µL WBCs but 
negative by Steinherz/Bleyer^ algorithm in traumatic lumbar punctures. 
CNS-3: In CSF, presence of ≥5/μL WBCs and cytospin positive for blasts and/or clinical signs of 
CNS leukemia. 
Method of Evaluating Initial Traumatic Lumbar Punctures:  
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and 
contains ≥5 WBC/µL and blasts, the following algorithm should be used to distinguish between 
CNS-2 and CNS-3 disease: 
If CSF WBC ÷ CSF RBC >2 × blood WBC ÷ blood RBC, then patient has CNS-3 disease  
If CSF WBC ÷ CSF RBC <2 × blood WBC ÷ blood RBC, then patient has CNS-2 disease  
Example: CSF WBC = 60/μL; CSF RBC = 1500/μL; blood WBC = 46000/μL; blood RBC = 
3.0 × 106/μL: 0.04 >2× 0.015: Patient has CNS-3 disease. 
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Appendix H Protocol History 
Date 
Amendment Number 
Amendment Type  
Region 
02 November 2023 
Amendment 4 
Substantial 
Global 
23 May 2023 
Amendment 3 
Substantial 
Global 
23 February 2021 
Amendment 2 
Substantial 
Global 
09 April 2020 
Amendment 1 
Substantial 
Global 
25 July 2019 
Initial Protocol 
Not applicable 
Global 
 
Protocol Amendment 3 Summary and Rationale: 
This section describes the changes to the protocol incorporating Amendment 3. The primary 
reasons for this amendment are to: 
• Modify inclusion Criterion 1 and exclusion Criterion 3 relating to diagnosis to allow globally 
the inclusion of patients with Philadelphia chromosome–like acute lymphoblastic leukemia 
(Ph-like ALL). Patients with Ph-like ALL will not be included in efficacy analyses. 
• Define the second cohort (cohort 2) of the phase 1 portion of the study, including information 
on the composition of each weight group and the ponatinib dose assignment. 
• Revise the disease assessment at end of reinduction and consolidation blocks to add a visit at 
Day 35 (±3) for hematology assessment (for recovery of platelets and neutrophils). 
• Include administration and dosing information for the age-appropriate formulation that is 
now available. 
• Modify the medical management of elevated alanine aminotransferase. 
• Clarify the definition for dose-limiting toxicities (DLT) for liver toxicities given the liver 
toxicities observed in phase 1 cohort 1. 
In addition, the protocol was updated to: 
• Change a secondary objective (“to characterize BCR-ABL1 domain mutations both prior to 
and following ponatinib treatment”) to an exploratory objective and update the corresponding 
endpoint and analyses of molecular mutations to be performed. 
• Divide a secondary objective (“to describe the proportion of patients in continued complete 
remission (CR) or who achieve CR at the end of consolidation and the proportion of patients 
with minimal residual disease (MRD) status <0.01% at the end of each treatment block”) into 
2 objectives for clarity. 
• Revise the optional ponatinib continuation to extend beyond 12 months under specified 
conditions, remove the optional continuation phase monthly Day 14 visit, and add an 
investigator’s assessment of disease at the second end of treatment (EOT2) visit. 
• Provide information on clinical experience for phase 1 cohort 1. 
• Add the possibility that some study-related activities may be performed remotely. 
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• Correct in the schedule of events (SOEs) on which days the study treatment is administered. 
• Provide additional guidance to sites regarding: enrollment under T315I mutation eligibility 
criterion; method of disease diagnosis in patients with Ph-like ALL; study treatment; use of 
concomitant medications; mandatory/non-mandatory hepatitis testing and HIV testing; nature 
of bone marrow (BM) samples (aspirate and/or biopsy); timing of complete blood cell count 
and BM evaluation for CR assessment; timing of peripheral blood samples for molecular 
mutations during follow-up; results of the assessments used to confirm the relapse from CR 
and completed as clinically indicated; necessity to perform a complete blood cell count; 
chemistry parameters to be assessed; testing of baseline samples; threshold of platelet counts 
to start the consolidation block or optional continuation therapy; assessment of adverse event 
(AE) relationship; hospitalization or surgical procedures not considered as AEs; SAE follow-
up; reporting of drug exposure during pregnancy and birth events; method to assess the left 
ejection fraction; samples of BM not to be centrally assessed; patient population to be 
administered the palatability questionnaire; management of nonhematologic treatment-
related toxicities; frequency of follow-up visits for patients eligible to receive optional 
ponatinib continuation treatment; and timings of pharmacokinetic sample collection. 
• Clarify that the required number of patients in phase 1 of the study corresponds to DLT-
evaluable patients. 
• Clarify that patients with Ph-like ALL and Philadelphia chromosome-positive mixed 
phenotype acute leukemia will not be included in efficacy analyses. 
• Update the definition of progression-free survival event for death. 
• Correct or clarify the patients’ age for Karnofsky performance status scale and Lansky play 
scale. 
• Clarify that lumbar puncture for cell count and cytospin cytology is to be conducted while 
patient is receiving optional ponatinib continuation therapy if done in combination with 
intrathecal chemotherapy. 
In this amendment, minor grammatical, editorial, formatting (including bibliographic references 
format), and administrative changes not affecting the conduct of the study are included for 
clarification and administrative purposes only and may not be listed in the summary of changes 
below. 
Protocol Amendment 3 
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. 
 Throughout the document. 
Changed “caregivers” to 
“parents/legal guardians”. 
Administrative change for consistency 
across the document. 
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Protocol Amendment 3 
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 1.1 Contacts 
Added text with regards to 
contact information. 
To provide additional guidance to sites, 
consistently with the sponsor protocol 
template. 
3. 
 Section 1.2 Approval  
Updated the list of 
approvers. 
Administrative change. 
4. 
 Section 4.1.3 Ponatinib 
Nonclinical Data 
Removed the investigator’s 
brochure version and the 
section number of the 
investigator’s brochure. 
Administrative change: the investigator’s 
brochure being updated each year, 
version and section numbers may not be 
up-to-date. 
5. 
 Section 4.2.4.1 Cohort 1 of 
the Phase 1 Portion of the 
Study 
Revised to provide dosing 
information for pediatric 
patients <30 kg due to 
availability of the AAF. 
The AAF is available for use as of 
protocol amendment 3. 
6. 
 Section 2.0 STUDY 
SUMMARY (and 
Figure 2.a) 
Section 4.2.4.1 Cohort 1 of 
the Phase 1 Portion of the 
Study 
Section 6.1 Overview of 
Study Design (and 
Figure 6.a) 
Section 7.0 STUDY 
POPULATION 
Section 8.1.1 
Investigational Therapy: 
Ponatinib 
Section 8.1.2 Study 
Treatment Regimen 
Section 8.12.1 Ponatinib 
Tablets 
Modified language and 
updated study design 
schema as enrollment to 
cohort 1 of the phase 1 
portion of the study is 
completed. 
To update the section and indicate 
phase 1 cohort 1 status. 
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Protocol Amendment 3 
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 
7. 
 Section 2.0 STUDY 
SUMMARY (and 
Figure 2.a, Table 2.a) 
Section 4.2.4.2 Safety Data 
from Cohort 1 of the Phase 
1 Portion of the Study 
Section 4.2.4.3 Cohort 2 of 
the Phase 1 Portion of the 
Study 
Section 6.1 Overview of 
Study Design (and 
Figure 6.a) 
Section 7.0 STUDY 
POPULATION 
Section 8.1.1 
Investigational Therapy: 
Ponatinib 
Section 8.1.2 Study 
Treatment Regimen (and 
Table 8.a) 
Section 8.4.2.4 Dose Re-
escalation After Resolution 
of Adverse Drug Reactions 
Section 8.10 Description of 
Investigational Agents 
Section 8.11 Preparation, 
Reconstitution, and 
Dispensation 
Section 8.12.2 Ponatinib 
Age-Appropriate 
Formulation (AAF) 
Section 8.13.2 Handling 
and Accountability 
Added 2 new sections 
(Sections 4.2.4.2 and 
4.2.4.3). 
Added clinical experience 
from phase 1 cohort 1. 
Added rationale and text 
relative to the opening of 
second cohort (cohort 2) to 
the phase 1 portion of the 
study. 
Included the minimum 
number of patients in each 
weight group in phase 1 
cohort 2, and related 
requirements with regards 
to patients’ age and weight. 
Modified text related to the 
AAF that is now available. 
Provided further 
information on the AAF 
and the doses for phase 1 
cohort 2. 
Modified study design 
schema: 
• 
Changed “to confirm 
RP2D for 
2 formulations” to “to 
confirm RP2D” in 
phase 1 box. 
• 
Removed arrow 
between phase 1 box 
and phase 2 box. 
• 
Added that enrollment 
to phase 1 cohort 1 is 
complete. 
• 
Added phase 1 
cohort 2. 
To indicate phase 1 cohort 1 status, add 
information related to phase 1 cohort 2 
and clarify. 
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Protocol Amendment 3 
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 
8. 
 Section 4.3 Age-
Appropriate Formulation 
for Ponatinib 
Added a new section with 
conclusions of Study INCB 
84344-103 that assessed the 
relative bioavailability of 
the AAF versus the tablet 
formulation. 
To provide information regarding the 
relative bioavailability of the AAF versus 
the tablet formulation to support use of 
the AAF in this pediatric study. 
9. 
 Section 2.0 STUDY 
SUMMARY 
Section 5.1.2.1 Phase 1 
Secondary Objectives 
Section 5.1.2.2 Phase 2 
Secondary Objectives 
Section 5.1.3 Exploratory 
Objectives 
Changed a secondary 
objective (“to characterize 
BCR-ABL1 domain 
mutations both prior to and 
following ponatinib 
treatment”) to an 
exploratory objective (“Ph+ 
ALL only: To characterize 
biomarkers of sensitivity 
and resistance to ponatinib-
containing therapy, which 
may include molecular 
mutations (eg, BCR-ABL1, 
IKZF1, CDKN2A/2B) in 
samples both prior to and 
following ponatinib 
treatment”). 
Clarified that this objective 
is only for patients with 
Philadelphia chromosome-
positive acute 
lymphoblastic leukemia 
(Ph+ ALL). 
To allow flexibility with the sites, to 
prioritize the samples for MRD 
assessment, and to broaden the analyses 
of molecular mutations. 
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Protocol Amendment 3 
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 
10. 
 Section 2.0 STUDY 
SUMMARY 
Section 5.1.2.2 Phase 2 
Secondary Objectives 
Divided the secondary 
objective relating to CR 
and MRD (“to describe the 
proportion of patients in 
continued CR or who 
achieve CR at the end of 
consolidation and the 
proportion of patients with 
MRD status <0.01% at the 
end of each treatment 
block”) into 2 objectives to 
clarify the assessment 
based on patients’ CR 
status. (“to describe the 
proportion of patients who 
achieved CR at the end of 
consolidation” and “to 
describe the proportion of 
patients with MRD status 
<0.01% among those who 
achieved CR at the end of 
each treatment block”)  
To clarify. 
11. 
 Section 2.0 STUDY 
SUMMARY 
Section 5.1.2.2 Phase 2 
Secondary Objectives 
Appendix A, Schedules of 
Events (Table 1 and 
Table 2) 
Clarified that the secondary 
objectives relating to CR 
and MRD are only for 
patients with Ph+ ALL. 
To clarify as MRD cannot be followed 
for patients with Ph-like ALL or MPAL 
due to heterogeneity of underlying 
molecular mutations and challenges in 
finding assays for them with adequate 
sensitivity. 
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Protocol Amendment 3 
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 2.0 STUDY 
SUMMARY 
Section 5.2.2.1 Phase 1 
Secondary Endpoints 
Section 5.2.2.2 Phase 2 
Secondary Endpoints 
Section 5.2.3 Exploratory 
Endpoints 
Section 9.3.15 Biomarkers 
and Pharmacokinetic 
Measurements 
Section 9.3.15.2 Peripheral 
Blood Samples for 
Molecular Mutations 
Appendix A, Schedules of 
Events (Table 1 and 
Table 2) 
Grouped a secondary 
endpoint (“characterization 
of BCR-ABL1 domain 
mutations both prior to and 
following ponatinib 
treatment”) and an 
exploratory endpoint 
(“biomarkers of disease 
sensitivity and resistance to 
ponatinib and/or 
biomarkers affecting 
ponatinib”) into a single 
exploratory endpoint (“Ph+ 
ALL only: Biomarkers of 
potential sensitivity and 
resistance to ponatinib-
containing therapy, which 
may include molecular 
mutations (eg, BCR-ABL1, 
IKZF1, CDKN2A/2B) in 
samples both prior and 
following ponatinib 
treatment”). 
Clarified that this endpoint 
is only for patients with 
Ph+ ALL. 
Updated the intended use of 
blood samples for 
molecular mutations at 
screening and clarify these 
analyses are only for 
patients with Ph+ ALL 
(including Table 9.a). 
To allow flexibility with the sites, to 
prioritize the samples for MRD 
assessment, and to broaden the analyses 
of molecular mutations. 
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Protocol Amendment 3 
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 
13. 
 Section 2.0 STUDY 
SUMMARY 
Section 5.2.2.2 Phase 2 
Secondary Endpoints 
Section 6.3.3 Timeframes 
for Primary and Secondary 
Endpoints to Support 
Disclosures (Table 6.a) 
Divided the secondary 
endpoint relating to CR and 
MRD (“proportion of 
patients in continued CR or 
who achieve CR at the end 
of consolidation and the 
proportion of patients with 
MRD negative status 
(<0.01%) at the end of each 
treatment block”) into 
2 endpoints to clarify the 
assessments based on the 
patients’ CR status 
(“proportion of patients 
who achieved CR at the end 
of consolidation” and 
“proportion of patients with 
MRD negative status 
(<0.01%) among those who 
achieved CR at the end of 
each treatment block”). 
To clarify. 
14. 
 Section 2.0 STUDY 
SUMMARY 
Section 5.2.2.2 Phase 2 
Secondary Endpoints 
Section 6.3.3 Timeframes 
for Primary and Secondary 
Endpoints to Support 
Disclosures (Table 6.a) 
Section 9.3.15 Biomarkers 
and Pharmacokinetic 
Measurements (Table 9.a) 
Section 9.3.15.1 Bone 
Marrow Samples for MRD 
Assessment 
Section 13.1.3.3 Definitions 
of Response Criteria 
(Table 13.a) 
Appendix A, Schedules of 
Events (Table 1) 
Clarified that the secondary 
endpoints relating to CR 
and MRD are only for 
patients with Ph+ ALL. 
To clarify as MRD will not be followed 
for patients with Ph-like ALL or MPAL. 
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CONFIDENTIAL 
Protocol Amendment 3 
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 
15. 
 Section 2.0 STUDY 
SUMMARY (Figure 2.a) 
Section 6.1 Overview of 
Study Design (Figure 6.a) 
Appendix A, Schedules of 
Events (Table 1) 
Added 1 visit at Day 35 
(±3) of both the reinduction 
and consolidation blocks 
for assessment of platelets 
and neutrophils recovery. 
Added the other following 
events for these additional 
visits: concomitant 
medications and 
procedures, AE reporting, 
and administration of study 
treatment. 
Updated the study design 
schema: disease assessment 
at Day 35 instead of Day 29 
of both the reinduction 
block and the consolidation 
block. 
To assess the disease at a more 
appropriate timing for peripheral counts 
recovery. 
To update the schedule of events and the 
study design schema for the additional 
visits. 
16. 
 Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview of 
Study Design 
Section 7.0 STUDY 
POPULATION 
Section 7.1 Inclusion 
Criteria (inclusion 
Criterion 1) 
Section 7.2 Exclusion 
Criteria (exclusion 
Criterion 3) 
Deleted “United States 
(US) only”. 
To include patients with Ph-like ALL 
globally, based on a specific molecular 
definition, as these patients will most 
likely benefit from ponatinib treatment. 
17. 
 Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview of 
Study Design 
Section 8.1.2 Study 
Treatment Regimen 
Added the minimum of 
DLT-evaluable patients in 
each weight group of 
phase 1 cohort 2 and added 
the maximum number of 
patients >16 years of age in 
each weight group. 
Grouped information on 
design, DLTs, and cohorts 
in Section 6.1 (and deleted 
them from Section 8.1.2). 
To provide information on the 
composition of each weight group. 
To clarify. 
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CONFIDENTIAL 
Protocol Amendment 3 
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 
18. 
 Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview of 
Study Design 
Section 13.1.1 Analysis 
Sets 
Updated/added the 
definition of DLT-
evaluable population and 
clarified the replacement of 
patients who are not 
evaluable for DLT 
(indicated in Section 6.2). 
To take into account the percentage of 
planned dosing to be received for a 
patient to be included in the DLT-
evaluable population and to clarify. 
19. 
 Section 2.0 STUDY 
SUMMARY (and 
Figure 2.a) 
Section 6.1 Overview of 
Study Design (and 
Figure 6.a) 
Clarified which study 
treatment (ponatinib and 
chemotherapy or ponatinib 
alone) is given. 
To clarify that for each treatment block, 
treatment with ponatinib and 
chemotherapy for 29 days is followed by 
a chemotherapy rest period. 
20. 
 Section 2.0 STUDY 
SUMMARY (and 
Figure 2.a) 
Section 6.1 Overview of 
Study Design (and 
Figure 6.a) 
Section 6.3.1 Duration of 
an Individual Patient’s 
Study Participation 
Clarified the extension of 
the optional continuation 
treatment with ponatinib 
beyond 12 months if 
patients continue deriving 
clinical benefit. 
To clarify that the intention was to allow 
flexibility, under the protocol, to permit 
patients who continue to benefit from 
treatment to continue to receive treatment 
under the study after 12 months. 
21. 
 Section 6.1 Overview of 
Study Design 
Appendix A, Schedules of 
Events (Table 1) 
Section 8.1.1.2 Age-
Appropriate Formulation 
Clarified that the 
palatability questionnaire of 
ponatinib is for AAF only. 
To provide additional guidance to sites. 
22. 
 Section 6.1 Overview of 
Study Design 
Section 9.3.14.1 Evaluation 
of CR 
Section 13.1.3.3 Definitions 
of Response Criteria 
(Table 13.a) 
Appendix A, Schedules of 
Events (Table 1) 
Changed “bone marrow 
aspirate” to “bone marrow 
sample (aspirate and/or 
biopsy). 
To provide additional guidance to sites, 
ie when BM aspirate cannot be obtained, 
a BM biopsy can be used. 
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02 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 3 
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 
23. 
 Section 2.0 STUDY 
SUMMARY 
Section 6.2 Number of 
Patients 
Clarified that the required 
number of patients in 
phase 1 of the study 
(approximately 18 patients) 
corresponds to DLT-
evaluable patients. 
Clarified the replacement of 
patients withdrawn from 
treatment during the 
reinduction block. 
To clarify. 
24. 
 Section 6.3.1 Duration of 
an Individual Patient’s 
Study Participation 
Clarified when the EOT1 
visit should be performed. 
To clarify. 
25. 
 Section 6.3.3 Timeframes 
for Primary and Secondary 
Endpoints to Support 
Disclosures (Table 6.a) 
Deleted “BCR-ABL1 
domain mutations” rows 
(secondary endpoint). 
To modify in accordance with the change 
of secondary to exploratory endpoint. 
26. 
 Section 6.3.3 Timeframes 
for Primary and Secondary 
Endpoints to Support 
Disclosures (Table 6.a) 
Section 13.1.3.3 Definitions 
of Response Criteria 
(Table 13.a) 
Updated the definition of 
death used for progression-
free survival endpoint: 
“death due to any cause” to 
“death related to disease 
under study”. 
To clarify the events that are progression 
of disease and to not count deaths due to 
other causes, instead these will be 
censored (different from event-free 
survival events). 
27. 
 Section 6.3.3 Timeframes 
for Primary and Secondary 
Endpoints to Support 
Disclosures (Table 6.a) 
Clarified that for disease 
progression definition, the 
increase of at least 25% in 
the absolute number of 
circulating or BM blasts or 
development of new 
extramedullary disease is 
an increase from baseline. 
To clarify. 
28. 
 Section 2.0 STUDY 
SUMMARY 
Section 7.0 STUDY 
POPULATION 
Section 7.1 Inclusion 
Criteria (inclusion 
Criterion 2) 
Added minimum weight in 
the age inclusion criterion. 
To provide guidance to sites with regards 
to the patients’ minimum weight. 
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CONFIDENTIAL 
Protocol Amendment 3 
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 
29. 
 Section 2.0 STUDY 
SUMMARY 
Section 7.0 STUDY 
POPULATION 
Clarified that patients must 
have BM involvement to be 
eligible. 
To clarify. 
30. 
 Section 2.0 STUDY 
SUMMARY 
Section 7.1 Inclusion 
Criteria (inclusion 
Criterion 1c)ii)) 
Updated phase 1 eligibility 
criteria at the time of 
enrollment prior to 
availability of the AAF as 
the formulation is now 
available. 
Added phase 1 eligibility 
criteria at the time of 
enrollment for patients to 
be administered ponatinib 
as the AAF. 
To update as the AAF is now available. 
31. 
 Section 2.0 STUDY 
SUMMARY 
Section 7.1 Inclusion 
Criteria (inclusion 
Criterion 1b)ii)) 
Section 9.3.1 Screening 
Period Procedures 
Added that RNA 
sequencing or alternative 
accredited method is 
required to identify 
specified targetable kinase-
activating lesions for the 
diagnosis of the disease in 
patients with Ph-like ALL, 
and that no confirmation by 
a sponsor central laboratory 
is required. 
To provide guidance to sites with regards 
to Ph-like diagnosis for enrollment in the 
study. 
32. 
 Section 2.0 STUDY 
SUMMARY 
Section 7.1 Inclusion 
Criteria (inclusion 
Criterion 1c)) 
Clarified that the last 
2 numbered items relate to 
disease status by adding a 
sub-criterion heading 
(“disease status”). 
To clarify. 
33. 
 Section 2.0 STUDY 
SUMMARY 
Section 7.0 STUDY 
POPULATION 
Section 7.1 Inclusion 
Criteria (inclusion 
Criterion 1c)ii)) 
Added information on the 
confirmation of T315I 
mutation eligibility 
criterion. 
To clarify that for patients enrolled under 
T315I mutation eligibility criterion, the 
mutation needs to be confirmed by the 
central laboratory, and to provide 
additional guidance to sites. 
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CONFIDENTIAL 
Protocol Amendment 3 
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 
34. 
 Section 2.0 STUDY 
SUMMARY 
Section 7.1 Inclusion 
Criteria (inclusion 
Criterion 1) 
Section 9.3.11 Adverse 
Events 
Deleted “at least possibly” 
in “at least possibly 
related” as it was clarified 
in Section 10.1.2 that AE 
relationship should be 
assessed as related or not 
related. 
To clarify. 
35. 
 Section 2.0 STUDY 
SUMMARY 
Section 7.1 Inclusion 
Criteria (inclusion 
Criterion 3) 
Section 9.3.6 Performance 
Status 
Appendix D, Performance 
Score Scales 
Corrected the inclusion of 
16 years old in the age 
threshold to use Karnofsky 
performance status scale or 
Lansky play scale. 
Clarified the patients’ age 
for Karnofsky performance 
status scale and Lansky 
play scale in Appendix D. 
To correct and to clarify. 
36. 
 Section 2.0 STUDY 
SUMMARY (Table 2.b) 
Section 7.1 Inclusion 
Criteria (Table 7.a) 
Added the source and 
method for determination 
of maximum serum 
creatinine value by age and 
sex. 
To provide source and method. 
37. 
 Section 2.0 STUDY 
SUMMARY (Table 2.c) 
Section 7.1 Inclusion 
Criteria (Table 7.b) 
Updated reference for 
Schwartz formula. 
To correct. 
38. 
 Section 2.0 STUDY 
SUMMARY 
Section 7.1 Inclusion 
Criteria (inclusion 
Criterion 8) 
Added that besides 
multigated acquisition scan, 
echocardiogram can be 
used to assess the left 
ejection fraction. 
To provide guidance to sites. 
39. 
 Section 8.1.1 
Investigational Therapy: 
Ponatinib 
Added that any change to 
the ponatinib 
administration schedule 
should be discussed with 
the sponsor’s medical 
monitor/designee. 
To clarify. 
40. 
 Section 2.0 STUDY 
SUMMARY 
Section 8.1.2 Study 
Treatment Regimen 
Updated ponatinib doses in 
the table to include dosing 
information for patients 
<30 kg due to availability 
of the AAF. 
To update ponatinib dosing information 
starting with cohort 2 in the phase 1 
portion of the study. 
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CONFIDENTIAL 
Protocol Amendment 3 
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 
41. 
 Section 8.1.2 Study 
Treatment Regimen 
(Table 8.b and Table 8.c) 
Section 8.3 Criteria for 
Beginning a Consolidation 
Block or Optional 
Continuation Therapy 
Appendix A, Schedules of 
Events (Table 5) 
Decreased the threshold of 
platelets counts from 
≥75,000/µL to 50,000/µL 
to start the consolidation 
block or optional 
continuation therapy. 
To avoid treatment delays, while 
maintaining safe thresholds of peripheral 
platelet counts. 
42. 
 Section 8.1.2 Study 
Treatment Regimen 
(Table 8.c) 
Section 8.4.3.7 
Intermediate-Dose 
Methotrexate Infusion 
Guidelines and Dose 
Modifications for Toxicity 
Clarified the meaning of 
“D5” (5% dextrose in 
water). 
To clarify. 
43. 
 Section 8.1.2 Study 
Treatment Regimen 
Corrected the ponatinib 
dose during optional 
continuation therapy and 
added information in case 
of dose reduction during 
consolidation block. 
To correct, as patients need to complete 
consolidation, and to provide additional 
guidance to sites. 
44. 
 Section 8.2 Definitions of 
Dose-limiting Toxicities 
Updated text relating to 
events related to ponatinib, 
ie, “probably”, “possibly”, 
and “definitely” removed. 
To clarify for consistency with data 
captured. 
45. 
 Section 8.2 Definitions of 
Dose-limiting Toxicities 
Revised definition of dose-
limiting toxicities. 
To align with definition in current early-
phase pediatric studies. 
46. 
 Section 8.3 Criteria for 
Beginning a Consolidation 
Block or Optional 
Continuation Therapy 
Section 8.4.2.1 
Nonhematologic 
Treatment-Related 
Toxicity: Ponatinib 
(Table 8.e) 
Increased thresholds for 
hepatic toxicity. 
To modify in accordance with current 
pediatric ALL protocols and in line with 
current pediatric oncology protocols. 
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Protocol Amendment 3 
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 
47. 
 Section 8.3 Criteria for 
Beginning a Consolidation 
Block or Optional 
Continuation Therapy 
Clarified study treatment 
discontinuation in case of 
treatment delay at a 
reduced level when further 
reductions are not 
permitted. 
To clarify and to provide additional 
guidance to sites. 
48. 
 Section 8.4.1 Early Safety 
Stopping Rules 
Modified the early safety 
stopping rule if ≥4 patients 
in the first 15 patients 
accrued develop Grade ≥3 
veno-occlusive event: it 
applies regardless of the 
presence or absence of a 
central vascular access 
device. 
To correct an error. 
49. 
 Section 8.4.2.1 
Nonhematologic 
Treatment-Related 
Toxicity: Ponatinib 
(Table 8.e) 
Modified medical 
management of 
nonhematologic treatment-
related toxicities 
(pancreatitis and elevation 
of lipase, and alanine 
aminotransferase 
elevation). 
To align with current early-phase 
pediatric studies and to provide 
additional guidance to sites. 
50. 
 Section 8.4.3.3.2 For Acute 
Neurotoxicity 
Clarified the meaning of 
“Ara-C” (cytarabine). 
To clarify. 
51. 
 Section 8.5 Excluded 
Concomitant Medications 
and Procedures 
To clarify the use of 
concomitant medications 
(medication that prolong 
the QT interval but are not 
associated with a known 
risk of torsades de pointes). 
To provide additional guidance to sites. 
52. 
 Section 9.3 Study 
Procedures 
Added “and Table 2” where 
it was missing. 
To correct as there are 2 SOEs in the 
protocol. 
53. 
 Section 9.3 Study 
Procedures 
Removed “Appendix A, 
Table 1” at several 
instances in the section and 
subsequent subsections. 
To avoid repetitions. 
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Protocol Amendment 3 
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 
54. 
 Section 9.3.13.5 Hepatitis B 
and C 
Appendix A, Schedules of 
Events (Table 1) 
Clarified mandatory/non-
mandatory hepatitis testing 
for countries with/without 
regulatory requirements for 
testing. 
To provide additional guidance to sites. 
55. 
 Section 9.3.13.6 HIV 
Appendix A, Schedules of 
Events (Table 1) 
Clarified mandatory/non-
mandatory HIV testing for 
countries with/without 
regulatory requirements for 
testing. 
To provide additional guidance to sites. 
56. 
 Section 9.3.14.1 Evaluation 
of CR 
Clarified that after EOT1, 
complete blood cell count 
and BM evaluation for CR 
assessment may be 
performed at other times 
than that indicated in 
Appendix A, Table 1. 
Update the section heading 
from “Bone Marrow 
Aspirate and 
Biopsy/Evaluation of CR” 
to “Evaluation of CR”. 
To provide additional guidance to sites. 
57. 
 Section 9.3.14.1 Evaluation 
of CR 
Appendix A, Schedules of 
Events (Table 1) 
Added that when relapse 
from CR is confirmed, 
results of the assessments 
used to confirm the relapse 
and their date must be 
provided in the electronic 
data capture. 
To provide additional guidance to sites. 
58. 
 Section 9.3.14.1 Evaluation 
of CR 
Section 13.1.3.3 Definitions 
of Response Criteria 
(Table 13.a) 
Appendix A, Schedules of 
Events (Table 1) 
Added the necessity of a 
complete blood cell count 
should also be performed if 
a BM sample is used for the 
diagnosis of recurrence. 
To provide additional guidance to sites. 
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Protocol Amendment 3 
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 
59. 
 Section 9.3.15 Biomarkers 
and Pharmacokinetic 
Measurements (Table 9.a) 
Added a row for peripheral 
blood sample to be 
collected at screening for 
MRD assessment if a BM 
blood sample cannot be 
obtained. 
To clarify, consistently with the 
schedules of events. 
60. 
 Section 9.3.15.2 Peripheral 
Blood Samples for 
Molecular Mutations 
Appendix A, Schedules of 
Events (Table 1) 
Added information on 
testing of baseline samples 
for patients requiring 
enrollment eligibility 
confirmation and other 
patients. 
To provide additional guidance to sites. 
61. 
 Section 9.3.17 Follow-up 
Assessments 
Appendix A, Schedules of 
Events (Table 1) 
Added that any disease 
assessments completed as 
clinically indicated need to 
be recorded in the 
electronic data capture. 
To clarify and provide additional 
guidance to sites. 
62. 
 Section 9.3.17 Follow-up 
Assessments 
Appendix A, Schedules of 
Events (Table 1 and 
Table 2) 
Added the possibility of 
remote contacts for the 
scheduled long-term 
follow-up, and defined a 
patient lost to follow-up 
and a patient documented 
as lost to follow-up. 
To allow telephone contact reports and to 
provide additional guidance to sites. 
63. 
 Section 9.3.18 Changes to 
Study Procedures Due to 
COVID-19 Public Health 
Emergency 
Section 9.5 Reasons for 
Discontinuation of 
Treatment 
Changed “pandemic” to 
“public health emergency”. 
Administrative change for consistency 
across the document. 
64. 
 Section 9.4 Completion of 
Study Treatment 
Updated the requirements 
for patients to be 
considered to have 
completed study treatment 
with regards to optional 
continuation therapy. 
To correct. 
65. 
 Section 10.1.2 Adverse 
Event Definition 
Added that AE relationship 
should be assessed as 
related or not related. 
To clarify. 
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Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
66. 
 Section 10.2 Procedures for 
Recording and Reporting 
Adverse Events and Serious 
Adverse Events 
Added information relative 
to follow-up SAE reports. 
Added that SAEs should be 
followed until resolution or 
permanent outcome of the 
event. 
To provide additional guidance to sites, 
consistently with the sponsor protocol 
template. 
67. 
 Section 10.2 Procedures for 
Recording and Reporting 
Adverse Events and Serious 
Adverse Events 
Clarified that planned 
hospitalization or surgical 
procedures are not to be 
considered AEs. 
To provide additional guidance to sites. 
68. 
 Section 10.3 Monitoring of 
Adverse Events and Period 
of Observation 
Clarified the review of 
safety and response data by 
the sponsor, the medical 
monitor, and participating 
investigators. 
To clarify the review of study data. 
69. 
 Section 10.4 Procedures for 
Reporting Drug Exposure 
During Pregnancy and Birth 
Events 
Updated text with regards 
to the reporting of drug 
exposure during pregnancy 
and birth events. 
To provide additional guidance to sites, 
consistently with the sponsor protocol 
template. 
70. 
 Section 11.2 IDMC 
Deleted duplicated text. 
Moved text from 
Section 10.3 Monitoring of 
Adverse Events and Period 
of Observation with regards 
to the reception of listing 
updates by the IDMC. 
Administrative change. 
To group responsibility of the IDMC 
within the same section, for consistency. 
71. 
 Section 12.0 DATA 
HANDLING AND 
RECORDKEEPING 
Added the version of World 
Health Organization Drug 
Dictionary used. 
Administrative change, for consistency 
across the document. 
72. 
 Section 12.1 eCRFs 
Corrected the meaning of 
the abbreviation CRO 
(contract research 
organization). 
To correct. 
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Protocol Amendment 3 
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Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
73. 
 Section 2.0 STUDY 
SUMMARY 
Section 13.1.3 Efficacy 
Analysis 
Added that patients with 
Ph-like ALL and Ph+ 
MPAL will not be included 
in efficacy analyses (they 
will be included in safety 
and other descriptive 
analyses). 
To clarify as there is no clinical evidence 
showing the 2 subtypes of ALL to have 
identical response to tyrosine kinase 
inhibitor therapy. 
74. 
 Section 15.2 Subject 
Information, Informed 
Consent, and Subject 
Authorization 
To add the possibility of 
remote consenting and 
assenting for patients who 
would have to travel long 
distances to the study site, 
if permitted by local 
regulations. 
To allow remote consenting and to 
provide additional guidance to sites. 
75. 
 Section 15.4.4 Data Sharing 
Added numbered heading. 
To correct. 
76. 
 Appendix A, Schedules of 
Events (Table 1) 
Added that for patients with 
an early EOT1, the 
echocardiogram or 
multigated acquisition scan 
does not need to be 
repeated if specified 
circumstances are met. 
To clarify and provide additional 
guidance to sites. 
77. 
 Appendix A, Schedules of 
Events (Table 1) 
Added that during follow-
up, peripheral blood 
samples for molecular 
mutations are required in 
case of relapse only. 
To clarify and provide additional 
guidance to sites. 
78. 
 Appendix A, Schedules of 
Events (Table 1) 
Corrected in the SOEs that 
the study treatment is also 
administered on Days 1, 15, 
22, and 29 of the 
consolidation block (daily 
administration). 
To correct, consistently with the 
protocol. 
79. 
 Appendix A, Schedules of 
Events (Table 1 and 
Table 2) 
Added a row in both SOEs 
for the investigator’s 
assessment of disease and 
for collection of alternative 
therapy (anticancer 
therapy). 
To clarify when the disease is to be 
assessed and when alternative therapy is 
collected. 
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Protocol Amendment 3 
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 
80. 
 Appendix A, Schedules of 
Events (Table 1 and 
Table 2) 
Added that EOT1 (Table 1) 
and EOT2 (Table 2) should 
be completed before 
alternative anticancer 
therapy(ies) are given. 
To clarify and provide additional 
guidance to sites. 
81. 
 Appendix A, Schedules of 
Events (Table 1 and 
Table 2) 
Clarified in the chemistry 
panel of both SOEs that the 
‘direct’ bilirubin is to be 
assessed. 
To provide additional guidance to sites. 
82. 
 Appendix A, Schedules of 
Events (Table 1 and 
Table 2) 
Added triglycerides in the 
chemistry panel of both 
SOEs. 
To provide additional guidance to sites. 
83. 
 Appendix A, Schedules of 
Events (Table 1) 
Added that no BM sample 
is to be shipped for central 
laboratory MRD 
assessment for patients with 
MPAL and for patients 
with Ph-like ALL. 
To provide additional guidance to sites to 
ensure samples are collected only from 
patients for whom an analysis can be 
performed (patients with Ph+ ALL). 
84. 
 Appendix A, Schedules of 
Events (Table 1) 
Clarified than when a 
relapse from CR is reported 
for patients with Ph+ ALL, 
a peripheral blood sample 
is to be taken before 
alternative therapy(ies) are 
given. 
To clarify. 
85. 
 Appendix A, Schedules of 
Events (Table 2) 
Removed the optional 
ponatinib continuation 
phase monthly Day 14 visit 
and assessments. 
To reduce the patient’s burden in the 
optional treatment phase and align with 
standard practice in this population. 
86. 
 Appendix A, Schedules of 
Events (Table 2) 
Changed that peripheral 
blood samples for 
molecular mutations are 
only required “if relapse 
occurs” rather than “if 
relapse is suspected”. 
To clarify. 
87. 
 Appendix A, Schedules of 
Events (Table 2) 
Added an investigator’s 
assessment of disease to the 
EOT2 visit. 
To clarify expectation for investigator to 
record the patient’s disease status at the 
end of study treatment which will 
support secondary endpoint evaluation of 
duration of response and/or relapse.  
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Study No. 1501 
Page 174 of 183 
Protocol Incorporating Amendment No. 4 
02 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 3 
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 
88. 
 Appendix A, Schedules of 
Events (Table 2) 
Clarified the frequency of 
follow-up visits for patients 
eligible to receive optional 
ponatinib continuation 
treatment. 
To provide additional guidance to sites. 
89. 
 Appendix A, Schedules of 
Events (Table 2) 
Updated when 
echocardiograms 
multigated acquisition 
scans are to be performed. 
To harmonize, consistently with Table 1. 
90. 
 Appendix A, Schedules of 
Events (Table 2) 
Clarified the wording of 
when lumbar puncture for 
cell count and cytospin 
cytology is to be 
performed. 
To clarify and provide additional 
guidance to sites. 
91. 
 Appendix A, Schedules of 
Events (Table 2) 
Added that BM assessment 
and other pertinent 
investigations are to be 
performed as clinically 
indicated at the follow-up 
visit and listed data to be 
collected if relapse from 
complete remission is 
confirmed. 
To clarify and for consistency with 
Appendix A, Table 1. 
92. 
 Appendix A, Schedules of 
Events (Table 3 and 
Table 4) 
Clarified timing of 
pharmacokinetic sample 
collection if ponatinib 
dosing is interrupted or 
delayed. 
To provide additional guidance to sites. 
93. 
 Appendix A, Schedules of 
Events (Table 5) 
Clarified initial intrathecal 
chemotherapy administered 
on Day 1 of reinduction 
block for CNS-1/2 patients 
and CNS-3 patients. 
To provide additional guidance to sites. 
94. 
 Appendix F, Tanner Scale 
Updated the table heading 
for pubertal stages in boys. 
To harmonize within Appendix F. 
AAF: age-appropriate formulation; AE: adverse event; BCR-ABL1: breakpoint cluster region Abelson 1; BM: 
bone marrow; CNS: central nervous system; CR: complete remission; DLT: dose-limiting toxicities; EOT1: end 
of treatment 1; IDMC: independent data monitoring committee; MPAL: mixed phenotype acute leukemia; MRD: 
minimal residual disease; Ph-like ALL: Philadelphia chromosome–like acute lymphoblastic leukemia; RP2D: 
recommended phase 2 dose; SAE: serious adverse event; SOE: schedule of events. 
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Ponatinib 
 
Study No. 1501 
Page 175 of 183 
Protocol Incorporating Amendment No. 4 
02 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 2 Summary and Rationale: 
This section describes the changes in reference to the protocol incorporating Amendment 2. The 
primary reasons for this amendment are: 
• To remove a dose of asparaginase therapy given in combination with ponatinib. 
• To clarify procedural details for enhanced patient safety. 
• To maintain patient safety, confidentiality, and study integrity in the context of health care 
delivery challenges presented by the coronavirus disease 2019 (COVID-19) pandemic.  
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only. 
Protocol Amendment 2 
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 4.2.4 
Rationale for the 
Dose of Ponatinib 
Added a sentence to the beginning of the section to 
provide additional context for the design of phase 1 
of the study. 
To provide additional 
context for the design of 
phase 1 of the study. 
2. 
 
Section 5.2.3 
Exploratory 
Endpoints 
Added endpoint to match last exploratory objective. 
To match the 
exploratory objective 
with a corresponding 
endpoint. 
3. 
 
Section 6.1 
Overview of Study 
Design and 
Section 8.1.2 
Study Treatment 
Regimen 
Added language to clarify the transition of patients 
to the optional continuation therapies and 
expectations of end of treatment visits. Also clarified 
the dose of ponatinib used in optional continuation 
therapy. 
To provide clarity for 
investigators on 
expectations for 
continuation therapies. 
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Protocol Incorporating Amendment No. 4 
02 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 2 
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 
4. 
 
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 6.3.3 
Timeframes for 
Primary and 
Secondary 
Endpoints to 
Support 
Disclosures Table 
6.a Section 6.3.4 
Section 9.3.17 
Follow-up 
Assessments, and 
Appendix A 
Schedules of 
Events, Table 1 
and Table 2 
Clarified the period of follow-up. 
To allow for at least 3 
years of follow-up. 
5. 
 
Section 6.3.2 End 
of Study/Study 
Completion 
Definition and 
Planned Reporting 
Clarified the end of study definition. 
To provide clarity. 
6. 
 
Section 2.0 Study 
Summary and 
Section 6.3.4 Total 
Study Duration 
Clarified the period of evaluation.  
To allow for at least 36 
months of evaluation. 
7. 
 
Section 6.3.4 Total 
Study Duration 
Updated the projected duration of study. 
To update based on 
current projections. 
8. 
 
Section 2.0 Study 
Summary and 
Section 6.2 
Number of 
Patients 
Updated the number of study sites and countries. 
To update numbers. 
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Protocol Incorporating Amendment No. 4 
02 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 2 
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 
9. 
 
Section 2.0 Study 
Summary and 
Section 7.1 
Inclusion Criteria 
Inclusion Criterion 1 was changed to clarify the 
eligibility criteria for diagnosis. 
To provide further 
clarity on diagnosis of 
patients that would be 
appropriate for the 
study. 
10. 
 
Section 2.0 Study 
Summary and 
Section 7.1 
Inclusion Criteria 
In Inclusion Criterion 6.a, adequate renal function 
was defined using estimated glomerular filtration 
rate as calculated by the Schwartz formula. 
To provide a formula 
for characterizing renal 
function in the pediatric 
population. 
11. 
 
Section 2.0 Study 
Summary and 
Section 7.1 
Inclusion Criteria 
Changed Inclusion Criteria 11 and 12 to require “at 
least 6 months” of contraception after the end of 
study therapy for both male and female patients in 
the study. 
This change was made 
to address contraception 
requirements for all 
study treatments. 
12. 
 
Section 2.0 Study 
Summary and 
Section 7.2 
Exclusion Criteria 
Deleted the exception from Exclusion Criterion 7 
relating to patients with hypertriglyceridemia. 
This change was made 
to ensure patient safety. 
13. 
 
Section 2.0 Study 
Summary and 
Section 7.2 
Exclusion Criteria 
Changed Exclusion Criterion 11 to include 
contraindications to any study drugs. 
To ensure patient 
safety. 
14. 
 
Section 2.0 Study 
Summary and 
Section 7.2 
Exclusion Criteria 
Added exclusion criterion for hepatitis B, hepatitis 
C, and HIV infections. 
To ensure patient 
safety. 
15. 
 
Section 2.0 Study 
Summary and 
Section 7.2 
Exclusion Criteria 
Exclusion Criterion #17 was modified in the 
exception to state that all neurologic deficits and 
causative factor(s) have resolved. 
To ensure patient 
safety. 
16. 
 
Section 2.0 Study 
Summary, Section 
7.2 Exclusion 
Criteria, and 
Section 8.5 
Excluded 
Concomitant 
Medications and 
Procedures 
Added that live vaccines are exclusionary before and 
during the study. 
To ensure patient 
safety. 
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Page 178 of 183 
Protocol Incorporating Amendment No. 4 
02 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 2 
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 
17. 
 
Section 8.1.2 
Study Treatment 
Regimen and 
Section 8.2 
Definitions of 
Dose-limiting 
Toxicities 
Clarified the dose-limiting toxicity (DLT) 
observation period to be 35 days on treatment in 
phase 1 unless there are residual hematologic 
toxicities on Day 35, in which case the patient will 
be followed for up to an additional 7 days for DLT 
evaluation. 
This change was made 
to provide clarity and 
internal consistency in 
the document. 
18. 
 
Section 8.1.2 
Study Treatment 
Regimen and 
Appendix A 
Schedules of 
Events, Table 5 
Deleted the Day 15 dose of polyethylene glycol 
(PEG)-asparaginase from the reinduction block in 
Table 8.b and Table 8.c Section 8.1.2. 
To mediate the concern 
about asparaginase 
therapy in combination 
with ponatinib. 
 
19. 
 
Section 8.1.2 
Study Treatment 
Regimen 
Deleted doses of triple intrathecal chemotherapy on 
Days 1, 15, 22, and 29 in the consolidation block 
from Table 8.c to match dosing in Schedule of 
Events. 
For internal consistency 
in the document (this 
was a typographical 
error in the original) 
and to reflect what was 
to be dosed. 
20. 
 
Section 8.1.2 
Study Treatment 
Regimen 
Appendix A 
Schedules of 
Events, Table 5, 
Schedule of Drugs 
Changed the availability of Erwinia-asparaginase as 
an alternative for PEG-asparaginase in cases where 
patients are allergic or PEG-asparaginase is not 
available. Also added language to allow PEG-
asparagine dosing over a range of days in case of 
supply shortage. 
To allow for 
substitution of Erwinia-
asparaginase for PEG-
asparaginase for allergy 
or availability of PEG-
asparaginase. 
21. 
 
Section 8.1.2, 
Table 8.c and 
Appendix A 
Schedules of 
Events, Table 1 
Made the following change in Table 8.c and the note 
in Appendix A, Table 1: 
Initial IT chemotherapy: Day 1; may include 
methotrexate (CNS-1/2), or triple IT chemotherapy 
(CNS-3) 
To clarify the dosing 
based on central 
nervous system (CNS) 
disease status. 
22. 
 
Section 8.4.2 Dose 
Reduction for 
Treatment-related 
Toxicity 
Added row for Grade 2 to Table 8.e under General 
Toxicities 
To provide guidance to 
investigators for dose 
modifications. 
23. 
 
Section 8.7 
Precautions and 
Restrictions 
Added a definition for women of childbearing 
potential. 
To clarify restrictions 
on pregnancy. 
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Study No. 1501 
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Protocol Incorporating Amendment No. 4 
02 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 2 
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 
24. 
 
Section 8.13.2 
Handling and 
Accountability 
Added text to allow for alternative study drug 
delivery in case of supply issues caused by 
coronavirus disease 2019 (COVID-19) public health 
emergency. 
To ensure delivery of 
investigational product 
to study participants, to 
prevent shortages 
caused by COVID-19–
related quarantines, 
cancellations of on-site 
visits, or concerns about 
possible COVID-19 
exposure.  
25. 
 
Section 9.3.1 
Screening Period 
Procedures 
Added text to allow for rescreening (if sponsor 
agrees) of patients discontinued due to COVID-19–
related factors. 
To allow for the 
rescreening of patients 
with COVID-19 at the 
discretion of the 
sponsor. 
26. 
 
Section 9.3.13.5 
Hepatitis B and C 
and Section 
9.3.13.6 HIV 
Added these sections to Section 9.3.13 Clinical 
Laboratory Evaluations. 
To describe the 
assessment of status of 
patients for hepatitis B 
and C and HIV. 
27. 
 
Section 9.3.14.2 
Cerebrospinal 
Fluid 
Added a section to describe collection of 
cerebrospinal fluid. 
To ensure complete 
description of 
assessments in the 
study. 
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Study No. 1501 
Page 180 of 183 
Protocol Incorporating Amendment No. 4 
02 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 2 
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 
28. 
 
Section 9.3.18 
Changes to Study 
Procedures Due to 
COVID-19 
Pandemic, Section 
14.1 Study Site 
Monitoring Visits, 
and Section 14.2 
Protocol 
Deviations 
Added text to address situations that might arise due 
to the COVID-19 public health emergency. 
To ensure patient 
monitoring and 
evaluation during the 
COVID-19 public 
health emergency. 
To ensure that only 
strictly necessary site 
visits are conducted 
during the COVID-19 
public health 
emergency. Site visits 
may be converted to 
phone or video visits or 
home health care visits. 
Some scheduled visits 
may be canceled or 
postponed with larger 
intervals between on-
site visits. 
29. 
 
Section 9.5 
Reasons for 
Discontinuation of 
Treatment 
Added text to clarify how to capture study drug 
discontinuation due to COVID-19 public health 
emergency. 
To ensure that patient 
discontinuation due to 
COVID-19–related 
factors are documented 
in the electronic case 
report form. 
30. 
 
Section 9.8 
Criteria for 
Premature 
Termination or 
Suspension of the 
Study 
Added Section 9.8 to describe situations in which the 
study might be suspended or terminated. 
To provide clarity on 
suspension or 
termination of the entire 
study. 
31. 
 
Section 10.3 
Monitoring of 
Adverse Events 
and Period of 
Observation 
A paragraph was added to clarify who is responsible 
for reviewing the emerging data from phase 1 to 
make decisions regarding dose and enrollment and 
how the decisions and any important safety data are 
communicated to all investigators in a timely 
manner. 
This was added to 
clarify who was making 
decisions and 
communicating 
important safety data. 
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Protocol Incorporating Amendment No. 4 
02 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 2 
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 
32. 
 
Section 15.2 
Subject 
Information, 
Informed Consent, 
and Subject 
Authorization 
Added text to describe potential alternative methods 
for obtaining informed consent/assent if travel is 
unavailable due to the COVID-19 public health 
emergency. 
To permit the use of 
electronic informed 
consent during the 
COVID-19 public 
health emergency. 
33. 
 
Appendix A 
Schedules of 
Events, Table 1 
Added hepatitis B, hepatitis C, and HIV testing to 
screening tests in the Schedule of Events, Table 1. 
To ensure patient 
safety. 
34. 
 
Appendix A 
Schedules of 
Events, Table 1 
Added timing for electrocardiogram (ECG) 
assessments in Footnote m. 
To clarify when ECGs 
should be performed. 
35. 
 
Appendix A 
Schedules of 
Events, Table 1 
and Table 2 
Added neurological assessments to Table 1 and 
Table 2. Added footnotes to clarify. 
To ensure patient safety 
and to conform to 
agreements made in the 
Paediatric 
Investigational Plan 
(PIP). 
36. 
 
Appendix A 
Schedules of 
Events, Table 1 
and Table 2 
Added collection of blood samples for BCR-ABL1 
mutation status to Table 2 and edited the footnote in 
both Table 1 and Table 2 to clarify the collection of 
sample at follow-up visit only if suspicion of relapse. 
To ensure patient safety 
and to comply with the 
PIP. 
37. 
 
Appendix A 
Schedules of 
Events, Table 1 
and Table 2 
Changed “CSF and cytospin cytology” to “Lumbar 
puncture” and described in the footnote. 
To match wording on 
the case report forms. 
38. 
 
Appendix A 
Schedules of 
Events, Table 1 
and Table 2 
Added lipase and amylase to the chemistry panel.  
To monitor for 
pancreatitis during 
ponatinib 
administration. 
39. 
 
Appendix A 
Schedules of 
Events, Table 2 
Added the following to the table to be done on Day 1 
and follow-up: 
Free T4 and thyroid stimulating hormone (TSH). 
TSH and Free T4 will 
be assessed for all 
patients in FU 
regardless of whether or 
not the patient received 
the optional ponatinib 
continuation therapy. 
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Study No. 1501 
Page 182 of 183 
Protocol Incorporating Amendment No. 4 
02 November 2023 
 
CONFIDENTIAL 
Protocol Amendment 2 
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 
40. 
 
Appendix E 
Clarified the questions on how ponatinib age 
appropriate formulation was administered. 
Deleted “with juice” and “with other” from choices 
of how administered.  
The correct scale was added to Questions 7 and 8 as 
below. The wording in the 5 point scale was changed 
to: “Not Easy, OK, Easy”. 
To correct the scale. 
41. 
 
Appendix F 
Tanner Scale added to protocol. 
To provide this scale in 
appendices. 
42. 
 
Appendix G 
Added definitions of CNS-1, CNS-2, and CNS-3 in 
cerebrospinal fluid. 
To provide clarity on 
the definitions. 
 
Rationale for Amendment 01 
This document describes the changes to the protocol incorporating Amendment 01. The primary 
reasons for this amendment are to incorporate feedback from the Innovative Therapies for 
Children with Cancer (ITCC), European Consortium and Children’s Oncology Group (COG), as 
well as adjust and clarify timing of assessments and laboratory samples, clarify language for 
study conduct, include language on precautions (eg, sun protection, smoking, and eye 
examinations), provide guidance for the administration of ponatinib in a non-hospital setting, 
include an additional exploratory objective, and update the schedule of events associated with 
these updates. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
Changes in Amendment 01 
1. Update Sponsor name and address. 
2. Clarify the timing of BCR-ABL1 domain mutation characterization. 
3. Update the timing of event-free survival (EFS), progression-free survival (PFS), and overall 
survival (OS) assessments. 
4. Update the timing of end of treatment 1 (EOT1). 
5. Add exploratory objective to determine OS for patients receiving/not receiving hematopoietic 
stem cell transplantation (HSCT). 
6. Add language regarding primary analysis and follow-up time points. 
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Protocol Incorporating Amendment No. 4 
02 November 2023 
 
CONFIDENTIAL 
7. Add language for patients in need of additional ponatinib therapy. 
8. Add language to clarify posttrial access to ponatinib. 
9. Allow patients with a BCR-ABL1 T315I mutation to enroll based on local laboratory results, 
followed by central confirmation.  
10. Add language for patients with Ph-like ALL eligibility (United States [US] only). 
11. Remove qualifier for definition of adequate liver function, “(unless related to leukemic 
involvement).” 
12. Update the exclusion criterion for current systemic use of any medications or herbal 
supplements that are known to be strong inhibitors or strong inducers of cytochrome P450 
3A4 (CYP3A). 
13. Replace exclusionary language, “History of significant bleeding disorder” with “History of 
severe coagulopathy or vascular events.” 
14. Clarify that self-administration or administration of ponatinib by a parent or legal guardian 
will occur if the patient is not hospitalized. 
15. Provide hypothyroidism guidance. 
16. Addition of precautions for sun protection. 
17. Addition of precautions for smoking/vaping. 
18. Addition of ophthalmological examinations. 
19. Clarified timeframe for documentation of concomitant medications and procedures. 
20. Updated procedures for recording and reporting adverse events and serious adverse events. 
21. Updated procedures for reporting drug exposure during pregnancy and birth events. 
22. Addition of blood samples for coagulation testing. 
23. Addition of blood samples for troponin/ N-terminal pro-brain natriuretic peptide 
(NT-proBNP). 
24. Addition of blood samples for free T4 and thyroid dysfunction. 
25. Clarified complete remission (CR) assessment by bone marrow aspirate and/or biopsy. 
26. Removed peripheral blood samples for minimal residual disease (MRD). 
27. Clarified endpoint assessment timeframes. 
28. Added definition of relapse from CR. 
29. Clarified timing of peripheral blood samples for BCR-ABL1 domain mutation status. 
 
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Signature Page for Ponatinib-1501 Protocol Amend 4 2023-11-02
Title: Amendment 3 to A Pivotal Phase 1/2, Single-Arm, Open-label Study to Evalu
Document Number: TDN-000203467 v2.0
Approval
Statistics
03-Nov-2023 12:36:45 GMT+0000
Approval
Clinical
03-Nov-2023 13:17:56 GMT+0000
Approval
Clinical
03-Nov-2023 13:51:00 GMT+0000
Approval
Clinical
03-Nov-2023 14:19:40 GMT+0000
Approval
Clinical
03-Nov-2023 14:24:36 GMT+0000
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