Conditions: Chronic Myeloid Leukemia Ph+ Acute Lymphoblastic Leukemia
Keywords: CML ALL PH ponatinib Ph+ALL T315I mutation Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 449
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the (T)hreonine-315-(I)soleucine (T315I) mutation.

Detailed description:
The preliminary analysis of the phase 1 clinical trial revealed evidence of clinical antitumor activity in patients with resistance to approved second-generation tyrosine kinase inhibitors (TKI), dasatinib and nilotinib, including patients with the T315I mutation of the BCR-ABL gene (BCR-ABL). This Phase 1 study, taken together with the strong preclinical data that characterize ponatinib, provides the rationale for moving to a pivotal phase 2 trial of this agent in a population of patients with chronic myeloid leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL) who are resistant or intolerant to prior TKI therapy and in those patients with the T315I mutation.

PACE is a multi-center, international, phase 2, uncontrolled, open-label trial of oral ponatinib in patients with Philadelphia chromosome-positive (Ph+) disease. The study enrolled 449 patients. Participants assigned to 1 of 6 cohorts in accordance with disease group and received:

* Ponatinib 45 mg

This multi-center trial is conducted worldwide. The overall time to participate in this study is 96 months after last dose of study drug treatment.

Arms:
arm 1: CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). arm 2: CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). arm 3: AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). arm 4: AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). arm 5: BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). arm 6: BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). arm 7: Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not R-I to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).

Interventions: intervention 1: Ponatinib
Intervention descriptions: intervention 1: Ponatinib tablets.

Protocol document:
Prot_001.pdf: 



Title: A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic 
Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
NCT Number: NCT01207440
Protocol Approve Date: 03 April 2015
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


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A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic 
Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
ARIAD protocol number: 
AP24534-10-201
IND Reference Number:
78,375
EudraCT number:
2010-020414-28
Date of Protocol:
Original Protocol Version 1.0 - 16 July 2010
Amendment 1 Protocol Version 2.0 - 27 October 2010
Amendment 2 Protocol Version 3.0 – 08 April 2011
Amendment 3 Protocol Version 4.0 – 24 May 2012
Amendment 4 Protocol Version 5.0 – 27 March 2013
Amendment 5 Protocol Version 6.0 – 03 April 2015
Sponsor:
ARIAD Pharmaceuticals, Inc.
26 Landsdowne Street
Cambridge, MA 02139-4234
Telephone: (617) 494-0400
Medical Monitor:
Additional Contacts:
PPD
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April
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1
CONTACTS
1.1
Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI)
Any death, serious adverse event (SAE), or adverse event of special interest (AESI) experienced 
by the patient from the time of signing the informed consent to 30 days of receiving the last dose 
of study drug, or any death, SAE, or AESI believed to be study drug-related that occurs more 
than 30 days after receiving study drug, must be promptly reported (within 24 hours) by 
telephone or facsimile to the Sponsor or the Sponsor’s designee.
1.2
Contact for Emergencies and Study Related Issues
A list of the Sponsor's study personnel and their contact information is included in the Study 
Reference Manual(s).
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2
APPROVAL
The protocol must be read before signing.
2.1
Investigator Signature
I have read the protocol and agree that it contains all necessary details for carrying out the study 
as described.  I will conduct this protocol as outlined therein, including all statements regarding 
confidentiality.  I will make a reasonable effort to complete the study within the time designated.  
I will provide copies of the protocol and access to all information furnished by the Sponsor to 
study personnel under my supervision.  I will discuss this material with them to ensure they are 
fully informed about the study drug and the study.  I understand that the study may be terminated 
or enrollment suspended at any time by the Sponsor, with or without cause, or by me if it 
becomes necessary to protect the best interests of the study patients.
I agree to conduct this study in full accordance with all applicable regulations.
Investigator’s Signature
Date (dd-mmm-yyyy)
Investigator’s Name (print)
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2.2
Sponsor Representative Signature
ARIAD Pharmaceuticals, Inc. has approved of this protocol and assures that this study will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality.
Sponsor Representative’s Signature
Date (dd-mmm-yyyy)
Sponsor Representative’s Name (print)
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3
DISCLOSURE STATEMENT
3.1
Restricted Distribution of Documents
This document contains information that is confidential and proprietary to the Sponsor.  This 
information is being provided to you solely for the purpose of evaluation and/or conducting a 
clinical trial for the Sponsor.  For this purpose, you may disclose the contents of this document 
only to study personnel under your supervision, Institutional Review Boards (IRBs)/Ethics 
Committees (ECs), or duly authorized representatives of regulatory agencies under the condition 
that they maintain confidentiality.  The contents of this document may not be used in any other 
clinical trial, disclosed to any other person or entity, and/or published without the prior written 
permission of the Sponsor. The foregoing shall not apply to disclosure required by any 
regulation; however, you will give prompt notice to the Sponsor of any such disclosure.
Any information that may be added to this document is also confidential and proprietary to the 
Sponsor and must be kept in confidence in the same manner as the contents of this document
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4
TABLE OF CONTENTS
1
CONTACTS ..................................................................................................................2
1.1
Serious Adverse Events (SAEs) and Adverse Events of Special 
Interest (AESI) ..................................................................................................2
1.2
Contact for Emergencies and Study Related Issues ......................................2
2
APPROVAL ..................................................................................................................3
2.1
Investigator Signature ......................................................................................3
2.2
Sponsor Representative Signature ..................................................................4
3
DISCLOSURE STATEMENT.....................................................................................5
3.1
Restricted Distribution of Documents.............................................................5
4
TABLE OF CONTENTS..............................................................................................6
5
LIST OF ABBREVIATIONS ....................................................................................11
6
DEFINITION OF TERMS.........................................................................................14
7
SYNOPSIS ...................................................................................................................17
8
SCHEDULE OF EVENTS .........................................................................................28
9
INTRODUCTION.......................................................................................................36
9.1
Background......................................................................................................36
9.2
Preclinical Pharmacology Studies .................................................................39
9.3
Preclinical Toxicology Studies .......................................................................42
9.4
Clinical Studies................................................................................................43
9.4.1
Overview of Ponatinib Phase 1 ..........................................................43
9.4.2
Update of Data from This Ongoing Trial (AP24534-10-201)..........44
9.4.3
Multivariate Analyses of Data from the Phase 2 Clinical Trial 
(AP24534-10-201, PACE) ...................................................................46
10
OBJECTIVES .............................................................................................................47
11
TRIAL DESIGN..........................................................................................................47
11.1
Structure ..........................................................................................................47
11.2
Study Endpoints ..............................................................................................48
12
SELECTION OF STUDY POPULATION...............................................................48
12.1
Inclusion Criteria ............................................................................................49
12.2
Exclusion Criteria ...........................................................................................51
12.3
Classification of Chronic Myeloid Leukemia (CML) Patients ...................53
12.4
Philadelphia Positive Acute Lymphoblastic leukemia (Ph+ ALL) 
Patients.............................................................................................................53
12.5
BCR-ABL Mutation Testing..........................................................................53
12.6
Number of Patients .........................................................................................55
12.7
Screening Failures...........................................................................................55
13
STUDY PROCEDURES.............................................................................................55
13.2
Screening..........................................................................................................59
13.3
Active Study Period ........................................................................................61
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13.4
Study Drug Administration............................................................................61
13.5
Management of Missed Doses of Study Drug...............................................61
13.6
End-of-Treatment Visit ..................................................................................62
13.7
Removal of Patients from Study Drug Administration or Assessment......62
13.8
Criteria for Discontinuation...........................................................................62
13.9
Follow-up Visit ................................................................................................63
13.10
Survival Follow-up..........................................................................................63
14
STUDY DRUG ............................................................................................................63
14.1
Study Drug Administration............................................................................63
14.2
Monitoring of Study Drug Administration...................................................64
14.3
Supportive Care ..............................................................................................64
14.4
Management of Adverse Drug Reactions .....................................................64
14.4.1
Vascular Occlusion .............................................................................65
14.4.1.1
Arterial Occlusion and Thrombosis ........................................65
14.4.1.2
Venous Thromboembolism ......................................................65
14.4.2
Congestive Heart Failure and Left Ventricular Dysfunction .........66
14.4.3
Hypertension........................................................................................66
14.4.4
Cardiac Arrhythmias..........................................................................66
14.4.5
QT Prolongation..................................................................................66
14.4.6
Hemorrhage.........................................................................................66
14.4.7
Compromised Wound Healing and Gastrointestinal 
Perforation...........................................................................................67
14.4.8
Neuropathy ..........................................................................................67
14.4.9
Ocular Toxicity....................................................................................67
14.4.10
Hepatotoxicity......................................................................................67
14.4.11
Pancreatitis and Lipase or Amylase Elevations ...............................67
14.4.12
Fluid Retention and Edema ...............................................................67
14.4.13
Myelosuppression................................................................................68
14.4.14
Tumor Lysis Syndrome (TLS)...........................................................68
14.4.15
Rash and/or Pruritus ..........................................................................68
14.4.16
Diarrhea, Nausea, and Vomiting .......................................................69
14.4.17
Constitutional Symptoms/Joint Pain.................................................69
14.5
Dose Delays and Reductions...........................................................................69
14.6
Dose Delay and/or Reduction for Adverse Events (AEs) Attributable 
to the Study Drug ............................................................................................69
14.6.1
Dose Modifications for Vascular Occlusive Events..........................75
14.6.1.1
Arterial Thrombotic and Occlusive Events .............................75
14.6.1.2
Venous Thromboembolic Events.............................................76
14.7
Dose Re-Escalation after Resolution of Adverse Drug Reactions ..............77
14.8
Formulation, Packaging, and Labeling.........................................................77
14.9
Storage and Stability.......................................................................................78
14.10
Study Drug Accountability.............................................................................78
14.11
Disposition of Used Supplies ..........................................................................78
14.12
Inventory of Unused Supplies ........................................................................79
15
CONCOMITANT TREATMENT.............................................................................79
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15.1
Permitted Treatment ......................................................................................79
15.2
Prohibited Treatment .....................................................................................79
15.3
Potential Drug Interactions............................................................................80
16
MEASURES TO MINIMIZE/AVOID BIAS ...........................................................80
16.1
Patient Registration and Identification.........................................................80
17
SAFETY.......................................................................................................................81
17.1
Safety Variables...............................................................................................81
17.2
Safety Assessment Methods............................................................................81
17.3
Safety Laboratory Assessments .....................................................................81
18
EFFICACY..................................................................................................................81
18.1
Efficacy Variables ...........................................................................................81
18.2
Efficacy Assessment Methods ........................................................................82
19
STATISTICAL ANALYSIS.......................................................................................83
19.1
Sample Size and Power...................................................................................83
19.1.1
Overview of Trial Design....................................................................83
19.1.2
Sample Size Determination: Cohorts A and B .................................83
19.1.3
Sample Size Determination: Cohorts C-F.........................................84
19.1.4
Overall Sample Size ............................................................................84
19.2
Statistical and Analytical Plans .....................................................................85
19.2.1
Analysis Populations...........................................................................85
19.2.2
Demographic and Baseline Characteristics......................................86
19.2.3
Efficacy Analyses.................................................................................86
19.2.3.1
Definitions of Efficacy Endpoints ...........................................86
19.2.3.2
Primary Endpoint Analysis......................................................87
19.2.3.3
Secondary Endpoint Analyses .................................................87
19.2.4
Safety Analyses....................................................................................88
19.3
Procedures for Reporting Deviations to Original Statistical Analysis 
Plan...................................................................................................................89
20
STEERING COMMITTEES.....................................................................................89
21
CONTRAINDICATIONS, PRECAUTIONS AND WARNINGS..........................89
21.1
Precautions Regarding Conception, Pregnancy, and Nursing ...................89
21.2
Overdose ..........................................................................................................90
22
ADVERSE EVENTS...................................................................................................90
22.1
Adverse Event (AE) Definition ......................................................................90
22.2
Evaluation of Adverse Events (AEs) .............................................................90
22.2.1
Determination of Seriousness.............................................................90
22.2.1.1
Serious Adverse Event (SAE) ..................................................90
22.2.1.2
Adverse Events of Special Interest (AESIs)............................91
22.3
Determination of Severity...............................................................................92
22.4
Determination of Relatedness ........................................................................93
22.5
Documenting AEs............................................................................................94
22.6
Reporting SAEs, AESIs, and Patient Deaths................................................94
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22.7
Follow-up Information ...................................................................................95
22.8
Expectedness of Events...................................................................................95
23
DATA QUALITY ASSURANCE ..............................................................................95
24
INVESTIGATOR’S REGULATORY OBLIGATIONS.........................................96
24.1
Institutional Review Board (IRB) / Ethics Committee (EC) Approval......96
24.2
Pre-Study Documentation ..............................................................................96
24.3
Informed Consent ...........................................................................................96
24.4
Case Report Forms (CRF) .............................................................................97
24.5
Adverse Event (AE) Reporting ......................................................................97
24.6
Review of Source Records ..............................................................................97
24.7
Monitoring of the Study .................................................................................97
24.8
Protocol Amendments.....................................................................................98
24.9
Change in Investigator....................................................................................98
24.10
Termination of Study......................................................................................98
24.11
Final Study Report..........................................................................................99
24.12
Confidentiality.................................................................................................99
24.13
Records Retention...........................................................................................99
25
REFERENCES..........................................................................................................100
26
ATTACHMENTS .....................................................................................................104
TABLE OF TABLES
Table 8-1
Schedule of Events for CHRONIC PHASE (CP) PATIENTS*.........................28
Table 8-2
Schedule of Events for ACCELERATED PHASE (AP), BLAST PHASE 
(BP), AND Ph+ ALL PATIENTS* .......................................................................29
Table 8-3
Schedule of Events for End-of-Treatment Visit, Follow-up Visit, and 
Survival Follow-up*...............................................................................................32
Table 9-1
Kinase Inhibition Profile of Ponatinib for Native ABL, ABLT315I, and 
Selected Kinases......................................................................................................39
Table 9-2
Ponatinib IC50 Values for Ba/F3 Cellular Proliferation Assays and CML 
and Non-CML Cellular Proliferation Assays ......................................................40
Table 9-3
Ponatinib Phase 1 Clinical Trial (AP24534-07-101): Best Response to 
Ponatinib Treatment in Ph+ Disease....................................................................44
Table 9-4
Ponatinib Phase 2 Clinical Trial (AP24534-10-201) by Cohort: Best 
Response to Therapy: Treated Population ..........................................................45
Table 11-1
Patient Cohorts.......................................................................................................47
Table 12-1
Chronic Myeloid Leukemia (CML) Phase Classification...................................53
Table 14-1
Modifications for Adverse Events (AEs) Attributable to Study Drug ..............70
Table 14-2
Dose Modifications for Arterial Thrombotic Occlusive Events.........................76
Table 14-3
Dose Modifications for Venous Thromboembolic Events ..................................77
Table 19-1
Planned Number of Patients for Each Cohort.....................................................83
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Table B-1
Drugs Generally Accepted by the QTDrugs.org Advisory Board of the 
Arizona CERT to have a Known Risk of Causing Torsades de Pointes: 
Prohibited in this Study.......................................................................................108
TABLE OF FIGURES
Figure 9-1
Single-Agent Ponatinib (AP24354) Completely Suppresses Resistant 
Outgrowth in Cell-Based Mutagenesis Screens...................................................41
Figure 12-1 Schema for T315I Mutation Testing.....................................................................55
LIST OF APPENDICES
Attachment A
Response Criteria...................................................................................105
Attachment B
Prohibited Drugs with a Risk of Torsades de Pointes ........................108
Attachment C
Medications that Interact with CYP3A4, 5, and 7..............................111
Attachment D
National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE).............................................................112
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5
LIST OF ABBREVIATIONS
Abbreviation
Term
ADME
absorption, distribution, metabolism, excretion
AP
accelerated phase
AE
adverse event
ALL
acute lymphoblastic leukemia, also known as acute lymphocytic leukemia
AESI
adverse event of special interest
ALT
alanine aminotransferase
AML
acute myelogenous leukemia, also known as acute myeloid leukemia
ANC
absolute neutrophil count
ARIAD
ARIAD Pharmaceuticals, Inc.
ASCVD
atherosclerotic cardiovascular disease
ASO
allele-specific oligonucleotide
ASO qRT-PCR
allele-specific oligonucleotide quantitative reverse transcript-PCR
AST
aspartate aminotransferase
AUC
area under the curve
ß-HCG
beta-human chorionic gonadotropin
BM
bone marrow
BP
blast phase
BUN
blood urea nitrogen
CBC
complete blood count
CCyR
complete cytogenetic response
CFR
Code of Federal Regulations (USA)
CHR
complete hematologic response
CI
confidence interval
Cl
chloride
CLL
chronic lymphocytic leukemia
CML
chronic myelogenous leukemia, also known as chronic myeloid leukemia
CNS
central nervous system
CP
chronic phase
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
cTn
cardiac troponin
DDI
drug-drug interaction
DLT
dose-limiting toxicity
EC
Ethics Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ECHO
echocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
FDA
Food and Drug Administration (United States)
FGFR
fibroblast growth factor receptor
GCP
Good Clinical Practice
GVHD
graft-versus-host disease
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Abbreviation
Term
HBV
hepatitis B virus
HCV
hepatitis C virus
HDPE
high density polyethylene
hERG
human ether-a-go-go related gene
HHT
homoharringtonine
HIV
human immunodeficiency virus
HPFB
Health Products and Food Branch (Canada)
HTN
hypertension
I 
isoleucine
IC50
50% inhibitory concentration
ICH
International Conference on Harmonisation
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IV
Intravenous
LDL
Low-density lipoprotein
LLD
lower limit of detection
LLT
lowest level term
LOD
limit of detection
LVEF
left ventricular ejection fraction
MDS
myelodysplastic syndrome
MaHR
major hematologic response
MedDRA
Medical Dictionary for Regulatory Activities Terminology
MCyR
major cytogenetic response
MI
myocardial infarction
MMR
major molecular response
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute (of the United States)
NCI CTCAE,
v.4.0
NCI Common Terminology Criteria for Adverse Events, version 4.0
NEL
no evidence of leukemia
NIH
National Institutes of Health (of the United States)
NOAEL
No observed adverse effect level
PCR
polymerase chain reaction
PCyR
partial cytogenetic response
PDGFR
platelet-derived growth factor receptor
PFS
progression-free survival
P-gp
permeability glycoprotein
Ph
Philadelphia chromosome
Ph+
Philadelphia chromosome positive
PK
pharmacokinetic(s)
PT
prothrombin time
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Abbreviation
Term
PTT
partial thromboplastin time
QD
every day (daily)
QTcF
QT interval corrected (Fridericia)
RBC
red blood cell
SAE
serious adverse event
SC
subcutaneous
SCT
stem cell transplant
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
t1/2
half-life
T
threonine
TGA
Therapeutic Goods Administration (Australia)
TIA
transient ischemic attack
TKI
tyrosine kinase inhibitor
TLS
Tumor Lysis Syndrome
TRAE
treatment related adverse event
ULN
upper limit of normal
URL
upper reference limit
USA
United States of America
USAN
United States Adopted Name
VEGFR
vascular endothelial growth factor receptor
VOE
vascular occlusive event
WBC
white blood cell (count)
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6
DEFINITION OF TERMS
Term
Definition
Active Study 
Period
The active study period for a patient begins with administration of the 
first dose of ponatinib and continues through 30 days following 
discontinuation of ponatinib.
Adverse Drug 
Reaction
An adverse drug reaction is any adverse event that is deemed to be at 
least possibly related to the study drug.
Clinically 
Significant
A clinical observation or laboratory result that leads to a new intervention 
or change in therapy is defined in the context of this study as clinically 
significant.
Cycle
For the purposes of this study, a cycle consists of 28 days.
End-of-Trial
The end-of-trial (completion) date is when all patients have completed all 
study visits or have otherwise discontinued from the study.
Enrolled Patient
An enrolled patient is a patient who has signed the informed consent 
form, completed all screening evaluations, has been deemed eligible for 
the trial and for whom the enrollment procedure has been completed, and 
received first dose of ponatinib.
Ethics Committee
Throughout this document the term Ethics Committee (EC) refers to all 
appropriate properly constituted committees or boards recognized by the 
appropriate regulatory agencies for approving clinical studies.  These 
include independent EC and Institutional Review Boards.
Evaluable for 
Efficacy
Any eligible patient who receives ponatinib is considered evaluable for 
efficacy analyses.
Evaluable for 
Safety
Any patient who receives ponatinib is considered evaluable for safety 
analyses.
Follow-up Period
The follow-up period for a patient begins at the end of the active study 
period (i.e., at the Follow-up Visit) and continues for not more than 24 
months from the administration of the first dose of ponatinib.
Institutional 
Review Board
Throughout this document the term Institutional Review Board (IRB) 
refers to all appropriate properly constituted committees or boards 
recognized by the appropriate regulatory agencies for approving clinical 
studies.  These include independent ECs and IRBs.
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Term
Definition
On-Study Period
The on-study period for a patient begins with the signing of the informed 
consent form and concludes 30 days following the last dose of study drug.
Patient
Throughout this document the term patient refers to a patient in this 
clinical research study.
QTcF
For the purposes of this study, the corrected (Fridericia) QT interval is 
calculated using the following formula: 
QTcF = QT/(RR)1/3.
Regulation
Throughout this document the term regulation refers to all appropriate 
regulations, laws, and guidelines.  This study will be conducted according 
to all appropriate regulations. The regulations may be international, 
national, or local and may include, but not be limited to, the Code of 
Federal Regulations (CFR, United States); the Good Clinical Practice
(GCP): Consolidated Guideline (Canada); the International Conference on 
Harmonisation (ICH) Guideline for Good Clinical Practice; the 
Therapeutic Goods Administration Annotated International Conference on 
Harmonisation Guidelines (Australia); and the World Medical Association 
Declaration of Helsinki: Ethical Principles for Medical Research Involving 
Human Patients.
Regulatory Agency
Throughout this document the term regulatory agency refers to all 
appropriate health and regulatory agencies. These may be international, 
national, or local and may include but not be limited to the Australian 
Therapeutic Goods Administration (TGA), the Canadian Health Products 
and Food Branch (HPFB), the European Medicines Agency (EMA), and 
the United States Food and Drug Administration (FDA).
Screening Period
The screening period for a patient begins when the informed consent 
form is signed and continues until the first dose of study drug is 
administered.
Sponsor
Throughout this document the term Sponsor refers to all appropriate 
research departments within ARIAD Pharmaceuticals, Inc., or its designee.
Study Reference
Manual/s
In the context of this study, Study Reference Manual/s is a general term 
for the information provided to sites on technical aspects of the trial. 
Study Drug
A study drug is any drug, device, biological agent, or comparator 
(including placebo) used in the Sponsor’s clinical research and 
development studies. For the purposes of this protocol, the study drug is 
ponatinib.
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Term
Definition
Study Start Date
The study start date is the date that the first patient signs the informed 
consent form.
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7
SYNOPSIS
Study Title
A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic 
Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
Clinical Phase
Phase 2
Study Rationale
Introduction
AP24534 (United States Adopted Name [USAN]: ponatinib) is a novel synthetic 
orally-active tyrosine kinase inhibitor (TKI). Ponatinib was specifically developed to 
inhibit BCR-ABL, the fusion protein that is the product of the Philadelphia 
chromosome (Ph) in chronic myeloid leukemia (CML) and in a subset of acute 
lymphoblastic leukemia (ALL). It potently inhibits the BCR-ABL protein, as well as 
mutated forms of the protein that arise in patients resistant to prior therapies with TKIs; 
for this reason, it is a pan-BCR-ABL inhibitor.
The approved therapies for Ph positive (Ph+) disease work well. For example, there 
are 3 clinical trials of imatinib in untreated patients that provide prolonged follow-up 
of patients. The largest of these, the IRIS trial, demonstrates a 5-year overall survival 
of 89% (Druker, 2006). But, population studies suggest patients in community settings 
may fare worse. Lucas and colleagues (2008) report in their longitudinal series that 
49% of patients initially treated with imatinib discontinued therapy because of either 
the development of resistance or intolerance at 24 months. Recently both dasatinib 
(Kantarjian et al, 2010) and nilotinib (Saglio et al, 2010) have been demonstrated to be 
superior to imatinib in terms of response rates; but, at this time, follow-up from these 
studies is too limited to estimate long-term failure rates.
The treatments for CML have evolved over the course of the conduct of this phase 2 
trial.  At the time the trial was initiated, the only TKIs approved to treat CML or Ph+ 
ALL were imatinib, dasatinib, and nilotinib.  During the course of the trial, bosutinib 
and ponatinib received marketing authorizations.  Imatinib is used for the treatment of 
newly diagnosed CML patients in chronic phase (CP), or accelerated phase (AP), after 
failing interferon therapy, and nilotinib is now also approved for this indication.  For 
the treatment of patients intolerant or resistant to prior therapy, including imatinib in 
the second line, both dasatinib and nilotinib are approved. Bosutinib is approved for 
CML patients who have experienced failure of prior therapy. 
Resistance to prior therapy is the major reason Ph+ patients suffer loss of disease 
control.  The most important mechanism of resistance to TKI therapy is the evolution 
of mutations in BCR-ABL that render the protein product of the oncogene refractory to 
kinase inhibition.  Ponatinib has been demonstrated to inhibit all mutations, in vitro, 
that it has been tested against and that arise during the development of resistance 
(O’Hare et al, 2009). Moreover, in a preclinical experiment formulated to assess the 
potential for emergence of additional mutations during ponatinib treatment, complete 
suppression of the development of resistant mutations was demonstrated. These 
characteristics support the testing of ponatinib in patients resistant to prior TKI 
therapy.
The most common single resistant mutation is a transition point mutation at position 
944 of the BCR-ABL gene, resulting in a substitution of isoleucine (symbol I) for 
threonine (T) at position 315 of the protein: designated T315I (Quintas-Cardama and 
Cortes, 2008). The T315I mutation accounts for 15%-20% of all mutants observed in 
refractory CML. Although dasatinib is effective against some mutations that confer 
resistance to imatinib therapy, and nilotinib also treats some imatinib-induced 
mutations, neither inhibit T315I; hence, there is no approved drug active against 
T315I. Ponatinib inhibits T315I. Other mutations confer resistance to both imatinib 
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and dasatinib, such as F317L, while other mutations confer resistance to imatinib and 
nilotinib, such as E255V. Ponatinib inhibits these mutations, as well.
A factor that contributes to therapeutic failure of the first or second generation agents 
is intolerance to therapy. Although the marketed drugs are convenient and safe, they 
cause adverse events (AEs) that result in dose reduction or even cessation of therapy in 
a proportion of patients. The side effect profile of imatinib includes edema, fluid 
retention, myelosuppression, cardiac toxicity, hepatotoxicity, and hemorrhage.  
Dasatinib is associated with severe myelosuppression, hemorrhage, fluid retention, 
effusions, and QT prolongation. Nilotinib is also associated with myelosuppression, 
QT prolongation, and sudden death.  These AEs, and especially fluid retention and 
myelosuppression, lead to intolerance to continued therapy in a number of patients.
In summary, while the approved therapies for Ph+ disease represent substantial 
progress, they fail in a significant proportion of patients because of either the 
development of resistance or intolerance. Thus, the need for new therapies is evident.
This phase 2 pivotal trial of ponatinib completed enrollment in October 2011 and 
enrolled 449 patients.  This amendment provides recommendations to investigators for 
dose reduction based on response, provides updated information on the risks of 
vascular occlusion, neuropathy, and cardiac failure and recommendations for 
management of these events, and adds a definition of overdose and guidance for 
reporting of overdose.
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Study Objective(s)
Primary Objective:
To determine the efficacy of ponatinib in patients with CML in CP, AP or BP or with 
Ph+ ALL who either:
are resistant or intolerant to either dasatinib or nilotinib,
Or:
have the T315I mutation.
Secondary Objectives:
●
To further characterize the anti-leukemia activity of ponatinib in these patients 
as evidenced by clinical responses, molecular responses, and clinical 
outcomes,
●
To characterize the molecular genetic status of patients, and
●
To examine the safety of ponatinib in these patients.
Trial Design
This is a multi-center, international, phase 2, single-arm, open-label trial of oral 
ponatinib in patients with Ph+ disease.  Eligible patients will have CML in CP, AP, or 
BP as defined below, or Ph+ ALL.  Patients will either 1) have disease resistant to, or 
be intolerant to, therapy with either dasatinib or nilotinib; or 2) have the T315I 
mutation of BCR-ABL.  Patients will receive once daily oral administration of 
ponatinib at a dose of 45 mg.  Patients will be assessed for hematologic response, 
cytogenetic response, and molecular response.  Molecular genetic analyses will also be 
performed.  Adverse events will be assessed throughout and categorized by the United 
States of America (USA) National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 4.0 (NCI CTCAE, v.4.0) (see Attachment D). Patients will be 
evaluated according to the Schedule of Events in Section 8.  Assessments will be 
according to standard international criteria.  Patients will remain on treatment until 
disease progression or intolerance develops or they meet one or more of the criteria 
listed in Section 13.8.  Progression-free survival and overall survival data will also be 
collected and analyzed. Patients will be grouped in the following cohorts:
Chronic Phase
(CP)
Accelerated Phase
(AP)
Blast Phase
(BP)/Ph+ ALL
Resistant or 
intolerant to 
dasatinib or 
nilotinib
Cohort A
Cohort C
Cohort E
T315I mutation
Cohort B
Cohort D
Cohort F
Each of the 6 cohorts proposed in this trial are representative of distinct patient 
populations with different primary endpoints.   Each cohort of patients will be analyzed 
separately for efficacy.  The safety data from all cohorts will be pooled for the purpose 
of describing the safety of all treated patients as a whole.  These cohorts can be viewed 
as 6 separate studies that are enrolled through this single “umbrella” protocol; 
therefore, no adjustments for multiplicity are planned.    
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Study Endpoints
Primary Endpoint:
●
For CML patients in CP at study entry: major cytogenetic response (MCyR), 
defined as complete cytogenetic response (CCyR) or partial cytogenetic 
response (PCyR).
CP patients in CCyR are not eligible for this study.
●
For CML patients in AP at study entry: major hematologic response (MaHR), 
defined as complete hematologic response (CHR) or no evidence of leukemia 
(NEL).
AP patients in MaHR are not eligible for this study.
●
For CML patients in BP at study entry or Ph+ ALL patients: MaHR, 
consisting of CHR or NEL. 
BP and Ph+ ALL patients in MaHR are not eligible for this study.
Secondary Endpoints:
●
For CML patients in CP:
-
Hematologic responses: CHR;
-
Cytogenetic responses: confirmed MCyR; and
-
Molecular responses: major molecular response (MMR).
●
For CML patients in AP or BP or Ph+ ALL patients:
-
Cytogenetic responses: CCyR, PCyR, confirmed MCyR; and
-
Molecular responses: MMR.
●
For all patients: time to response, duration of response, progression-free 
survival, and overall survival.
●
For all patients: safety and tolerability.
Exploratory Endpoints:
Diagnosis and Main 
Criteria for Inclusion
1.
Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ 
ALL (defined in Sections 12.3 and 12.4).
a.
All patients must have screening bone marrow (BM) cytogenetics 
with conventional banding performed within 42 days prior to
beginning treatment
b.
Examination of at least 20 metaphases is required.  If less than 20 
metaphases are examined, the BM aspirate should be repeated.
Patients must either meet criterion 2 or 3:
2.
Be previously treated with and resistant, or intolerant, to either dasatinib or 
nilotinib:
2.1
Resistance is defined for CML CP patients (CP at the time of initiation 
of dasatinib or nilotinib therapy) as follows.  Patients must meet at least 
1 criterion.
a.
Three months after the initiation of therapy: No cytogenetic 
response (>95% Ph+) or failure to achieve CHR.
b.
Six months after the initiation of therapy: Less than a minor 
cytogenetic response (>65% Ph+).
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c.
Twelve months after the initiation of therapy: Less than a PCyR
(> 35% Ph+).
d.
At any time after the initiation of therapy, the development of 
new BCR-ABL kinase domain mutations in the absence of 
CCyR.
e.
At any time after the initiation of therapy, the development of 
new clonal evolution in the absence of CCyR.
f.
At any time after the initiation of therapy, the loss of any 
cytogenetic response [from complete (0%), partial (1% to 
35%), minor (36% to 65%), or minimal (66% to 95%) to a 
response at least 1 grade worse], confirmed in at least 
2 consecutive analyses separated by at least 4 weeks.
g.
At any time after the initiation of therapy, progression of 
disease (to AP or BP).
2.2
Resistance is defined for CML AP patients (AP at the time of initiation 
of dasatinib or nilotinib therapy) as follows.  Patients must meet at least 
1 criterion.
a.
Three months after the initiation of therapy: failure to achieve a 
MaHR.
b.
At any time after the initiation of therapy, the loss of a MaHR, 
confirmed in at least 2 consecutive analyses separated by at 
least 4 weeks.
c.
At any time after the initiation of therapy, the development of 
new BCR-ABL kinase domain mutations in the absence of a 
MaHR.
2.3
Resistance is defined for CML BP patients (BP at the time of initiation 
of dasatinib or nilotinib therapy) and Ph+ ALL patients as follows.  
Patients must meet at least 1 criterion.
a.
One month after the initiation of therapy: failure to achieve a 
MaHR.
b.
At any time after the initiation of therapy, the loss of a MaHR, 
confirmed in at least 2 consecutive analyses separated by at least 
1 week.
c.
At any time after the initiation of therapy, the development of 
new BCR-ABL kinase domain mutations in the absence of a 
MaHR.
2.4
Intolerance to dasatinib or nilotinib is defined as:
a.
Non-hematologic intolerance: Patients with grade 3 or 4 toxicity 
while on therapy, or with persistent grade 2 toxicity, 
unresponsive to optimal management, including dose adjustments 
(unless dose reduction is not considered in the best interest of the 
patient if response is already suboptimal) in the absence of a 
CCyR for CP patients or MaHR for AP, BP or Ph+ ALL patients.
b.
Hematologic intolerance: Patients with grade 3 or 4 toxicity 
(absolute neutrophil count [ANC] or platelets) while on therapy 
that is recurrent after dose reduction to the lowest doses 
recommended by manufacturer (80 mg daily [QD] for dasatinib; 
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400 mg QD for nilotinib) in the absence of a CCyR for CP 
patients or MaHR for AP, BP or Ph+ ALL patients.
NOTE:
Although, the above criteria define failure after dasatinib or nilotinib 
(mostly according to Baccarani et al. 2009), patients who have gone 
on to later line therapy are eligible having failed dasatinib or nilotinib.
OR
3.
Develop the T315I mutation after any TKI therapy.
3.1
Patients with T315I mutation after any TKI need not have been treated 
with dasatinib or nilotinib.
3.2
Patients with T315I in CP must have less than a CCyR (> 0% Ph+).
3.3
Patients with T315I in AP, BP, or Ph+ ALL must have less than a 
MaHR.
3.4
Patients with any history of T315I mutation will be eligible for study 
participation.  However, only those patients who carry a T315I mutation 
that is detected by direct sequencing in a pre-treatment blood sample 
using the study’s central laboratory will be analyzed in the T315I subset.  
Details are provided in Section 12.5.
Patients must meet all of the remaining criteria to be eligible for the study:
4.
Must be ≥18 years old.
5.
Provide written informed consent.
6.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
7.
Minimum life expectancy of 3 months or more.
8.
Adequate renal function defined as serum creatinine < 1.5 × upper limit of 
normal (ULN) for institution.
9.
Adequate hepatic function defined as:
a.
Total bilirubin < 1.5 × ULN,
b.
Alanine aminotransferase (ALT [SGPT]) and aspartate 
aminotransferase (AST [SGOT]) < 2.5 × ULN for institution 
(< 5 × ULN if liver involvement with leukemia),
c.
Prothrombin time (PT) < 1.5 × ULN.
10.
Normal pancreatic status defined as:
a.
Lipase ≤ 1.5 × ULN for institution,
b.
Amylase ≤ 1.5 × ULN for institution.
11.
Normal QTcF interval on screening electrocardiogram (ECG) evaluation, 
defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
12.
For females of childbearing potential, a negative pregnancy test must be 
documented prior to enrollment.
13.
Female and male patients who are of childbearing potential must agree to use an 
effective form of contraception with their sexual partners throughout 
participation in this study.
14.
Ability to comply with study procedures, in the Investigator’s opinion.
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Exclusion Criteria
Patients are not eligible for participation in the study if they meet any of the following 
exclusion criteria:
1.
Received TKI therapy within 7 days prior to receiving the first dose of 
ponatinib, or have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs 
(except alopecia) due to agents previously administered.
2.
Received other therapies as follows:
a. For CP and AP patients, received hydroxyurea or anagrelide within 24 hours 
prior to receiving the first dose of ponatinib, interferon, cytarabine, or 
immunotherapy within 14 days, or any other cytotoxic chemotherapy, 
radiotherapy, or investigational therapy within 28 days prior to receiving the 
first dose of ponatinib. 
b. For BP patients, received chemotherapy within 14 days prior to the first dose 
of ponatinib. Otherwise 2a applies. 
c. For Ph+ ALL patients, received corticosteroids within 24 hours before the 
first dose of ponatinib, or vincristine within 7 days prior to the first dose of 
ponatinib, or received other chemotherapy within 14 days prior to the first 
dose of ponatinib. Otherwise, 2a applies. 
d. All patients are excluded if they have not recovered (> grade 1 by NCI 
CTCAE, v. 4.0) from AEs (except alopecia) due to agents previously 
administered.
3.
Underwent autologous or allogeneic stem cell transplant < 60 days prior to 
receiving the first dose of ponatinib; any evidence of on-going graft versus-host 
disease (GVHD), or GVHD requiring immunosuppressive therapy.
4.
Take medications that are known to be associated with Torsades de Pointes.  
These prohibited medications are listed in Attachment B.
5.
Require concurrent treatment with immunosuppressive agents, other than 
corticosteroids prescribed for a short course of therapy.
6.
Have previously been treated with ponatinib.
7.
Patients with CML CP are excluded if they are in CCyR.
8.
Patients with CML AP, CML BP, or Ph+ ALL are excluded if they are in 
MaHR.
9.
Have active central nervous system (CNS) disease as evidenced by cytology or 
pathology.  In the absence of clinical CNS disease, lumbar puncture is not 
required.  History itself of CNS involvement is not exclusionary if CNS has 
been cleared with a documented negative lumbar puncture.
10.
Have significant or active cardiovascular disease, specifically including, but not 
restricted to:
a.
Myocardial infarction within 3 months prior to first dose of ponatinib,
c.
History of clinically significant atrial arrhythmia or any ventricular 
arrhythmia,
d.
Unstable angina within 3 months prior to first dose of ponatinib,
e.
Congestive heart failure within 3 months prior to first dose of ponatinib.
11.
Have a significant bleeding disorder unrelated to CML or Ph+ ALL.
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12.
Have a history of pancreatitis or alcohol abuse.
13.
Have uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL).
14.
Have malabsorption syndrome or other gastrointestinal illness that could affect 
absorption of orally administered ponatinib.
15.
Have been diagnosed with another primary malignancy within the past 3 years 
(except for non-melanoma skin cancer or cervical cancer in situ, or controlled 
prostate cancer, which are allowed within 3 years).
16.
Are pregnant or lactating.  Women of childbearing potential must agree to 
effective contraception from the time of signing informed consent through the 
Follow-up Visit, approximately 30 days after last dose of ponatinib.
17.
Underwent major surgery (with the exception of minor surgical procedures, such 
as catheter placement or BM biopsy) within 14 days prior to first dose of 
ponatinib.
18.
Have ongoing or active infection (including known history of human 
immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus 
[HCV]). Testing for these viruses is not required in the absence of history.
19.
Suffer from any condition or illness that, in the opinion of the Investigator or the 
medical monitor, would compromise patient safety or interfere with the 
evaluation of the safety of the study drug.
Approximate Number of 
Patients
The overall total enrollment will be approximately 450 patients.
Approximate Duration 
of Patient Participation
Each patient will undergo a period of up to 3 weeks for screening prior to treatment.  
The duration of therapy will be determined by the patient’s response and toxicity.  At a 
minimum, all patients benefiting from treatment will be followed for up to 24 months
after first dose of ponatinib.  After 24 months, patients can remain on ponatinib if 
continuing to benefit from treatment,
Approximate Number of 
Study Centers
Approximately 60 centers; multi-national.
Approximate Duration 
of Study
The estimated duration of the trial is approximately 8 years, including 12 months of 
enrollment.  Patients will remain on treatment until they meet one or more of the 
criteria in Section 13.8.
Dosage and 
Administration
Ponatinib will be administered orally once daily at a dose of 45 mg per day.
Dose Reduction Recommendations Based on Response

All CP-CML patients currently on trial who had already achieved MCyR had
their dose reduced to 15 mg QD, unless, in the judgment of the investigator, 
the benefit/risk analysis taking into account the patient’s CML characteristics, 
BCR-ABL mutation status, and the patient’s cardiovascular risk justified
treatment with a higher dose. 

All CP-CML patients currently on trial who had not yet achieved MCyR had
their dose reduced to 30 mg QD, unless, in the judgment of the investigator, 
the benefit/risk analysis taking into account the patient’s CML characteristics, 
BCR-ABL mutation status, and the patient’s cardiovascular risk justified
treatment with a higher dose.
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
All AP-CML, BP-CML, and Ph+ ALL patients currently on trial had their 
dose reduced to 30 mg QD, unless, in the judgment of the investigator, the 
benefit/risk analysis taking into account the patient’s CML characteristics, 
BCR-ABL mutation status, and the patient’s cardiovascular risk justified
treatment with a higher dose.

All patients who lose response at a lower dose may have their dose escalated
(up to a maximum of 45 mg QD) as long as the dose had not been previously
lowered as a result of an adverse event.
These dose reductions were implemented via direct communication to investigators in 
October 2013.  For all patients, the dosing changes based on the above 
recommendations or the justification not to change the patient from his or her current 
dose should be documented in the patient’s chart and in the study drug administration 
page of the electronic case report form (eCRF).
Concomitant Treatment
Medical or surgical treatment necessary for the patient’s well-being is permitted.  
Management of known risk factors for cardiac disease, such as diabetes, hypertension, 
and hyperlipidemia should be optimized.
Prohibited Treatment
The following concurrent medications are prohibited:
-
Any other anticancer therapy including, but not limited to, chemotherapeutic 
agents, immunotherapy, biological response modifiers, radiotherapy, surgery 
and/or systemic hormonal therapy.  However, intrathecal therapy for CNS 
relapse in lymphoid BP or Ph+ ALL is allowed.  NOTE: patients with active 
CNS disease at study entry are excluded (see exclusion criteria 9).
-
Use of any other investigational drug or device.
-
Medications with a known risk of Torsades de Pointes (see Attachment B).
-
Herbal preparations or related over-the-counter preparations containing herbal 
ingredients (eg, St. John’s Wort, Blue Cohosh, Estroven) either during or within 
2 weeks prior to the first dose of ponatinib.
-
Elective surgery requiring in-patient care.
Medications that are potent inhibitors or inducers of CYP3A4 (see Attachment C) 
should be avoided, but are not prohibited (see Section 15.3).
Medications that prolong the QT interval without 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, then additional ECG monitoring should be performed as 
clinically indicated.
Where appropriate, patients may be treated with hematopoietic growth factors for 
limited times.
Efficacy Evaluation
Hematologic response rate, cytogenetic response rate, and disease progression will be 
assessed according to standard criteria.  Refer to Attachment A for definition of 
response criteria.
Safety Evaluation
Safety assessments will include physical and laboratory examination.  Adverse events 
will be graded according to the NCI CTCAE v 4.0.
All patients receiving at least 1 dose of ponatinib will be considered evaluable for 
safety.  The AE incidence rates, as well as the frequency of occurrence of overall 
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toxicity, categorized by toxicity grades (severity), will be described for each cohort of 
the trial.  Listings of laboratory test results will also be generated, and descriptive 
statistics summarizing the changes in laboratory tests over time will be presented.
Statistical Analysis
Overview of Trial Design
This is a phase 2, single-arm trial in patients with CML and Ph+ ALL.
Cohort A will consist of CP CML patients resistant or intolerant to dastinib or 
nilotinib.  Cohort B will consist of CP CML patients with T315I mutations.  Cohorts C 
and E will consist of AP and BP/Ph+ ALL patients, respectively, who are resistant or 
intolerant to dasatinib or nilotinib.  Cohorts D and F will consist of AP and BP/Ph+, 
respectively, with the T315I mutation.
Each of the 6 cohorts proposed in this trial are representative of distinct patient 
populations.  Each cohort of patients will be analyzed separately for efficacy.  The 
safety data from all cohorts will be pooled for the purpose of describing the safety of 
all treated patients as a whole.  These cohorts can be viewed as 6 separate studies that 
are enrolled through a single “umbrella” protocol; therefore, no adjustments for 
multiplicity are planned.
Sample Size Determination: Cohorts A and B
The primary endpoint for this trial for patients with CP CML (Cohorts A and B) will 
be MCyR.  The MCyR rate is defined as the proportion of patients who have achieved 
a CCyR or PCyR after the initiation of study treatment.
The primary analysis of the primary endpoint of MCyR will be performed using a 
2-sided exact 95% confidence interval (CI) for MCyR rate among all treated patients in 
each cohort.
Data on the use of second generation TKIs in patients who have failed dasatinib and 
nilotinib are available in several small studies (Giles et al, 2007; Quintas-Cardama et 
al, 2007; Garg et al, 2009).  These 3 studies demonstrate approximately 30% MCyR in 
these patients.  However, these are highly selected patient populations; they do not 
include patients who have failed more than 2 agents, and responses are typically of 
short duration.  Thus, for the purposes of this trial, the null or uninteresting MCyR rate 
is set at 20% for Cohort A (resistant and intolerant CP patients).  The alternative 
MCyR rate is set at 35% for Cohort A.  The overall alpha level for each cohort will be 
set at 0.05.  With a cohort size of 100 patients, a minimum of 29 responders (ie, those 
with a CCyR and a PCyR) would need to be observed in Cohort A in order to observe 
an exact 95% CI such that the lower bound exceeds 20% and the upper bound exceeds 
35%.  Therefore, 100 patients will provide at least 85% power to distinguish between a 
null response rate of 20% and an alternative response rate of 35% in Cohort A.  The 
study will also provide at least 98% power to distinguish between 20% and 40%, in 
which case 29 responses will also be required, and at least 78% power to distinguish 
between 30% and 45%, in which case 40 responses would be required.
With a cohort size of 100 patients, the maximum width of the exact 95% CI will be 
approximately 20% when the MCyR rate is in the expected range of 20% to 35%.
For Cohort B (T315I CP patients), the null or uninteresting MCyR rate is set at 10% 
and the alternative MCyR rate is set at 35%.  Data on the use of second generation 
drugs (Muller et al, 2009; Garg et al, 2009) in these patients suggest that less than 10% 
of patients achieve MCyR.  With a cohort size of 60 patients, a minimum of 14 
responders would need to be observed in Cohort B in order to observe an exact 95% CI 
such that the lower bound exceeds 10% and the upper bound exceeds 35%.  Therefore, 
60 patients will provide approximately 98% power to distinguish between a null 
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response rate of 10% and an alternative response rate of 35% in Cohort B.
With a cohort size of 60 patients, the maximum width of the exact 95% CI will be 25% 
when the MCyR rate is in the expected range of 10% to 35%.
Sample Size Determination: Cohorts C-F
The sample sizes for Cohorts C to F (AP and BP/Ph+ ALL) are based on similar 
considerations for each cohort (Garg et al, 2009).  The endpoint for these cohorts is 
MaHR.  Major hematologic response rate is defined as the proportion of patients 
achieving a CHR or NEL response.  The null or uninteresting MaHR rate is set at 10% 
and the alternative MaHR 30%.  With a cohort size of 40 patients, a minimum of 9 
responders would need to be observed in cohorts C to F in order to observe an exact 
95% CI such that the lower bound exceeds 10% and the upper bound exceeds 30%.  
Forty patients in each cohort will provide approximately 89% power to distinguish 
between the null response rate of 10% and an alternative response rate of 30% in these 
cohorts.
Overall Sample Size Determination
For each disease phase, after the initiation of treatment, patients will be tested for the 
T315I mutation.  Depending on the outcome of the test, patients will be assigned to a 
resistant/intolerant cohort (cohorts A, C or E, respectively, depending on disease 
phase) or a T315I cohort (cohorts B, D, or F).  For example, a CP patient will be tested 
and assigned to cohort A or B, an AP patient will be assigned to cohorts C or D, and a 
BP or Ph+ ALL patient will be assigned to cohort E or F.  Therefore, enrollment and 
assignment to the paired cohorts comprising a disease phase are linked by the relative 
prevalence of T315I patients and the T315I testing scheme.
Early enrollment experience demonstrates that patients whose disease is resistant or 
intolerant to therapy are relatively more common than patients who carry the T315I 
mutation.  Since the scientific objectives of the study require meeting accrual goals for 
the T315I cohorts (and, indeed, all cohorts), it is anticipated that the higher relative 
proportion of resistant/intolerant patients to T315I patients will require over-
enrollment of the resistant/intolerant cohorts (A, C, and E) to ensure full T315I patient 
enrollment.
Thus, overall total enrollment will be determined by the need to fill the T315I cohorts. 
At the time of this amendment, it is anticipated the trial may require up to 450 patients 
to ensure reaching the planned sample sizes of the T315I cohorts. Individual cohorts 
may be closed by the Sponsor to control overall enrollment to the study.
Rationale for Number of 
Patients
Approximately 450 patients will be enrolled in this study, to allow the T315I cohorts to 
enroll completely. See Section 19.1 for additional details.
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8
SCHEDULE OF EVENTS
Table 8-1
Schedule of Events for CHRONIC PHASE (CP) PATIENTS*
CYCLE
(1 cycle = 28 days)
Screening
Cycle 1
Cycle 2
Cycle 3
Cycles
4 to 
13
End 
of 
Cycles 
6,9,12
End 
of 
Cycles 
15, 18, 
21, 24, 
27, 30, 
33, 36, 
39
End of 
Every 
Subsequent 
6th Cycle 
DAY
-21 to 11
1
8
15
22
1
15
1
15
28
1
28
28
28
PROCEDURE
Informed Consent2
X
Medical/Surgical History & 
Demographics3
X
Cancer Diagnosis & Prior 
Cancer Therapy4
X
BCR-ABL Mutation
History5
X
Vital Signs6
X
X
X
X
X
X
X
X
Physical Exam including 
Hepatosplenomegaly & 
ECOG Performance Status7
X
X
X
X
X
X
X
X
Complete Blood Count 
(CBC) with Differential8
X
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry, Amylase, 
Lipase9
X
X
X
X
X
X
X
X
X
X
Serum Triglycerides9
X
Fasting Cholesterol/Lipid 
Assessment9
X
X
HbA1c9
X
X
Prothrombin Time 
(PT)/PTT10
X
Pregnancy11
X
Electrocardiogram (ECG)12
X
X
X
Echocardiogram (ECHO)13
X
X
Adverse Events
THROUGHOUT STUDY
Concomitant Medications
THROUGHOUT STUDY
RESPONSE ASSESSMENT
Bone Marrow (BM) 
Aspirate & Cytogenetic 
Response14
X
X
X
X22
X22
Molecular Response15
X
X
X
X
X
Additional Disease 
Assessments16
X
X
X
X
X
MUTATION ANALYSIS
Direct Sequencing for 
T315I17
X
EXPLORATORY TESTS
*See notes following Table 8-2 and footnotes following Table 8-3.
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Table 8-2
Schedule of Events for ACCELERATED PHASE (AP), BLAST PHASE 
(BP), AND Ph+ ALL PATIENTS*
CYCLE
(1 cycle = 28 days)
Screening
Cycle 1
Cycle 2
Cycle 3
Cycles 
4 to 26
End 
of 
Even 
Cycles 
4 to 24
End of
Cycles 27, 
30, 33, 36, 
39 and then 
Every 
Subsequent
6th Cycle
DAY
-21 to 11
1
8
15
22
28
1
15
28
1
15
28
1
15
28
28
PROCEDURE
Informed Consent2
X
Medical/Surgical 
History & 
Demographics3
X
Cancer Diagnosis & 
Prior Cancer 
Therapy4
X
BCR-ABL Mutation
History5
X
Vital Signs6
X
X
X
X
X
X
X
Physical Exam
including 
Hepatosplenomegaly 
& ECOG 
Performance Status7
X
X
X
X
X
X
X
Complete Blood 
Count (CBC) with 
Differential8
X
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry, 
Amylase, Lipase9
X
X
X
X
X
X
X
X
Serum Triglycerides9
X
Fasting 
Cholesterol/Lipid 
Assessment9
X
HbA1c9
X
Prothrombin Time 
(PT)/PTT10
X
Pregnancy11
X
Electrocardiogram 
(ECG)12
X
X
X
Echocardiogram 
(ECHO)13
X
X
Adverse Events
THROUGHOUT STUDY
Concomitant 
Medications
THROUGHOUT STUDY
RESPONSE ASSESSMENT
Bone Marrow (BM) 
Aspirate & 
Cytogenetic 
Response14
X
X
X
X
X23
Molecular Response15
X
X
X
X
Additional Disease 
Assessments16
X
X
X
X
MUTATION ANALYSIS
Direct Sequencing for 
T315I17
X
EXPLORATORY TESTS
*See notes below and footnotes following Table 8-3.
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Notes for both Schedule of Events Table 8-1 and Table 8-2:
Unless otherwise specified, the manner in which Cycle 1 tests are performed should be repeated in later cycles.
Screening tests must be performed within 21 days prior to the first dose of study drug (see exceptions for screening
bone marrow [BM] and pregnancy test below). Otherwise, samples or activities should occur within 3 days of the 
scheduled study day unless otherwise noted in Schedule of Events.  Bone marrow aspirates should occur within 7 
days of the scheduled study day.
Day 28 procedure/laboratory tests of a finishing cycle may be performed on Day 1 of the next cycle unless otherwise 
specified.
Please pay special attention to tests required for primary and secondary assessments:
Chronic phase (CP) (Table 8-1):
Complete hematologic response (CHR): Hematologic response determination occurs for CP patients with 
each complete blood count (CBC) and differential. The criteria for CHR also include the absence of 
extramedullary involvement, so an assessment of hepatosplenomegaly must be recorded at each physical 
examination.
Major cytogenetic response (MCyR): For CP patients, BM aspirate for morphology and cytogenetics 
occurs every 3 cycles up to Cycle 27. Any time after 27 cycles, patients who are not in CCyR continue to 
require a BM aspirate and cytogenetic assessment every 6 cycles through Cycle 39 and at least yearly 
thereafter (more frequent is acceptable if clinically indicated).  Patients documented to be in CCyR after the 
BM aspirate and cytogenetic assessment at Cycle 27 (or later) are not required to have any further BM 
aspirates unless there is at least a 10-fold increase in BCR-ABL transcripts from the lowest point obtained 
on study and the patient is not currently in MMR, at which time BM aspirate and cytogenetics must be 
obtained.  Bone marrow and cytogenetic assessments thereafter should be performed as clinically indicated 
based on the clinical situation and the results of the previous bone marrow cytogenetics. Patients who are 
in MMR any time after Cycle 27 are not required to have BM or cytogenetic assessments unless clinically 
indicated.
Any time a bone marrow aspirate is performed, conventional banding for cytogenetics is required.  More 
frequent aspirates are allowed, but these are not required.
Major molecular response (MMR): Collection of peripheral blood for determination of molecular response 
occurs every 3 cycles up to Cycle 39, and subsequently every 6 cycles for the duration of the study.
Accelerated phase (AP), blast phase (BP), and Ph+ ALL (Table 8-2):
Major hematologic response (MaHR): For AP, BP and Ph+ ALL patients, hematologic response 
determination requires an assessment of extramedullary involvement by physical examination, a CBC and 
differential and a BM aspirate.  An assessment of hepatosplenomegaly must be recorded at each physical 
examination. A BM aspirate is required Cycle 1 Day 28, Cycle 2 Day 28, and at the end of each even-
numbered cycle thereafter through Cycle 24, then at the end of Cycle 27. Any time after 27 cycles, patients 
who are not in CCyR continue to require a BM aspirate and cytogenetic assessment every 3 cycles until 
Cycle 39 and at least yearly thereafter (more frequent is acceptable if clinically indicated).  Patients 
documented to be in CCyR and MMR after the BM aspirate and cytogenetic assessment at Cycle 27 (or 
later) are not required to have any further BM aspirates unless there is at least a 10-fold increase in BCR-
ABL transcripts from the lowest point obtained on study and the patient is not in MMR, at which time BM 
aspirate and cytogenetics must be obtained.  Bone marrow and cytogenetic assessments thereafter should be 
performed as clinically indicated based on the clinical situation and the results of the previous bone marrow 
cytogenetics. Patients who are in MMR any time after Cycle 27 are not required to have BM or 
cytogenetic assessments unless clinically indicated.
MCyR: For AP, BP and Ph+ ALL patients, BM aspirate for morphology and cytogenetics occurs on Cycle 
1 Day 28, Cycle 2 Day 28, and then every 2 cycles through Cycle 24, then at the end of Cycle 27. Further 
need for BM aspirates beyond Cycle 27 are as described in the MaHR paragraph above.  Any time a bone 
marrow aspirate is performed conventional banding for cytogenetics is required.  More frequent 
assessments are allowed, but these are not required.
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MMR: Collection of peripheral blood for determination of molecular response occurs every 2 cycles up to 
Cycle 24, every 3 cycles until Cycle 39, and subsequently every 6 cycles for the duration of the study. For 
BP and Ph+ ALL, a sample of marrow aspirate for molecular response is also collected, if a BM aspirate is 
performed.
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Table 8-3
Schedule of Events for End-of-Treatment Visit, Follow-up Visit, and 
Survival Follow-up*
Procedure
Visit
Survival Follow-up21
End-of-Treatment Visit20
Follow-up Visit20
Vital Signs6
X
X
Physical Exam including Hepatosplenomegaly & 
ECOG Performance Status7
X
X
Complete Blood Count (CBC) with Differential8
X
X
Serum Chemistry, Amylase, Lipase9
X
X
Fasting Cholesterol/Lipid Assessment9
X
Pregnancy Test (if applicable)11
X
Electrocardiogram (ECG)12
X
Echocardiogram (ECHO)13
X
X
Adverse Events & Concomitant Medications
X
X
RESPONSE ASSESSMENT
Bone Marrow (BM) Aspirate & Cytogenetic 
Response14
X
Molecular Response15
X
MUTATION ANALYSIS
Direct Sequencing for T315I17
X
EXPLORATORY TESTS
SURVIVAL FOLLOW-UP
Survival21
X
*See footnotes below.
Footnotes for Schedule of Events Table 8-1, Table 8-2, and Table 8-3.
1.
Screening tests and procedures are used to establish eligibility of the patient for the trial. All screening 
tests must be done within 21 days prior to the first dose of ponatinib with the exception of the screening
bone marrow (BM) aspirate (within 42 days) and screening pregnancy test (within 7 days). Patients must 
continue to maintain laboratory values within eligibility perimeters if any given procedure or laboratory test 
is repeated prior the start of ponatinib on Cycle1, Day 1.
2.
Informed consent, documented by a signed consent form, must be obtained prior to any screening activities 
not otherwise part of the patient’s care.
3.
Demographic information and medical and surgical history will be recorded. Demographic information 
consists of the patient’s age, gender, race, and ethnicity (as allowed by local law and regulations).
4.
Both the initial leukemia diagnosis and the current screening diagnosis must be recorded. Prior therapy 
history consists of the specific oncologic regimens a patient has received, the dates of the regimen and the 
best response to the regimen, and the reason for failure or intolerance to each regimen. Stem cell transplant 
or experimental therapy history is also recorded.
5.
At the time of screening, prior and current history of any known BCR-ABL mutations must be recorded 
(note: actual screening BCR-ABL mutation testing is covered in footnote 18).
6.
Vital signs are temperature, pulse, respiratory rate, and blood pressure (when patient is seated). Height and 
weight are required only at screening.
7.
A screening complete physical examination must be performed on Cycle 1, Day1 prior to the first 
administration of study drug. The extent of the physical examination should be consistent with the medical 
history and the patient’s underlying disease. Subsequent physical examination may be directed to relevant 
findings in the patient. ECOG performance status should be evaluated during each physical examination.
However, screening and directed physical examination in all patients need to assess for 
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Page 33 of 112
hepatosplenomegaly.  In patients with extramedullary involvement in AP, BP or Ph+ ALL, the site(s) of 
involvement must be assessed at screening and in subsequent directed examination. The End-of-Treatment 
Visit physical examination should be a complete physical examination. The Follow-up Visit physical 
examination may be directed to any relevant findings.
8.
Complete blood count (CBC) with differential is defined as peripheral blood total white blood cell (WBC) 
count, hemoglobin, hematocrit, platelet count, absolute neutrophil count (ANC) and WBC differential 
reported individually for each cell type including immature cells such as metamyelocytes, promyelocytes, 
and blasts, when present.
9.
Serum Analysis 
a)
Serum Chemistry, Amylase, Lipase 
Serum chemistry consists of a peripheral blood draw with the following assessments: sodium, potassium, 
chloride, bicarbonate (or total carbon dioxide [CO2]), blood urea nitrogen (BUN, or urea), fasting glucose, 
albumin, creatinine, total bilirubin (direct and indirect), alanine aminotransferase (AST [SGOT]), aspartate 
aminotransferase (ALT [SGPT]), alkaline phosphatase, magnesium, phosphorous, calcium, amylase, and
lipase.  The full chemistry panel must be obtained as specified in the Schedule of Events (Table 8-1, Table 
8-2, and Table 8-3) or more frequently as clinically indicated.
b)
Serum Triglycerides
A fasting or non-fasting serum triglyceride level must be collected during screening.  If a patient is 
ineligible based on a non-fasting level, the test may be repeated with a fasting level to determine eligibility.
c)
Fasting Cholesterol/Lipid Assessment
Fasting serum cholesterol and lipid panel (total cholesterol, high-density lipoprotein cholesterol, low-
density lipoprotein cholesterol, HDL/LDL ratios, and triglycerides) must be collected as specified in the 
Schedule of Events (Table 8-1, Table 8-2, and Table 8-3) beginning with the patient’s next scheduled visit.  
More frequent measurements may be required as clinically indicated.
d)
HbA1c 
Hemoglobin A1c (HbA1c) testing must be performed as specified in the Schedule of Events (Table 8-1, 
Table 8-2, and Table 8-3) beginning with the patient’s next scheduled visit.  More frequent measurements 
may be required as clinically indicated.
10.
The prothrombin time (PT) may be expressed as an International Normalization Ratio (INR) or in seconds. 
11.
The pregnancy test must be a beta-human chorionic gonadotropin (β-HCG) test and either urine or serum 
can be used.  Women who are not of childbearing potential (status post hysterectomy, status post-bilateral 
oophorectomy, or post menopausal [defined as amenorrhea for at least 12 months]) do not need to have the 
test performed. The test must be known to be negative prior to the study drug administration and be within 
7 days prior to first study drug administration.  Women of child-bearing potential at study start must also 
complete the pregnancy test at the End-of-Treatment Visit.
12.
All electrocardiograms (ECGs) must be 12-lead ECGs.  The screening ECG must be performed within the 
21-day screening window prior to study drug administration.  For consistency, the QTcF method must be 
used for all calculating of QTc intervals and the QTcF interval must be normal on screening as specified in 
the eligibility criteria (Section 12.1).  Additionally, 12-lead ECGs must be performed at the times specified 
in the Schedule of Events, or more frequently if clinically indicated.  If other 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.
13.
An echocardiogram (ECHO) for assessment of left ventricular ejection fraction (LVEF) must be performed 
within the 21-day screening window and at the end of Cycle 3.  Additional ECHOs should be performed as 
clinically indicated. An ECHO is necessary at the End-of-Treatment or Follow-up Visit only if 
abnormality develops during trial.
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14.
The BM aspirate with or without an optional biopsy must occur within 42 days prior to the first dose of 
ponatinib and ± 7 days of the subsequent scheduled assessments.  Biopsy and aspirate results must list the 
components required for assessing response of the patient as delineated in Attachment A.  Bone marrow 
examination must include cytogenetic assessment by conventional banding. Cytogenetic assessment 
requires examination of at least 20 metaphases. If less than 20 metaphases are examined, the BM aspirate 
should be repeated.
Regardless of a patient’s response status, a BM aspirate is required every 3 months for CP patients through 
the end of Cycle 27; and at the end of Cycle 1, Cycle 2, and then every 2 months until Cycle 24 and at the 
end of Cycle 27 for AP, BP and Ph+ ALL patients.  For BM aspirate requirements after Cycle 27 for CP 
patients please refer to footnote 23 below and for BM aspirate requirements after Cycle 27 for AP, BP and 
Ph+ALL patients please refer to footnote 24 below. 
A BM aspirate is performed at the End-of-Treatment if it has been ≥ 12 weeks for CP and ≥ 8 weeks for AP 
or BP or Ph+ ALL since the last BM aspirate.  See notes above for relation to response assessments.  Bone 
marrow aspirates and biopsies may be performed at other times when clinically indicated.  Results of any 
BM aspirate or biopsy, whether scheduled or unscheduled, must be recorded in the patient’s electronic case 
report form (eCRF).
15.
Samples of peripheral blood (in CP and AP) or peripheral blood and BM (in BP and Ph+ ALL) for 
molecular response (BCR-ABL transcript quantification) must be collected on these days.  Specific 
instructions will be supplied in the Study Reference Manual.
16.
Additional disease evaluations as appropriate to fully assess disease status in patients with extramedullary 
involvement; the site(s) of involvement must be assessed at screening and in subsequent disease evaluation 
points with appropriate laboratory tests or procedures.
17.
BCR-ABL mutation testing of peripheral blood is required for participation in this trial.  A sample must be 
collected and submitted during screening to document the type(s) of BCR-ABL mutations present at the 
time of screening.  This screening sample will be used to identify patients with T315I mutations for later 
subset analysis.  The sample must be submitted and documentation of receipt by the central laboratory 
received prior to the initiation of study drug treatment. Additional blood samples will be collected and 
stored for additional analyses of the T315I mutation.  Specific instructions will be supplied in the Study 
Reference Manual.
18.
19.
20.
The End-of-Treatment Visit should be performed within 2 weeks (14 days) of the patient’s last dose of 
study drug or the investigator/patient decision to discontinue treatment, whichever occurs later.  The 
Follow-up Visit will be conducted approximately 30 days (± 7 Days) after the last dose of study drug.  For 
both the End-of-Treatment and Follow-up Visits, the information may be collected from tests that were 
performed for the study or as part of the patient’s routine medical care.
21.
Survival data will be collected every 12 weeks +/- 2 weeks starting after the last dose of study drug or the 
investigator/patient decision to discontinue treatment, whichever occurs later, and continuing for up to 96 
months from the time the last patient is assigned to treatment.  These data do not need to be obtained during 
a visit, and phone contact is acceptable.
22.
Any time after 27 cycles, CP patients who are not in CCyR continue to require a BM aspirate and 
cytogenetic assessment every 6 cycles through Cycle 39, and at least yearly thereafter (more frequent is 
acceptable if clinically indicated).  Patients documented to be in CCyR any time after the BM aspirate and 
cytogenetic assessment at Cycle 27 (or later) are not required to have any further BM aspirates unless there 
is at least a 10-fold increase in BCR-ABL transcripts from the lowest point obtained on study, and the 
patient is not currently in MMR, at which time BM aspirate and cytogenetic assessments must be obtained.  
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Page 35 of 112
Subsequent BM aspirate and cytogenetic assessments should be performed as clinically indicated. Patients
who are in MMR any time after Cycle 27 are not required to have BM aspirate or cytogenetic assessments 
unless clinically indicated.
23.
Any time after 27 cycles, AP, BP and Ph+ ALL patients who are not in CCyR continue to require a BM 
aspirate and cytogenetic assessment every 3 cycles through Cycle 39, and at least yearly thereafter (more 
frequent is acceptable if clinically indicated).  Patients documented to be in CCyR any time after the BM 
aspirate and cytogenetic assessment at Cycle 27 (or later) are not required to have any further BM aspirates 
unless there is at least a 10-fold increase in BCR-ABL transcripts from the lowest point obtained on study
and the patient is not currently in MMR, at which time BM aspirate and cytogenetic assessments must be 
obtained.  Subsequent BM aspirate and cytogenetic assessments should be performed as clinically
indicated. Patients who are in MMR any time after Cycle 27 are not required to have BM aspirate or 
cytogenetic assessments unless clinically indicated.
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9
INTRODUCTION
9.1
Background
AP24534 (United States Adopted Name [USAN]: ponatinib) is a novel, synthetic, orally-active 
multi-targeted tyrosine kinase inhibitor (TKI).  The primary target for ponatinib is BCR-ABL, an 
abnormal tyrosine kinase that is the hallmark of chronic myeloid leukemia (CML) and 
Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL).  Ponatinib was 
designed using the Sponsor’s computational and structure-based drug design platform to inhibit 
the enzymatic activity of BCR-ABL with very high potency and broad specificity.  The agent 
was intended to target not only native BCR-ABL, but also BCR-ABL isoforms that carry 
mutations that confer resistance to treatment with existing TKIs, including especially the T315I 
mutation for which no effective therapy exists. Preclinical data demonstrate that the compound 
inhibits the activity of all the isoforms tested, as well as the proliferation and survival (in vitro 
and in vivo) of cell lines expressing known BCR-ABL mutants that confer broad TKI resistance.  
Clinical data from an ongoing phase 1 trial also suggest clinical activity against resistant BCR-
ABL mutants.  Thus, ponatinib exhibits broad-spectrum inhibition of BCR-ABL mutants; it is a 
pan-BCR-ABL inhibitor.  It is proposed to carry out pivotal clinical studies of ponatinib in CML 
and Ph+ ALL patients resistant or intolerant to therapy with either of the second generation 
approved TKIs, dasatinib or nilotinib, or who carry the T315I mutation.
Current Treatments for Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome 
Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Prior to the approval of the first TKI that targeted the BCR-ABL fusion oncoprotein, imatinib, 
studies of interferon therapy for CML resulted in approximately a 10% complete cytogenetic 
response (CCyR) rate and an approximately 57% 5-year survival (O’Brien et al, 2003). 
Treatment for CML was significantly advanced in 2001 following the approval of imatinib. 
Since then, targeted therapy with imatinib in the first line has become standard. Recent studies 
have demonstrated that both nilotinib (Saglio et al, 2010) and dasatinib (Kantarjian et al, 2010), 
second generation TKIs with improved potencies, are more effective therapies in untreated CML 
patients than imatinib.  These drugs are both now approved in the first-line patient population.
Imatinib is an effective drug and in initial studies, the CCyR rate was reported as 76% (O’Brien 
et al, 2003).  In recent comparison trials, nilotinib demonstrated a CCyR rate by 12 months of 
80% versus 65% for imatinib (Saglio et al, 2010). Similarly, dasatinib exhibited a 77% 
confirmed CCyR rate compared with 66% for imatinib, with a minimum of 12 months of 
follow-up.  Long term data from these studies are not yet available.  However, at 7 years of 
follow-up from the initial imatinib studies, approximately 40% of patients discontinue therapy 
due to resistance or intolerance to this agent (Baccarani et al, 2009). Dasatinib and nilotinib also 
are approved for the treatment of patients who are or become resistant to imatinib therapy, ie, in 
the second line after imatinib failure. These drugs yield CCyR rates from 30% to 50% in this 
setting (Talpaz et al, 2006; Kantarjian et al, 2006).  Thus, a sizable fraction of first- and second-
line patients fail to achieve CCyR, and so, despite these major advances in treatment, resistance 
continues to be a significant challenge in the treatment of CML.  Bosutinib is also now available 
for CML patients who have experienced failure of prior TKI therapy. 
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Despite these advances in therapy, resistance and intolerance continue to be a significant 
challenge in the treatment of CML.
The molecular biology of Ph+ ALL is similar to that of CML; thus, TKIs have been utilized in 
this condition as well. Historically, patients with Ph+ ALL have been treated with standard 
cytotoxic chemotherapy regimens; however, the results have been unsatisfactory with overall 
survival of approximately 40% (Kantarjian et al, 2008). Treatment with allogeneic 
hematopoietic stem cell transplantation (SCT) lowers the 5-year risk of relapse and increases 
event-free survival and overall survival in eligible patients (Gruber et al, 2009). However, 
allogeneic SCT is a limited treatment option.  More recently, the TKI imatinib was demonstrated 
to improve complete responses during induction therapy in first line patients with Ph+ ALL over 
standard chemotherapy induction (Ottmann et al, 2007): imatinib is indicated for Ph+ ALL.  
Unfortunately, most often these results are not durable as resistance develops. Dasatinib is also 
indicated in the treatment of patients with Ph+ ALL who are resistant or intolerant to prior 
therapy.  Data have emerged that demonstrate that many of these patients carry the T315I 
mutation resistant to all currently approved TKIs (Gruber et al, 2009).
The best understood mechanism of resistance to TKI therapy is the development of point 
mutations in BCR-ABL. More than 100 different mutations (such as T315I) in the kinase 
domain of ABL have been discovered and have been shown to be responsible for 40% to 50% of 
the resistance to existing TKIs (Jabbour et al, 2009).  The detection of kinase domain mutations 
even early in disease is adversely prognostic (Khorashad et al, 2008), is higher in accelerated 
phase (AP)/blast phase (BP) compared with chronic phase (CP), and increases with the duration 
of disease (Quintas-Cardama and Cortes, 2008).  For patients who fail imatinib therapy, the 
frequency of BCR-ABL mutations ranges from 40% to 90%, depending on the phase and method 
of detection (Quintas-Cardama and Cortes, 2008).
The most common single resistant mutation, which occurs in approximately 15% of patients who 
develop resistance to imatinib (Quintas-Cardama and Cortes, 2008), is a transition point mutation 
at position 944 of the BCR-ABL gene, resulting in a substitution of isoleucine (symbol I) for 
threonine (T) at position 315 of the protein: designated T315I. The T315I mutation accounts for 
15%-20% of all mutants observed in refractory CML (Nicolini et al, 2009). Although dasatanib 
is effective against some mutations that confer resistance to imatinib therapy, and nilotinib also 
treats some imatinib-induced mutations, no approved drug inhibits T315I. Ponatinib, however, 
does inhibit T315I. Some mutations confer resistance to both imatinib and dasatanib, such as 
F317L, while other mutations confer imatinib and nilotinib resistance, such as E255V: ponatinib
inhibits these mutations, as well.
As discussed above, there are currently no approved therapies for patients with the T315I 
mutation (Nicolini et al, 2009).  In a recent study of second generation agents used in resistant 
patients, no cytogenetic responses in patients with the T315I mutation were observed (Garg et al,
2009), in keeping with the known lack of efficacy of existing drugs against this mutation.  
Another study examined patients carrying characterized mutations treated with dasatinib, and in 
this series, 2 of 21 patients with the T315I mutation experienced partial cytogenetic responses
(PCyR), but no CCyR (Muller et al, 2009).  Several investigational agents have been or are 
currently in development against this gatekeeper mutation.  The agent that is furthest along in 
development is omacetaxine mepesuccinate, a semisynthetic formulation of the cytotoxic plant 
alkaloid homoharringtonine (HHT), which is administered subcutaneously (SC) daily. 
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The mechanism of action by which HHT exerts its antitumor activity is through inhibition of 
protein synthesis and promotion of apoptosis (Quintas-Cardama et al, 2009a). Omacetaxine is 
not a TKI, and does not specifically interact with BCR-ABL carrying the T315I mutation. Data 
on 44 patients with CML and the T315I mutation were presented (25 CP, 11 AP, 8 BP). In CP 
patients, complete hematologic response (CHR) rate was 80%, and the CCyR rate was reported 
as 16%, with a major cytogenetic response (MCyR) rate of 20%. These data on omacetaxine 
suggest a modest cytogenetic response rate using this agent, but only in the limited subset of 
patients carrying the T315I mutation.
There are a variety of methods available to detect BCR-ABL kinase domain point mutations, 
including direct sequencing, polymerase chain reaction (PCR)-based methods including 
allele-specific variants, and denaturing high-performance liquid chromatography. Direct 
sequencing typically detects mutations when they are present in 10% to 30% of circulating 
BCR-ABL transcripts (Baccarani et al, 2009). Direct (Sanger) sequencing has been considered 
the standard test for mutation detection, as was recommended by a panel of experts at a National 
Institutes of Health (NIH) consensus conference in late 2005 (Hughes et al, 2006). It was used, 
for example, uniformly in the study of Muller and colleagues (2009) cited above to determine 
mutation status in all patients treated with dasatinib. Allele-specific methods can detect much 
lower levels of BCR-ABL transcripts. These are the 2 most important detection methods.  In this 
clinical trial, the T315I + population is defined on the basis of the ability to detect the T315I 
mutation with direct sequencing.  Allele-specific oligonucleotide (ASO) testing for the T315I 
mutation will be performed.
Minimal data exist on treatment of the broader patient population who has failed second 
generation agents, ie, the population not limited to the T315I mutants. Garg and colleagues at 
MD Anderson, cited above, conducted a single institution study of 1 second-generation agent 
(dasatinib or nilotinib) used as therapy in 48 patients who failed the alternative 
second-generation treatment (Garg et al, 2009).  The patient population included a variety of 
resistant mutations. This study reports a 32% CCyR rate in CP patients, but only half of these 
CCyR were sustained beyond 12 months.  Giles et al. (2007; 2010) reported their experience 
using nilotinib in patients who failed imatinib and then dasatinib.  In their study (Giles et al, 
2010), they studied 39 CP and 21 AP patients.  Most patients (67% in CP) were intolerant, and 
not resistant, to prior therapy.  They reported a 16 MCyR (41%) in all CP patients. Quintas-
Cardama et al. (2007) reported results using dasatinib after nilotinib failure in 23 patients, but in 
these patients (mostly AP or BP) responses (26%) were more often partial (4 PCyR) than 
complete (2 CCyR), and were of short duration.
Taken together, the above data 1) suggest that existing second generation agents have minimal 
activity in the third line, with modest MCyR rates of short duration, 2) suggest that omacetaxine 
has limited activity confined to the T315I patient population, and 3) underscore the need for a 
TKI with activity against the broad spectrum of resistant mutants including, but not limited to, 
T315I.
Recently, updated standard recommendations for the management of CML, as formulated by 
European Leukemia Net, were published (Baccarani et al, 2009). Leading CML experts 
reviewed the relevant data and literature on CML therapy and promulgated consensus 
approaches to defining responses, recommending monitoring strategies, and providing a 
therapeutic algorithm that accounts for such emerging data as summarized above.
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In brief, therapy recommendations comprise imatinib in the first line; for imatinib failures, 
second line dasatinib or nilotinib, or allogeneic SCT for AP/BP patients and those who carry the 
T315I mutation; and for dasatinib or nilotinib failures, allogeneic transplant is also available. 
Allogeneic transplant is a limited option, available only to patients with excellent performance 
status with an appropriate donor. Apart from SCT, there is no agreed standard of care for 
patients who fail a second generation drug, or for patients who carry the T315I mutation.
This protocol will test ponatinib in the patient population defined by the experts cited above, ie, 
patients who are resistant or intolerant to either dasatinib or nilotinib, or who carry the T315I 
mutation after any TKI therapy.
9.2
Preclinical Pharmacology Studies
A preclinical development program has been completed to support the clinical development of 
ponatinib.  Studies conducted to examine the nonclinical pharmacologic and pharmacodynamic 
activity of ponatinib (O’Hare et al, 2009) are summarized below.
In vitro kinase assays demonstrated that ponatinib inhibits native BCR-ABL and all 5 mutants 
tested, including T315I, with 50% inhibitory concentration (IC50) of 0.37 to 2.0 nM.  Ponatinib
also inhibited the activity of other TKIs in vitro with IC50 < 10 nM including members of the 
SRC, vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor 
(FGFR) and platelet-derived growth factor receptor (PDGFR) families (Table 9-1).
Table 9-1
Kinase Inhibition Profile of Ponatinib for Native ABL, ABLT315I, and 
Selected Kinases
Kinase
IC50 (nM)
ABL
0.37
ABLT3151
2.0
ABLQ252H
0.44
ABLY253F
0.30
ABLM351T
0.30
ABLH396P
0.34
c-SRC
5.4
LYN
0.24
c-KIT
12.5
VEGFR2
1.5
FGFR1
2.2
PDGFRα
1.1
IR
>1000
IGF-1R
>1000
Aurora A
>1000
CDK2/Cyclin E
>1000
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In cellular assays, ponatinib inhibited proliferation of Ba/F3 cells expressing native BCR-ABL 
and all 14 clinically relevant mutants tested, including T315I, with IC50 of 0.5 to 36 nM (Table 
9-2).  Ponatinib also inhibited the phosphorylation of BCR-ABL, as well as the direct BCR-ABL 
substrate CrkL.  In assays using primary cells derived from CML patients with T315I mutant 
BCR-ABL, ponatinib inhibited cell growth, colony formation and levels of phosphorylated CrkL.
Table 9-2
Ponatinib IC50 Values for Ba/F3 Cellular Proliferation Assays and CML and 
Non-CML Cellular Proliferation Assays
Ba/F3 Cell Proliferation Assay
IC50 (nM)
BCR-ABL
Ponatinib
Imatinib
Nilotinib
Dasatinib
Native
0.5
260
13
0.8
M244V
2.2
2000
38
1.3
G250E
4.1
1350
48
1.8
Q252H
2.2
1325
70
3.4
Y253F
2.8
3475
125
1.4
Y253H
6.2
>6400
450
1.3
E255K
14
5200
200
5.6
E255V
36
>6400
430
11
T315A
1.6
971
61
125
T315I
11
>6400
>2000
>200
F317L
1.1
1050
50
7.4
F317V
10
350
nd
53
M351T
1.5
880
15
1.1
F359V
10
1825
175
2.2
H396P
1.1
850
41
0.6
Parental
1713
>6400
>2000
>200
O’Hare T. et al (2005) Cancer Res. 65: 4500-4505
O’Hare T. et al (2007) Blood.  110: 2242-2249
O’Hare T. et al (2009) Cancer Cell. 16: 401-412
Ba/F3 cells expressing T315I BCR-ABL were used to test the antitumor activity of ponatinib in 
vivo. In a xenograft model, in which cells were injected SC, significant inhibition of tumor 
growth occurred with daily oral dosing of ponatinib at doses of > 10 mg/kg. Inhibition of 
BCR-ABL and CrkL phosphorylation was observed in tumors from mice treated with ponatinib. 
In a survival model, in which cells were injected intravenously, daily oral administration of 
ponatinib significantly improved survival at doses as low as 5 mg/kg. Ponatinib also improved 
survival significantly when Ba/F3 cells expressing native BCR-ABL were injected.
To identify mutations that may confer resistance to ponatinib a mutagenesis screen was 
performed using Ba/F3 cells expressing native BCR-ABL.  This screen has successfully 
identified clinically relevant mutations that confer resistance to other BCR-ABL inhibitors 
(Bradeen et al, 2006).  When the selection was performed in the presence of 40 nM ponatinib,
outgrowth of resistant clones was suppressed completely (Figure 9-1).  Thus, by this assessment, 
ponatinib appears to be a pan-BCR-ABL inhibitor.  Since exposure of cells to 40 nM suppressed 
the emergence of any resistant mutants, and since this concentration had potent activity against 
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all individual mutants tested in Ba/F3 cells, including T315I, 40 nM can be considered a target 
efficacious trough concentration.
Figure 9-1
Single-Agent Ponatinib (AP24354) Completely Suppresses Resistant 
Outgrowth in Cell-Based Mutagenesis Screens
(A) Resistant clones recovered from ENU-treated Ba/F3 cells starting from native BCR-ABL cultured with graded 
concentrations of ponatinib (10, 20, 40 nM). Each bar represents the relative percentage of the indicated BCR-ABL 
kinase domain mutant among recovered subclones. Since the percentage of surviving resistant subclones and the 
concentration of ponatinib are inversely related, a different number of sequenced subclones are represented in the 
graph for each concentration of ponatinib. The percent of wells surveyed that contained outgrowth is indicated to 
the right of each graph.
In summary, these studies demonstrate ponatinib is an orally-active multi-target TKI that 
inhibits, with high potency, native BCR-ABL and all mutants tested.
In vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) studies have 
been performed to understand the pharmacokinetics (PK) and metabolism of ponatinib. 
Ponatinib was bioavailable after oral administration to mice, rats and cynomolgus monkeys.  The 
absolute bioavailability after an oral dose was 18.2% and 20.6%, respectively, in rats and 
monkeys. The blood clearance of ponatinib was low, approximately 17% of the hepatic blood 
flow in both rats and monkeys.  The steady state volume of distribution (Vss) was large, 
indicating that ponatinib was extensively distributed in extravascular compartments.  The 
terminal half-life (t½) after an intravenous (IV) dose was 10.2 and 5.3 hours, respectively, in rats 
and monkeys.
In vitro, ponatinib was very highly bound to plasma proteins (>99%) of mice, rats, monkeys and 
humans, and did not show preferential partitioning into red blood cells (RBCs) in whole blood.  
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Ponatinib is most likely to be a permeability glycoprotein (P-gp) substrate based on the Caco-2 
model.
In vitro, ponatinib was metabolized to mainly AP24567 (N-desmethyl metabolite), and to a 
lesser extent to AP24734 (N-oxide).  There were other mono-oxygenated metabolites whose 
contribution to the overall metabolism was insignificant. CYP3A4 was the major Cytochrome 
P450 isozyme responsible for the metabolism of ponatinib. In rat and monkey plasma also 
AP24567 and AP24734 were the principal metabolites. In mouse plasma, AP24567 was found 
to be a major metabolite.
Ponatinib is a substrate of CYP3A4, and is an inhibitor of CYPs 3A4, 2D6, and 2C19. It is 
likely that ponatinib might cause drug-drug interaction (DDI) with CYP3A4 inhibitors and 
substrates of CYPs 3A4/5, 2D6, and 2C19.
Overall, the metabolism of ponatinib in rats and monkeys (both in vivo and in vitro) was 
qualitatively similar to the metabolism of ponatinib in human liver microsomes and hepatocytes. 
All human in vitro metabolites were also present in the toxicological species, rat and monkey.
9.3
Preclinical Toxicology Studies
The safety of ponatinib has been investigated in laboratory animals and in in vitro systems. 
These investigations included single oral dose toxicology studies in mice, rats and cynomolgus 
monkeys, as well as 28-day and 6-month oral dose toxicology studies in rats and cynomolgus 
monkeys.  In addition, the mutagenic potential of ponatinib was evaluated in an in vitro reverse 
mutation assay, an in vitro chromosomal aberration assay, and in an in vivo micronucleus test in 
mice. A safety pharmacology program was also completed to determine the potential effects of 
ponatinib on the nervous, renal, pulmonary, gastrointestinal, and cardiovascular systems. 
Cardiovascular evaluations included in vitro effects on the human ether-a-go-go related gene 
(hERG) and an in vivo study in conscious telemetered dogs.
The rat was shown to be the most sensitive species to the toxicologic effects of ponatinib based 
on both single dose and multiple dose regimens.  Rats tolerated single oral doses of 10 mg/kg 
with mortality occurring at single oral doses of 30 mg/kg and greater.  Mice tolerated single oral 
doses of 500 mg/kg and cynomolgus monkeys tolerated single oral doses of 45 mg/kg (the 
highest dose tested).  In the 28-day oral toxicology study rats did not tolerate dose levels of 3 and 
6 mg/kg with death/moribundicity occurring in 11 and 24% of the animals, respectively. In 
addition, 1 death occurred in the low dose group of 1.5 mg/kg/day on the last day of the dosing 
period for which a drug-related cause of death could not be ruled out.  In the 28-day oral toxicity 
study in cynomolgus monkeys, an oral dose of 5 mg/kg/day was not tolerated, with 
mortality/moribundicity occurring in 3 of 10 animals during the last 2 weeks of the study. 
Histologic pancreatic changes observed in monkeys at the 5 mg/kg/day dose level included 
acinar cell necrosis, fibrosis and atrophy with a corresponding elevation in serum lipase level.  
The low- (1 mg/kg/day) and mid- (2.5 mg/kg/day) dose levels were tolerated by the monkeys 
with the exception of a mid-dose animal who appeared in poor physical condition toward the end 
of the dosing period.
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In the 6-month oral toxicology study in rats, the no observed adverse effect level (NOAEL) was 
0.25 mg/kg/day.  Higher dose levels of 0.75 and 2 mg/kg/day caused mortality of some animals, 
and decreased body weight and food consumption relative to control.  Histologic examination
revealed decreased numbers of chondrocytes along the physis in the femur at the 0.75 and 
2 mg/kg/day dose levels, and lymphoid depletion was observed in the thymus at the 2 mg/kg/day 
dose level.  The observation in the femur appears to be species specific since it was not observed 
in the nonhuman primate studies.  Another histologic observation in the 6-month rat study was a 
higher frequency and severity of chronic progressive nephropathy in the 2 mg/kg/day dose group 
in comparison with the vehicle control and lower dose group observations. Chronic progressive
nephropathy is a normal age-related finding in rats; however, the higher incidence and severity 
of this observation in the high dose group suggests a drug-related exacerbation of this normal 
occurrence.  Because chronic progressive nephropathy is a rodent specific entity, the observation 
of a chemically-related exacerbation is routinely regarded as having no relevance for 
extrapolation in human risk assessment.  The administration of ponatinib to cynomolgus 
monkeys for 6 months at oral dose levels of 0.25, 0.75 and 2 mg/kg/day was well-tolerated with 
no ponatinib-related microscopic findings being observed at any dose level.
Ponatinib was shown to be non-mutagenic in the 3 mutagenicity assays that were performed, and 
the drug was shown to have a favorable safety pharmacology profile.
9.4
Clinical Studies
9.4.1
Overview of Ponatinib Phase 1
ARIAD Protocol AP24534-07-101 is a phase 1 clinical trial of oral ponatinib.  The trial is a non-
randomized, multi-center, dose-escalation study to evaluate the safety, tolerability, maximum 
tolerated dose (MTD), and biologic properties of ponatinib in patients with hematologic 
malignancies.
Enrollment for this study closed in October 2010.  At the time of writing, the trial was ongoing; 
data as of 06 January 2014 are presented. A total of 81 patients with CP-CML, AP-CML, 
BP-CML, Ph+ ALL, and other hematologic malignancies who had no other effective treatment 
options enrolled in the study.  A total of 65 patients had Ph+ leukemia (that is, CML or 
Ph+ ALL), 12 patients had AML, and 4 patients had other hematologic malignancies.  Twenty-
four patients remain on study (all CP-CML), with a minimum duration of follow-up of 
approximately 37 months for these remaining patients.  Doses of 2, 4, 8, 15, 30, 45, and 60 mg 
were evaluated. Dose limiting toxicity of pancreatitis-related events was reported at 60 mg; 
therefore, the maximum tolerated dose and recommended phase 2 dose was determined to be 
45 mg.
Substantial anti-tumor activity of ponatinib was observed (Cortes et al, 2012).  The results are 
illustrated in Table 9-3 below (a more detailed presentation of treatment responses is provided in 
the Investigator’s Brochure). 
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Table 9-3
Ponatinib Phase 1 Clinical Trial (AP24534-07-101): Best Response to 
Ponatinib Treatment in Ph+ Disease
Best Response
CP-CML
n=43
AP-CML, BP-CML, Ph+ ALL
n=22
Hematologic
  CHR*, n (%)
42 (98)
N/A
  MaHR, n (%)
N/A
8 (36)
Cytogenetic
  MCyR, n (%)
31 (72)
7 (32)
  CCyR, n (%)
32 (49)
4 (18)
Molecular
  MMR, n (%)
22 (51)
2 (9)
Data extraction date: 06 January 2014.  CP-CML=chronic phase chronic myeloid leukemia; AP-CML=accelerated phase chronic myeloid 
leukemia; BP-CML=blast phase chronic myeloid leukemia; Ph+ ALL=Philadelphia chromosome positive acute lymphoblastic leukemia; 
CHR=complete hematologic response; MaHR=major hematologic response; MCyR=major cytogenetic response; CCyR=complete cytogenetic 
response; MMR=major molecular response. *Includes patients with new CHRs and patients who entered with CHR at baseline and maintained it.  
The most common treatment-emergent AEs (≥30%) were rash (48.1%), nausea (45.7%), 
abdominal pain (44.4%), fatigue (44.4%), headache (42%), arthralgia (39.5%), constipation 
(39.5%), vomiting (38.3%), hypertension (37.0%), oedema peripheral (35.8%), platelet count 
decreased (35.8%), and pyrexia (35.8%).  
Vascular occlusive events (VOEs, thrombotic and ischemic AEs) were identified as important 
adverse events with longer term treatment. These events include arterial events involving the 
cardiovascular, cerebrovascular, or peripheral vascular body systems, as well as venous 
thromboembolic events.  
Serious VOEs occurred in 19 patients (23%): 11 patients (14%) had cardiovascular SAEs, 4 
patients (5%) had cerebrovascular SAEs, 4 patients (5%) had peripheral vascular events, and 2 
patients (2%) had venous SAEs.  Some patients had events of more than one type.  Vascular 
occlusive SAEs occurring in more than one patient were myocardial infarction/acute myocardial 
infarction (4 patients; 5%), troponin increased (3 patients; 3.7%), cerebrovascular accident 
(2 patients; 2.5%), peripheral arterial occlusive disease (2 patients; 2.5%), and peripheral 
ischemia (2 patients; 2.5%).  A more detailed presentation of AEs is provided in the 
Investigator’s Brochure.
The phase 1 data demonstrate that ponatinib has substantial activity in refractory CML in all 
phases, as well as in Ph+ ALL.  The promising efficacy in phase 1 was the basis for the phase 2 
clinical trial of ponatinib in CML and Ph+ ALL.
9.4.2
Update of Data from This Ongoing Trial (AP24534-10-201)
The safety and efficacy data from this trial have been used to support marketing applications in 
various jurisdictions.  Data from this trial have been published (Cortes et al, 2013). 
This trial enrolled 449 patients.  Patients were enrolled in one of 6 cohorts depending on their 
disease type (CP-CML, AP-CML, or BP-CML/Ph+ ALL) and whether they had the T315I 
mutation of BCR-ABL.  Response rates for the various cohorts are presented in Table 9-4. 
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Table 9-4
Ponatinib Phase 2 Clinical Trial (AP24534-10-201) by Cohort: Best Response to Therapy: Treated 
Population
CP-CML
AP-CML
BP-CML, Ph+ ALL
Total
N=267
Cohort A 
CP/R-I
N=203
Cohort B
CP/T315I
N=64
Total
N=83
Cohort C
AP/R-I
N=65
Cohort D
AP/T315I
N=18
Total 
BP-CML, 
Ph+ ALL
N=94
Cohort E
BP, Ph+ 
ALL/R-I
N=48
Cohort F
BP, Ph+ ALL/ 
T315I
N=46
Hematologic, 
n (%)a
N=267
N=203
N=64
N=83
N=65
N=18
N=94
N=48
N=46
CHRa
250 (93.6)
192 (94.6)
58 (90.6)
N/A
N/A
N/A
N/A
N/A
N/A
MaHR
N/A
N/A
N/A
47 (56.6)
37 (56.9)
10 (55.6)
32 (34.0)
17 (35.4)
15 (32.6)
Cytogenetic, 
n (%)b
N=267
N=203
N=64
N=83
N=65
N=18
N=94
N=48
N=46
MCyR
149 (55.8)
104 (51.2)
45 (70.3)
32 (38.6)
22 (33.8)
10 (55.6)
29 (30.9)
13 (27.1)
16 (34.8)
CCyR 
124 ( 46.4)
82 ( 40.4)
42 (65.6)
20 (24.1)
14 (21.5)
6 (33.3)
23 (24.5)
11 (22.9)
12 (26.1)
PCyR
25 ( 9.4)
22 ( 10.8)
3 ( 4.7)
12 (14.5)
8 (12.3)
4 (22.2)
6 (6.4)
2 ( 4.2)
4 (8.7) 
Molecular, n 
(%)c
N=267
N=203
N=64
N=83
N=65
N=18
N=94
N=48
N=46
MMR
102 (38.2)
65 (32.0)
37 (57.8)
17 (20.5)
11 (16.9)
6 (33.3)
11 (11.7)
9 (18.8)
2 (4.3)
Source: AP24534-10-201 Table 14.2.4.1 (Cytogenetic and hematologic), Table 14.2.7.1 (MMR).  Data extraction date 06 January 2014.
a Hematologic response is defined as CHR for Cohorts A and B, and as MaHR (CHR or no evidence of leukemia) for Cohorts C-F.
b Patients entering the study in PCyR must achieve a CCyR to be considered as having met MCyR criteria.
c Patients for whom a valid baseline MMR assessment is missing or who met the criteria for MMR at baseline were analyzed as non-responders.  
CP-CML= chronic phase chronic myeloid leukemia, AP-CML= accelerated phase chronic myeloid leukemia, BP-CML= blast phase chronic myeloid leukemia, Ph+ ALL =acute 
lymphocytic leukemia, N/A = Not applicable; CHR=complete hematologic response; MaHR=major hematologic response; MCyR=major cytogenetic response; CCyR=complete 
cytogenetic response; PCyR=partial cytogenetic response; MMR=major molecular response.
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The most common treatment-emergent AEs (≥30%) were thrombocytopenia (38%), constipation 
(37%), headache (37%), dry skin (35%), and abdominal pain (31%).  The most common 
treatment-related AEs (≥20%) were platelet count decreased (38%), rash (35%), dry skin (32%), 
and abdominal pain (23%).  The overall rate of VOEs was 20%, including cardiovascular (9%), 
cerebrovascular (6%), peripheral vascular (6%), and venous thromboembolic (5%). 
Treatment-emergent vascular occlusive SAEs were reported in 14% of patients overall, which 
included: cardiovascular (6%), cerebrovascular (4%), peripheral vascular (4%), and venous 
thromboembolic (3%), with some patients experiencing more than one type of event. 
A more detailed discussion of the results of this study is provided in the Investigator’s Brochure.
9.4.3
Multivariate Analyses of Data from the Phase 2 Clinical Trial (AP24534-10-201, 
PACE)
Multivariate analyses were performed on data from this trial to evaluate the relationships 
between dose intensity and efficacy, and between dose intensity and safety. 
A significant relationship was found between dose intensity and the occurrence of ≥grade 3 
serious adverse events including vascular occlusion, thrombocytopenia, pancreatitis, neutropenia, 
rash, increased ALT, increased AST, increased lipase, and myelosuppression in CML patients 
treated with ponatinib.  In general, increasing dose intensity correlated with an increased 
probability of experiencing adverse events.  Factors associated with a lower probability of 
adverse events were younger age, less time since diagnosis, and fewer prior TKIs.  
With longer follow-up and the accumulation of VOEs, the relationship between dose intensity 
and vascular occlusive and arterial occlusive events was further examined using multivariate 
analysis with an expanded set of covariates with a minimum of 24 months of follow-up.  All 
modeling showed a statistically significant association between dose intensity (up to the time of 
the events) and an increase in event rate in univariate models; this relationship became more 
significant when adjusting for covariates in multivariate models.  These results are consistent 
with univariate analyses demonstrating relationships between a variety of historical risk factors, 
including prior myocardial infarction or coronary disease, diabetes mellitus, hypertension, and 
hypercholesterolemia, and the occurrence of vascular complications.
Increasing dose intensity is associated with higher response rates, but response rates are 
sufficiently high that it is reasonable to attempt to identify prospectively and with greater 
resolution the effect of lower starting doses.  However, preliminary analyses in patients with AEs 
suggest that patients can maintain response on doses lower than 45 mg.  Data from the phase 2
trial demonstrate that patients who achieved response, either at 45 mg or 30 mg, maintained 
responses after dose reduction to 30 mg or 15 mg because of adverse events.  The maintenance 
of response appears to be independent of the length of dose reduction.  
Taken together, the data suggest that measures to lower exposure, such as dose reduction, may 
reduce risk while maintaining response rates.
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10
OBJECTIVES
The primary objective of this study is:
1.
To determine the efficacy of ponatinib in patients with CML in chronic, accelerated or 
blast phase or with Ph+ ALL who are either:
-
resistant or intolerant to either dasatinib or nilotinib,
or
-
have the T315I mutation.
The secondary objectives of this study are:
1.
To further characterize the anti-leukemia activity of ponatinib in these patients as 
evidenced by clinical responses, molecular responses, and clinical outcomes;
2.
To characterize the molecular genetic status of patients; and
3.
To examine the safety of ponatinib in these patients.
11
TRIAL DESIGN
11.1
Structure
This is a multi-center, international, phase 2, single-arm, open-label trial of oral ponatinib in 
patients with Ph+ disease.  Eligible patients will have CML in CP, AP, or BP as defined, or Ph+ 
ALL. Patients will either 1) have disease resistant to, or be intolerant to, therapy with either 
dasatinib or nilotinib; or 2) have the T315I mutation of BCR-ABL.  Patients will receive once 
daily oral administration of ponatinib tablet at a dose of 45 mg. Patients will be assessed for 
hematologic response, cytogenetic response, and molecular response.  Molecular genetic 
analyses will also be performed.  Adverse events will be assessed throughout and categorized by 
NCI CTCAE v, 4.0.  Patients will be evaluated according to the Schedule of Events tables in 
Section 8.  Assessments will be according to standard international criteria.  Patients will remain 
on treatment until disease progression or intolerance develops.  Progression-free survival (PFS) 
and overall survival data will also be collected and analyzed.  Patients will remain on treatment 
until they meet one or more criteria for withdrawal as listed in Section 13.8.
Patients will be grouped into cohorts as shown in Table 11-1.
Table 11-1
Patient Cohorts
Chronic Phase (CP)
Accelerated Phase (AP)
Blast Phase (BP)/Ph+
ALL
Resistant or intolerant 
to dasatinib or 
nilotinib
Cohort A
Cohort C
Cohort E
T315I mutation
Cohort B
Cohort D
Cohort F
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11.2
Study Endpoints
The primary endpoint of the study is:
1.
For CML patients in CP at study entry: major cytogenetic response (MCyR), defined as 
complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR).
CP patients in CCyR are not eligible for this study.
2.
For CML patients in AP at study entry: major hematologic response (MaHR), defined as 
complete hematologic response (CHR) or no evidence of leukemia (NEL).
AP patients in MaHR are not eligible for this study.
3.
For CML patients in BP at study entry or Ph+ ALL patients: MaHR, consisting of CHR 
or NEL.
BP and Ph+ ALL patients in MaHR are not eligible for this study.
The secondary endpoints of the study are:
1.
For CML patients in CP:
a.
Hematologic responses: CHR;
b.
Cytogenetic responses: confirmed MCyR; and
c.
Molecular responses: major molecular response (MMR).
2.
For CML patients in AP or BP or Ph+ ALL patients:
d.
Cytogenetic responses: CCyR, PCyR, confirmed MCyR; and
e.
Molecular responses: MMR.
4.
For all patients: time to response, duration of response, progression free survival, and 
overall survival.
5.
For all patients: safety and tolerability.
The exploratory endpoints of the study are:
12
SELECTION OF STUDY POPULATION
All patients must take part in the informed consent process.  During the consent process, the 
person obtaining consent must inform the patient of all elements of informed consent.  Adequate 
time must be allowed for questions and for the patient to make a voluntary decision.  No protocol 
specific procedures are to be performed until the patient has signed and dated an Institutional 
Review Board (IRB)/Ethics Committee (EC) approved informed consent form.
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Each patient's participation in the trial begins with the signing and dating of the informed consent 
form.  Patients must meet the inclusion and exclusion criteria to be enrolled in the trial.
12.1
Inclusion Criteria
1.
Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL 
(defined in Sections 12.3 and 12.4).
a.
All patients must have screening bone marrow (BM) cytogenetics with 
conventional banding performed within 42 days prior to initiating treatment.
b.
Examination of at least 20 metaphases is required.  If less than 20 metaphases are 
examined, the BM aspirate should be repeated.
Patients must either meet criterion 2 or 3:
2.
Be previously treated with and resistant, or intolerant, to either dasatinib or nilotinib:
2.1
Resistance is defined for CML CP patients (CP at the time of initiation of 
dasatinib or nilotinib therapy) as follows.  Patients must meet at least 1 criterion.
a.
Three months after the initiation of therapy: No cytogenetic response 
(>95% Ph+) or failure to achieve CHR.
b.
Six months after the initiation of therapy: Less than a minor cytogenetic 
response (>65% Ph+).
c.
Twelve months after the initiation of therapy: Less than a PCyR (>35% 
Ph+).
d.
At any time after the initiation of therapy, the development of new 
BCR-ABL kinase domain mutations in the absence of CCyR.
e.
At any time after the initiation of therapy, the development of new clonal 
evolution in the absence of CCyR.
f.
At any time after the initiation of therapy, the loss of any cytogenetic
response [from complete (0%), partial (1% to 35%), minor (36% to 65%), 
or minimal (66% to 95%) to a response at least 1 grade worse], confirmed 
in at least 2 consecutive analyses, separated by at least 4 weeks.
g.
At any time after the initiation of therapy, progression of disease (to AP or 
BP).
2.2
Resistance is defined for CML AP patients (defined at the time of initiation of 
dasatinib or nilotinib therapy) as follows.  Patients must meet at least 1 criterion.
a.
Three months after the initiation of therapy: failure to achieve a MaHR.
b.
At any time after the initiation of therapy, the loss of a MaHR, confirmed 
in at least 2 consecutive analyses, separated by at least 4 weeks.
c.
At any time after the initiation of therapy, the development of new 
BCR-ABL kinase domain mutations in the absence of a MaHR.
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2.3
Resistance is defined for CML BP patients (defined at the time of initiation of 
dasatinib or nilotinib therapy) and Ph+ ALL patients as follows.  Patients must 
meet at least 1 criterion.
a.
One month after the initiation of therapy: failure to achieve a MaHR.
b.
At any time after the initiation of therapy, the loss of a MaHR, confirmed 
in at least 2 consecutive analyses, separated by at least 1 week.
c.
At any time after the initiation of therapy, the development of new
BCR-ABL kinase domain mutations in the absence of a MaHR.
2.4
Intolerance to dasatinib or nilotinib is defined as:
a.
Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on 
therapy, or with persistent grade 2 toxicity, unresponsive to optimal 
management, including dose adjustments (unless dose reduction is not 
considered in the best interest of the patient if response is already 
suboptimal) in the absence of a CCyR for CP patients or MaHR for AP, 
BP or Ph+ ALL patients.
b.
Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute 
neutrophil count [ANC] or platelets) while on therapy that is recurrent 
after dose reduction to the lowest doses recommended by manufacturer 
(80 mg QD for dasatinib; 400 mg QD for nilotinib) in the absence of a 
CCyR for CP patients or MaHR for AP, BP or Ph+ ALL patients.
NOTE: 
Although the above criteria define failure after dasatinib or nilotinib (mostly 
according to Baccarani et al, 2009), patients who have gone on to later line 
therapy are eligible having failed dasatinib or nilotinib.
OR
3.
Develop the T315I mutation after any TKI therapy.
3.1
Patients with T315I mutation after any TKI need not have been treated with 
dasatinib or nilotinib.
3.2
Patients with T315I in CP must have less than a CCyR (>0% Ph+).
3.3
Patients with T315I in AP, BP, or Ph+ ALL must have less than a MaHR.
3.4
Patients with any history of T315I mutation will be eligible for study 
participation.  However, only those patients who carry a T315I mutation that is 
detected by direct sequencing in a pre-treatment blood sample using the study’s 
central laboratory will be analyzed in the T315I subset.  Details are provided in 
Section 12.5.
Patients must meet all of the remaining criteria to be eligible for the study:
4.
Patients must be ≥18 years old.
5.
Provide written informed consent.
6.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
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7.
Minimum life expectancy of 3 months or more.
8.
Adequate renal function defined as serum creatinine < 1.5× upper limit of normal (ULN) 
for institution.
9.
Adequate hepatic function defined as:
a.
Total bilirubin <1.5 × ULN,
b.
Alanine animotransferase  (ALT [SGPT]) and aspartate aminotransferase 
(AST [SGOT]) < 2.5 × ULN for institution (< 5 x ULN if liver 
involvement with leukemia),
c.
Prothrombin time (PT) < 1.5 × ULN.
10.
Normal pancreatic status defined as:
a.
Lipase ≤ 1.5 × ULN,
b.
Amylase ≤ 1.5 × ULN.
11.
Normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in 
males or ≤ 470 ms in females.
12.
For females of childbearing potential, a negative pregnancy test must be documented 
prior to enrollment.
13.
Female and male patients who are of childbearing potential must agree to use an effective 
form of contraception with their sexual partners throughout participation in this study.
14.
Ability to comply with study procedures, in the Investigator’s opinion.
12.2
Exclusion Criteria
Patients are not eligible for participation in the study if they meet any of the following exclusion 
criteria:
1.
Received TKI therapy within 7 days prior to receiving the first dose of ponatinib, or have 
not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs (except alopecia) due to 
agents previously administered.
2.
Received other therapies as follows:
a.
For CP and AP patients, received hydroxyurea or anagrelide within 24 hours 
prior to receiving the first dose of ponatinib, interferon, cytarabine, or 
immunotherapy within 14 days, or any other cytotoxic chemotherapy, 
radiotherapy, or investigational therapy within 28 days prior to receiving the first 
dose of ponatinib.
b.
For BP patients, received chemotherapy within 14 days prior to the first dose of 
ponatinib. Otherwise 2a applies.
c.
For Ph+ ALL patients, received corticosteroids within 24 hours before the first 
dose of ponatinib, or vincristine within 7 days prior to the first dose of ponatinib, 
or received other chemotherapy within 14 days prior to the first dose of 
ponatinib. Otherwise, 2a applies.
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d.
All patients are excluded if they have not recovered (> grade 1 by NCI CTCAE, 
v. 4.0) from AEs (except alopecia) due to agents previously administered.
3.
Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the 
first dose of ponatinib; any evidence of on-going graft-versus-host disease (GVHD), or 
GVHD requiring immunosuppressive therapy.
4.
Take medications that are known to be associated with Torsades de Pointes.  These 
medications are listed in Attachment B.
5.
Require concurrent treatment with immunosuppressive agents, other than corticosteroids 
prescribed for a short course of therapy.
6.
Have previously been treated with ponatinib.
7.
Patient with CML CP are excluded if they are in CCyR.
8.
Patients with CML AP, BP, or Ph+ ALL are excluded if they are in MaHR.
9.
Have active central nervous system (CNS) disease as evidenced by cytology or 
pathology. In the absence of clinical CNS disease, lumbar puncture is not required.  
History itself of CNS involvement is not exclusionary if CNS has been cleared with a 
documented negative lumbar puncture.
10.
Have significant or active cardiovascular disease, specifically including, but not restricted 
to:
a.
Myocardial infarction within 3 months prior to first dose of ponatinib,
b.
History of clinically significant atrial arrhythmia or any ventricular arrhythmia,
c.
Unstable angina within 3 months prior to first dose of ponatinib,
d.
Congestive heart failure within 3 months prior to first dose of ponatinib.
11.
Have a significant bleeding disorder unrelated to CML or Ph+ ALL.
12.
Have a history of pancreatitis or alcohol abuse.
13.
Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
14.
Have malabsorption syndrome or other gastrointestinal illness that could affect 
absorption of orally administered ponatinib.
15.
Have been diagnosed with another primary malignancy within the past 3 years (except 
for non-melanoma skin cancer or cervical cancer in situ, or controlled prostate cancer, 
which are allowed within 3 years).
16.
Are pregnant or lactating.  Women of childbearing potential must agree to effective 
contraception from the time of signing informed consent through the Follow-up Visit, 
approximately 30 days after last dose of ponatinib.
17.
Underwent major surgery (with the exception of minor surgical procedures, such as 
catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.
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18.
Have ongoing or active infection (including known history of human immunodeficiency 
virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV]).  Testing for these 
viruses is not required in the absence of history.
19.
Suffer from any condition or illness that, in the opinion of the Investigator or the medical 
monitor, would compromise patient safety or interfere with the evaluation of the safety of 
the study drug.
12.3
Classification of Chronic Myeloid Leukemia (CML) Patients
Patients with CML who enroll in the trial will be classified according to Talpaz and colleagues in 
their studies of dasatinib (Talpaz et al, 2006).  See Table 12-1 below.
Table 12-1
Chronic Myeloid Leukemia (CML) Phase Classification
CML Phase
Criteria
Chronic Phase (CP)
<15% blasts in peripheral blood or bone marrow
and
<20% basophils in peripheral blood
and
<30% blasts + promyelocytes in peripheral blood or bone marrow
and
>100 x 109 platelets/L in peripheral blood
and
No extramedullary disease
Accelerated Phase
(AP)
>15% and <30 % blasts in peripheral blood or bone marrow
or
>20% basophils in peripheral blood or bone marrow
or
>30% blasts + promyelocytes in peripheral blood or bone marrow (but < 30% 
blasts)
or
<100 x 109 platelets/L in peripheral blood unrelated to therapy
or
Cytogenetic, genetic evidence of clonal evolution
And
No extramedullary disease
Blast Phase (BP)
≥30% blasts in peripheral blood or bone marrow
or
Extramedullary disease other than hepatosplenomegaly
12.4
Philadelphia Positive Acute Lymphoblastic leukemia (Ph+ ALL) Patients
To be classified as having Ph+ ALL, patients must have > 30% blasts in blood or BM at the time 
of diagnosis and no prior history of CML.
12.5
CCI
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Direct (Sanger) sequencing is the standard test for mutation detection, as was recommended by a 
panel of experts at an NIH consensus conference in late 2005 (Hughes et al, 2006).  Direct 
sequencing can detect any potential single or compound mutation in BCR-ABL that is present in 
a sufficient percentage of transcripts (Muller et al, 2009).  Patients who demonstrate the T315I 
mutation by this assay, irrespective of prior treatments, will be included in one of the T315I 
cohorts (depending on their stage of disease) for analysis. T315I patients, and thus the T315I 
cohorts, will therefore be defined as those in whom the T315I mutation is detected by direct 
sequencing.
It is possible that some patients with a history of T315I mutation will not demonstrate a 
detectable mutation at the time of trial entry.  One potential explanation for this may be the 
well-described fall in the levels of T315I-containing CML clones, to below the limit of detection 
of the direct sequencing assay, when the selective pressure of TKI therapy is relaxed 
(Quintas-Cardama et al, 2008). Such patients (T315I- but T315I history+) will fall into one of 
2 groups: those treated with only imatinib, and those treated with dasatinib or nilotinib.  Patients 
who have been treated with dasatinib or nilotinib will be enrolled and assigned to one of the 
resistant/intolerant cohorts, as they meet the protocol eligibility criteria for this group 
irrespective of the absence of the T315I mutation.  Patients who have been treated with imatinib 
only, however, would only be eligible if they carry a detectable mutation. Nonetheless, these 
patients will be offered study treatment as their history of T315I mutation renders them unlikely 
to benefit from existing therapies.  But, they will not be included in the T315I cohorts (A, C, or 
E) as they do not meet the study-specified definition of a T315I carrier.  Based on our phase 1 
experience, we project that a small number of patients will have a T315I history, but will not be
negative for T315I by the direct sequencing assay result.
Since all patients who meet all eligibility criteria apart from the T315I determination will receive 
study drug, treatment initiation will be allowed once documentation is received by the central 
laboratory of receipt of the direct sequencing blood sample. Determination of inclusion in the 
T315I cohorts will be required prior to the first assessment of the primary endpoint, to avoid the 
introduction of bias in cohort assignment.
All patients will also undergo ASO qRT-PCR during screening.  This exploratory test is specific 
for T315I and is characterized by a 10-fold to 100-fold lower limit of detection (LLD) (ie, higher 
sensitivity) for the T315I mutation than the direct sequencing method (Deininger et al, 2006).  It 
will be utilized in an exploratory analysis to determine the presence of T315I mutations below 
the level of detection (LOD) of the direct sequencing method, and the extent to which these 
mutations contribute to resistance and patient outcomes.
The schema for testing and assignment to treatment cohorts is illustrated in Figure 12-1.
CCI
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Figure 12-1
Schema for T315I Mutation Testing
12.6
Number of Patients
At the time of this amendment, it is anticipated that approximately 450 patients will be enrolled 
in this study, to allow the T315I cohorts to enroll completely.  See Section 19.1 for additional 
details.
12.7
Screening Failures
Patients who have signed informed consent and subsequently fail to meet the inclusion and/or 
exclusion criteria are defined as screen failures.  For all screen failures, the Investigator is to 
maintain a screening log that documents the patient initials and reason(s) for screen failure.  A 
copy of the log should be retained in the Investigator’s study files.
13
STUDY PROCEDURES
See Section 8, Schedule of Events, for the procedures to be performed at each visit.
Patients are considered “on-study” beginning with the signing of the informed consent form.  
The “active study period” begins with administration of the first dose of ponatinib and continues 
through 30 days following discontinuation of ponatinib (ie, at the Follow-up Visit) (see 
Section 6: Definition of Terms).
The following describes the procedures/tests required for this study:
1.
Vital signs
Vital signs are temperature, pulse, respiratory rate, and blood pressure (when patient is 
seated).  Height and weight are required only at screening.
2. Physical Examination
Following the physical examination for Cycle 1, Day 1, all subsequent physical 
examinations may be directed to relevant findings in the patient.
CCI
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All physical examination should address the presence or absence of hepatosplenomegaly.
In patients with extramedullary involvement, the site(s) of involvement must always be 
assessed.  
3. Complete Blood Count (CBC) with Differential
Complete blood count (CBC) with differential is defined as peripheral blood total white 
blood cell (WBC) count, hemoglobin, hematocrit, platelet count, absolute neutrophil 
count (ANC) and white blood cell differential reported individually for each cell type 
including immature cells such as metamyelocytes, promyelocytes, and blasts, when 
present.
4. Prothrombin Time (PT) and Partial Thromboplastin Time (PTT)
The PT may be expressed as an International Normalized Ratio (INR) or in seconds.
5.
Serum Analysis
a)
Serum Chemistry, Amylase, Lipase 
Serum chemistry consists of a peripheral blood draw with the following assessments: 
sodium, potassium, chloride, bicarbonate (or total carbon dioxide [CO2]), blood urea 
nitrogen (BUN, or urea), fasting glucose, albumin, creatinine, total bilirubin (direct and 
indirect), alanine aminotransferase (AST [SGOT]), aspartate aminotransferase (ALT 
[SGPT]), alkaline phosphatase, magnesium, phosphorous, calcium, amylase, and lipase.  
The full chemistry panel must be obtained as specified in the Schedule of Events (Table 
8-1, Table 8-2, and Table 8-3) or more frequently as clinically indicated.
b)
Serum Triglycerides
A fasting or non-fasting serum triglyceride level must be collected during screening.  If a 
patient is ineligible based on a non-fasting level, the test may be repeated with a fasting 
level to determine eligibility.
c)
Fasting Cholesterol/Lipid Assessment
Fasting serum lipid cholesterol and lipid panel (total cholesterol, high-density lipoprotein 
cholesterol, low-density lipoprotein cholesterol, HDL/LDL ratios, and triglycerides) total, 
HDL, LDL) including triglycerides must be collected at the patient’s next visit for those 
who did not have fasting levels at screening and at subsequent time points as specified in 
the Schedule of Events (Table 8-1, Table 8-2, and Table 8-3) beginning with the patient’s 
next scheduled visit.  More frequent measurements may be required as clinically 
indicated.
d)
HbA1c 
Hemaglobin A1c (HbA1c) testing must be performed as specified in the Schedule of 
Events (Table 8-1, Table 8-2, and Table 8-3) beginning with the patient’s next scheduled 
visit.  More frequent measurements may be required as clinically indicated.
6.
Pregnancy Test
The pregnancy test must be a beta-human chorionic gonadotropin (β-HCG) test and either 
urine or serum can be used.  Women who are not of childbearing potential (status 
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post-hysterectomy, status post-bilateral oophorectomy, or postmenopausal [defined as 
amenorrhea for at least 12 months]) do not need to have the test performed.  The test 
must be known to be negative prior to the study drug administration and be performed 
within 7 days prior to first study drug administration.  Women of child bearing potential 
at study start must also complete the pregnancy test at the End-of-Treatment Visit.
7.
Electrocardiogram (ECG)
All ECGs must be 12-lead ECGs.  The screening ECG must be performed within the 
21-day screening window prior to study drug administration.  For consistency, the QTcF 
method must be used for all calculating of QTc intervals.  Additionally, 12-lead ECGs 
must be performed at the times specified in the Schedule of Events, or more frequently if 
clinically indicated. If other 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.
8.
Echocardiogram (ECHO)
An echocardiogram (ECHO) for assessment of left ventricular ejection fraction (LVEF) 
must be performed within the 21-day screening window and at the end of Cycle 3.  
Additional ECHOs need only be performed if clinically indicated. An ECHO is 
necessary at the End-of-Treatment or Follow-up Visit only if abnormality develops 
during the trial.
9.
Adverse Events (AEs) and Concomitant Medications
Adverse events and concomitant medications are to be recorded continuously throughout 
the entire study.
10.
Bone Marrow (BM) Aspirate/Cytogenetics
The BM aspirate results must list the components required for assessing response of the 
patient.  Bone marrow aspirates and biopsies may be performed at other times when 
clinically indicated.  Results of any BM aspirate or biopsy, whether scheduled or 
unscheduled, should be recorded in the patient’s electronic case report form (eCRF).  All 
BM examination must include blast count and cytogenetic assessment by conventional 
banding.
Bone marrow cytogenetics requires examination of at least 20 metaphases. If less than 
20 metaphases are examined, the BM aspirate should be repeated.
For assessment of MCyR for CP patients, a BM aspirate for morphology and cytogenetics 
occurs every 3 cycles up to Cycle 27. Any time after 27 cycles, CP patients who are not 
in CCyR continue to require a BM aspirate and cytogenetic assessment every 6 cycles
through Cycle 39, and at least yearly thereafter (more frequent is acceptable if clinically 
indicated).  Patients documented to be in CCyR after the BM aspirate and cytogenetic 
assessment at Cycle 27 (or later) are not required to have any further BM aspirates unless 
there is at least a 10-fold increase in BCR-ABL transcripts from the lowest point obtained 
on study, and the patient is not currently in MMR, at which time BM aspirate and 
cytogenetic assessments must be obtained.  Subsequent BM aspirate and cytogenetic 
assessments should be performed as clinically indicated.
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Patients who are in MMR any time after Cycle 27 are not required to have BM aspirate or 
cytogenetic assessments unless clinically indicated. Any time a bone marrow aspirate is 
performed, conventional banding for cytogenetics is required.  More frequent aspirates 
are allowed, but these are not required.
For assessment of MCyR for AP, BP and Ph+ ALL patients, a BM aspirate is required 
Cycle 1 Day 28, Cycle 2 Day 28, and at the end of each even-numbered cycle thereafter 
through Cycle 24, then at the end of Cycle 27. Any time after 27 cycles, patients who are 
not in CCyR continue to require a BM aspirate and cytogenetic assessment every 3 cycles 
through Cycle 39, and at least yearly thereafter (more frequent is acceptable if clinically 
indicated).  Patients documented to be in CCyR any time after the BM aspirate and 
cytogenetic assessment at Cycle 27 (or later) are not required to have any further BM 
aspirates unless there is at least a 10-fold increase in BCR-ABL transcripts from the 
lowest point obtained on study and the patient is not currently in MMR, at which time 
BM aspirate and cytogenetic assessments must be obtained.  Subsequent BM aspirate and 
cytogenetic assessments should be performed as clinically indicated.  Patients who are in 
MMR any time after Cycle 27 are not required to have BM aspirate or cytogenetic 
assessments unless clinically indicated.
For assessment of MCyR for AP, BP and Ph+ ALL patients, a BM aspirate for 
morphology and cytogenetics occurs on Cycle 1 Day 28, Cycle 2 Day 28, and then every 
2 cycles through cycle 24, then at the end of Cycle 27. Further need for BM aspirates 
beyond Cycle 27 are as described in the MaHR paragraph above.  Any time a bone 
marrow aspirate is performed conventional banding for cytogenetics is required.  More 
frequent assessments are allowed, but these are not required.
For MMR assessment for BP and Ph+ ALL, a sample of marrow aspirate for molecular 
response is also collected if a BM aspirate is performed.
A BM aspirate is performed at End of Treatment if it has been ≥12 weeks for CP and 
≥8 weeks for AP, BP, or Ph+ALL since the last BM aspirate.
11.
Additional Disease Assessments
Additional examination, laboratory studies, or imaging must be performed as appropriate 
to fully assess disease status.  This might include documentation of hepatosplenomegly, 
or in patients with extramedullary involvement, imaging of the site(s) of involvement.
12.
BCR-ABL T315I Mutation Detection by Direct Sequencing
Blood sample is required for BCR-ABL T315I mutation testing of peripheral blood by 
the Sanger direct sequencing method at screening and at the End-of-Treatment Visit.  The 
result of this test is used for eligibility, and will be reported to the participating 
investigator.  Additional samples will be collected and stored for additional T315I 
analyses.  Specific instructions will be supplied in the Study Reference Manual.
13.
BCR-ABL Molecular Response Assessment
Testing of peripheral blood (in all patients) or BM (in BP and Ph+ ALL patients) by 
quantitative real time PCR of the BCR-ABL transcript must be done at screening; during 
the treatment period at the same time as BM aspirates; and at the End-of-Treatment.
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This test quantifies molecular response to therapy, and will be reported to the 
participating investigator.  For assessment of molecular response for CP patients, 
collection of peripheral blood for determination of molecular response occurs every 3 
cycles up to Cycle 39, and subsequently every 6 cycles for the duration of the study. For 
AP, BP and Ph+ALL patients, collection of peripheral blood for determination of 
molecular response occurs every 2 cycles up to Cycle 24, every 3 cycles until Cycle 39, 
and subsequently every 6 cycles for the duration of the study.  For MMR assessment for 
BP and Ph+ ALL, a sample of marrow aspirate for molecular response is also collected if 
a BM aspirate is performed.  Specific instructions will be supplied in the Study Reference 
Manual.
14.
BCR-ABL T315I Mutation Detection by Allele-Specific Oligonucleotide (ASO) 
Testing
Blood sample is required for BCR-ABL T315I mutation testing of peripheral blood by 
quantitative ASO method at screening and at the End-of-Treatment.  This test is 
exploratory, and the result of this test is not used for eligibility.  Specific instructions will 
be supplied in the Study Reference Manual.
15.
Molecular Genetic Assessment
Peripheral blood for molecular genetic testing is to be collected for analysis of molecular 
determinants of response or resistance to ponatinib that are present at the initiation of 
study treatment, or that develop during study treatment.  This test is exploratory.  
Molecular genetic assessment must be done at screening; during the treatment period at 
the same time as BM aspirates (ie, at least 3 three months for CP and at least every 2 
months for AP, BP, and Ph+ ALL); and at the End-of-Treatment.  After Cycle 39, a 
separate molecular genetic sample is not required as the molecular genetic assessments 
may be performed using the molecular response sample (number 14 above).  Specific 
instructions will be provided in the Study Reference Manual.  
13.2
Screening
The following describes the procedures/tests required at screening (refer to Table 8-1 and Table 
8-2).
Please note: Screening tests and procedures are used to establish eligibility of the patient for the 
trial. Patients must continue to maintain laboratory values within eligibility perimeters if any 
given procedure or laboratory test is repeated prior to the start of study drug on Cycle1, Day 1.
●
Informed Consent
o
Informed Consent must be documented by a signed consent form prior to any 
screening activities not otherwise part of the patient’s care.
●
Medical and surgical history and demographics
o
Medical and surgical history includes diagnoses, therapies, medical and 
surgical treatments, and current medications.
o
Demographic information consists of the patient’s age, gender, race, and 
ethnicity (as allowed by local law and regulations).
●
Cancer diagnosis and prior cancer therapy
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o
The initial leukemia diagnosis including date and the current diagnosis at the 
time of screening, and the date of onset of the current diagnosis need to be 
recorded. Prior therapy history consists of the specific oncologic regimens a 
patient has received, the dates of the regimen and the best response to the 
regimen, and the reason for failure or intolerance to each regimen. Stem cell 
transplant or experimental therapy history is also recorded.
●
Current and past BCR-ABL mutation history
o
Any previously identified mutations, and the dates of identification, must be 
recorded.
●
Vital signs, including height and weight
●
Physical examination
●
ECOG performance status
●
CBC with differential
●
Serum chemistry including amylase and lipase
●
Serum triglycerides
●
PT/ PTT
●
Pregnancy test
●
ECG (within the 21-day screening window)
●
ECHO
●
AEs and concomitant medications
●
BM aspirate/cytogenetics
o
The BM aspirate with or without biopsy must occur within 42 days prior to 
the first dose of ponatinib and ± 7 days of all other scheduled assessments.
●
Additional disease assessments (eg, evaluation of extramedullary disease sites, in AP, 
BP and Ph+ ALL)
●
BCR-ABL mutation detection by Direct Sequencing
o
BCR-ABL mutation testing of peripheral blood is required for participation in 
this trial. A sample must be collected and shipped to the central laboratory 
during screening to document the type(s) of BCR-ABL mutations present at 
the time of screening. This screening sample will be used to identify patients 
with the T315I mutation. The sample must be submitted and documentation 
of receipt recorded by the central laboratory prior to a patient beginning 
treatment with ponatinib. However, the results of the test need not be 
available to initiate study drug administration. Results should be available 
within approximately 5 business days of receipt of sample by the central 
laboratory and before the end of Cycle 1. Additional blood samples will be 
collected and stored for additional analyses of the T315I mutation. Specific 
instructions will be supplied in the Study Reference Manual.
●
BCR-ABL T315I mutation detection by ASO testing
●
Molecular response assessment (quantitative PCR of BCR-ABL transcripts)
●
Molecular genetics assessment
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13.3
Active Study Period
Procedures to be performed during the study and timing of procedures are listed by disease state 
in Section 8 (refer to Table 8-1 and Table 8-2) and described in detail in Section 13.0.
Please maintain a special awareness of the assessments of the primary and secondary endpoints.
These are discussed in the notes accompanying Tables 8-1 and 8-2.
13.4
Study Drug Administration
Study drug (ponatinib) will be self-administered by the patient. The starting dose will be 45 mg 
taken orally once daily.  Each 28-day dosing period is referred to as 1 cycle.  Patients will take 
the prescribed number of tablets with water, with or without food, at approximately the same 
time each day.  
In October 2013 dose adjustments were made based on response to minimize the risk of adverse 
events with ponatinib while maintaining response:

All CP-CML patients currently on trial who had already achieved MCyR had their dose 
reduced to 15 mg QD, unless, in the judgment of the investigator, the benefit/risk analysis 
taking into account the patient’s CML characteristics, BCR-ABL mutation status, and the 
patient’s cardiovascular risk justified treatment with a higher dose. 

All CP-CML patients currently on trial who had not yet achieved MCyR had their dose 
reduced to 30 mg QD, unless, in the judgment of the investigator, the benefit/risk analysis 
taking into account the patient’s CML characteristics, BCR-ABL mutation status, and the 
patient’s cardiovascular risk justified treatment with a higher dose.

All AP-CML, BP-CML, and Ph+ ALL patients currently on trial had their dose reduced 
to 30 mg QD, unless, in the judgment of the investigator, the benefit/risk analysis taking 
into account the patient’s CML characteristics, BCR-ABL mutation status, and the 
patient’s cardiovascular risk justified treatment with a higher dose.

All patients who lose response at a lower dose may have their dose escalated (up to a 
maximum of 45 mg QD) as long as the dose had not been previously lowered as a result 
of an adverse event.
These dose reductions were implemented via direct communication to investigators. For all 
patients, the dosing changes based on the above recommendations or the justification not to 
change the patient from his or her current dose should be documented in the patient’s chart and 
in the study drug administration page of the electronic case report form (eCRF).
13.5
Management of Missed Doses of Study Drug
Patients who forget to take their scheduled dose of study drug more than 6 hours after it is due 
should not make up the missed dose. Any missing doses should be recorded, and subsequent 
training of patients should be documented in the appropriate source record (eg, clinic chart), 
patient diary card, and study drug administration eCRF.
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13.6
End-of-Treatment Visit
Study procedures at the End-of-Treatment Visit are to be conducted within 2 weeks following 
the last dose of ponatinib or the patient/investigator decision to end treatment, whichever is later 
(refer to Table 8-3).
The following are the procedures/tests required at the End-of-Treatment Visit:
●
Vital signs
●
Physical examination
o
The End-of-Treatment Visit physical examination should be a complete 
physical examination.
●
ECOG performance status
●
CBC with differential
●
Serum chemistry including amylase and lipase
●
Fasting cholesterol/lipid assessment
●
ECG
●
ECHO
o
An ECHO is necessary at the End-of-Treatment only if abnormality develops 
during the trial.
●
Pregnancy test, if applicable
●
BCR-ABL mutation detection by direct sequencing
●
BCR-ABL T315I mutation detection by ASO testing
●
Molecular response assessment
●
Molecular genetic assessment
●
AEs and concomitant medications
13.7
Removal of Patients from Study Drug Administration or Assessment
In the event that a patient is being considered to be withdrawn from the study, every effort will 
be made by the Investigator to discuss the circumstances regarding the permanent 
discontinuation from the study with the Sponsor’s Medical Monitor first, and if the patient is 
discontinued, document and report the reasons for withdrawal as thoroughly as possible.  The 
reason(s) for termination must be clearly reported on the appropriate page of the patient’s eCRF.  
An eCRF must be completed for any patient who receives study drug.  An End-of-Treatment 
reason must be recorded for any patient who receives study drug and/or is enrolled in the study.
If a patient is discontinued from the trial for any reason, every effort must be made to perform all 
clinical and laboratory procedures as scheduled for the End-of-Treatment Visit.  In the event that 
the patient fails to return for the necessary visit(s), an effort must be made to contact the patient 
to determine the reason, and this information should be recorded in the appropriate source record 
and the end-of-treatment eCRF.
13.8
Criteria for Discontinuation
Patients will be discontinued from further study drug administration in the event of any of the 
following: 
●
Intolerable toxicity as determined by the Investigator;
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●
Myocardial infarction, stroke, or urgent revascularization, unless the benefit of study drug
is believed to outweigh the risk, as determined by the investigator;
●
Progression of disease requiring an alternate therapy, in the opinion of Investigator;
●
Entry into another therapeutic clinical trial or start of additional anticancer therapy;
●
Significant deviation from the protocol or eligibility criteria, in the opinion of the medical 
monitor or Investigator;
●
Noncompliance with study or follow-up procedures;
●
Patient withdrawal of consent and decision to discontinue participation;
●
Termination of the trial by the sponsor;
●
Any other reason that, in the opinion of the Investigator, would justify removal of the 
patient from the study.
13.9
Follow-up Visit
The Follow-up Visit will be performed approximately 30 days (± 7 days) after the last dose of 
Study Drug.  The following procedures/tests are required at the Follow-up Visit or the 
patient/investigator decision to end treatment, whichever is later (refer to Table 8-3):
●
Vital signs
●
Physical examination
o
The Follow-up Visit physical examination may be directed to any relevant 
findings.
●
ECOG performance status
●
CBC with differential
●
Serum chemistry with amylase and lipase
●
ECHO
o
An ECHO is necessary at the Follow-up Visit only if an abnormality 
develops during trial.
●
AEs and concomitant medications
13.10
Survival Follow-up
Survival data will be collected every 12 weeks ± 2 weeks starting after the last dose of study 
drug or the investigator/patient decision to discontinue treatment, whichever occurs later, and 
continuing for up to 96 months from the time the last patient is assigned to study treatment.  
These data do not need to be obtained during a visit, and phone contact is acceptable.
14
STUDY DRUG
14.1
Study Drug Administration
Study drug will be administered only to eligible enrolled patients at the participating centers 
listed on the FDA Form 1572.  Patients do not need to continuously meet the eligibility criteria in 
order to continue on study drug.
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14.2
Monitoring of Study Drug Administration
Patients will take the prescribed number of tablets with water, with or without food, at 
approximately the same time each day.  Patients will be provided a diary card or equivalent 
where the date of administration will be recorded; complete instructions will be provided with 
the Study Reference Manual.  Patients who forget to take their dose more than 6 hours after it is 
due should not make up the missed dose.  Any missing doses should be recorded, and subsequent 
training of patients should be documented in the appropriate source record (eg, clinic chart).  
When possible, patients should take the study drug under observation during scheduled study 
visits to the clinic.
14.3
Supportive Care
An analysis of baseline risk factors in patients from this phase 2 study assessed the impact of 
hypertension, hypercholesterolemia, diabetes, and obesity, and revealed several risk factors that 
pre-dispose patients to vascular occlusive events (VOEs) on ponatinib (see Section 9.4.3).  Based 
on this analysis, the following supportive care recommendations are provided to decrease the risk 
of VOEs for patients taking ponatinib.
Diabetes Treatment
Patients with diabetes are at increased risk of experiencing arterial thrombotic events while being 
treated with ponatinib.  Therefore, as a part of the assessment and management of the patient’s 
cardiovascular risk factors, initiation of or modifications to diabetic care should be considered in 
patients being treated with ponatinib who have elevated glucose levels.  The American Diabetes 
Association guidelines should be followed, and anti-diabetes treatment and lifestyle intervention 
(including but not limited to weight loss, decreased fat intake, calorie restriction, increased 
physical activity, and smoking cessation) should be started in any patient with fasting glucose 
> 130 mg/dL (7.2 mM/L) and/or HbA1c ≥7% (Diabetes Prevention Program Research Group, 
2002; American Diabetes Association, Position Statement 2013).
Hypertension Treatment
Hypertension (HTN) may contribute to risk of vascular occlusive events.  Patients who have 
HTN should be managed appropriately.  During ponatinib treatment, blood pressure elevations 
should be monitored and managed.  Hypertension should be treated to achieve a goal of 
< 150/90 mmHg.  Initial antihypertensive treatment should generally include a thiazide-type 
diuretic, calcium channel blocker, angiotensin-converting enzyme inhibitor (ACEI), or 
angiotensin receptor blocker (ARB) (James et al, 2014).  Ponatinib treatment should be 
temporarily interrupted if HTN is not medically controlled (refer to Section 14.4.3 below for 
additional management recommendations).  Patients may require urgent clinical intervention for 
HTN associated with confusion, headache, chest pain, or shortness of breath.
14.4
Management of Adverse Drug Reactions
Dose reduction guidelines are outlined in Sections 14.5 and 14.6.  This section provides 
additional guidance for management of selected AEs for ponatinib. 
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Comprehensive assessments of any study drug-related AEs (adverse drug reactions) experienced 
by the patient will be performed throughout the course of the study.  Anticipated adverse drug 
reactions that may be experienced are described in the Investigator's Brochure.  The severity of 
the event, as well as clinical judgment, will be utilized to determine appropriate management of 
the patient for any AE experienced while participating in this trial.
Any medication, including those administered for therapy of symptoms considered to be 
associated with study drug administration, should be reported on the appropriate concomitant 
medication page of the patient’s eCRF.  The symptoms should be reported on the AE page.
14.4.1
Vascular Occlusion
Serious arterial and venous thrombotic and occlusive adverse events, including fatal myocardial 
infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular 
disease, and the need for urgent revascularization procedures have occurred in ponatinib-treated 
patients.  Patients with and without cardiovascular risk factors, including patients age 50 years or 
younger, experienced these events.  Vascular occlusive adverse events were more frequent with 
increasing age and in patients with prior history of ischemia, hypertension, diabetes, or 
hyperlipidemia.
14.4.1.1
Arterial Occlusion and Thrombosis 
Serious arterial thrombotic adverse events occurred in ponatinib-treated patients with some 
patients experiencing events of more than one type.  Serious cardiovascular thrombotic adverse 
events included myocardial infarction and coronary artery disease.  Some patients developed 
congestive heart failure concurrent or subsequent to the myocardial ischemic event.
Serious cerebrovascular adverse events were also reported in ponatinib-treated patients.  There 
were patients who developed stenosis of large arterial vessels of the brain (eg, carotid, vertebral, 
middle cerebral artery).  
Serious peripheral arterial adverse events were reported in ponatinib-treated patients.  Cases of 
digital or distal extremity necrosis were reported in patients with diabetes mellitus and peripheral 
arterial disease; some of these required amputations.  
Monitor and aggressively treat factors that increase cardiovascular risk, such as hypertension, 
cigarette smoking, hypercholesterolemia, and hyperglycemia.  Interrupt and consider 
discontinuation of study drug in patients who develop arterial thrombotic adverse events.  Any 
patient who experiences a serious adverse event of myocardial infarction, stroke, or urgent 
revascularization while on trial must be discontinued from the trial unless, for that individual 
patient, the investigator believes the potential benefits of ponatinib treatment are likely to exceed 
the risks of continued treatment and the patient has no other treatment options.  
14.4.1.2
Venous Thromboembolism
Serious venous thromboembolic adverse events occurred in ponatinib-treated patients, including 
deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein 
thrombosis.  Consider dose modification or discontinuation of ponatinib in patients who develop 
serious venous thromboembolic adverse events.
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Ponatinib should not be restarted in patients with serious venous occlusive adverse events unless 
the potential benefit outweighs the risk of recurrent venous occlusions and the patient has no 
other treatment options.  
14.4.2
Congestive Heart Failure and Left Ventricular Dysfunction
Severe congestive heart failure (CHF) and left ventricular (LV) dysfunction have been reported 
in patients taking ponatinib.  Patients with cardiac disease or risk factors for cardiac disease 
should be monitored carefully and any patient with signs or symptoms consistent with cardiac 
failure should be evaluated and treated.  Consider discontinuation of ponatinib in patients who 
develop serious CHF.
14.4.3
Hypertension
Blood pressure should be monitored at each visit.  Hypertension (HTN) detected by at least 2
blood pressure measurements should be graded according to CTCAE version 4.0, which defines 
HTN as a disorder characterized by a pathological increase in blood pressure; a repeated
elevation in the blood pressure exceeding 140 mm Hg for systolic over 90 mm Hg for diastolic.  
For patients who develop HTN or worsening HTN during study treatment, aggressive 
antihypertensive medication should be initiated or optimized to achieve target blood pressure 
before interruption or dose reduction of the study treatment at the discretion of the investigator.  
If hypertension is persistent despite adequate anti-hypertensive therapy including titration of 
anti-hypertensive medication or introduction of additional anti-hypertensive medications, or if 
grade 4 HTN develops, dose interruption and reduction is recommended according to Dose 
Modification Guidelines for general non-hematologic AEs in Table 14-1.
14.4.4
Cardiac Arrhythmias
Supraventricular tachyarrhythmias were reported in patients treated with ponatinib.  Advise 
patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Symptomatic 
bradyarrhythmias have also been reported.  Advise patients to report signs and symptoms 
suggestive of slow heart rate (fainting, dizziness, or chest pain, see Table 14-1).
14.4.5
QT Prolongation
The QT interval-prolonging potential of ponatinib was assessed in 39 leukemia patients, and no 
clinically significant QT prolongation was observed.  This finding was confirmed in ECG 
observations of 140 patients in the ponatinib arm of the phase 3 trial.  However, a thorough QT 
study has not been performed.  Therefore, a clinically significant effect on QT cannot be 
excluded.
14.4.6
Hemorrhage
Hemorrhagic events have occurred in patients receiving ponatinib.  Most hemorrhagic events 
occurred in patients with grade 4 thrombocytopenia.  Interrupt administration in the case of 
serious or severe hemorrhage.
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14.4.7
Compromised Wound Healing and Gastrointestinal Perforation
Based on its mechanism of action, ponatinib may compromise wound healing.  Interrupt 
ponatinib for at least 1 week prior to major surgery.  The decision when to resume ponatinib after 
surgery should be based on clinical judgment of adequate wound healing.
14.4.8
Neuropathy
Serious peripheral and cranial neuropathic adverse events have occurred in ponatinib-treated 
patients.  In clinical trials, serious peripheral neuropathic adverse events reported included the 
following: peripheral neuropathy, paresthesia, hypoesthesia, and hyperesthesia.  Of the patients 
who developed neuropathy, many developed neuropathy during the first month of treatment.  
Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, 
discomfort, a burning sensation, neuropathic pain, or weakness.  Consider interrupting ponatinib 
as described in Section 14.6 and evaluate any suspected neuropathy.
14.4.9
Ocular Toxicity
Serious ocular adverse event toxicities leading to blindness or blurred vision have occurred in 
ponatinib-treated patients.  Retinal toxicities including macular edema, retinal vein occlusion, 
and retinal hemorrhage have also occurred in ponatinib-treated patients.  Other ocular toxicities 
include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis.  Conduct comprehensive 
eye exams when clinically indicated.  See Table 14-1 for details.
14.4.10
Hepatotoxicity
Hepatotoxicity, most commonly manifested by reversible transaminase and alkaline phosphatase 
elevation and hyperbilirubinemia, has been observed with ponatinib. Monitoring of hepatic 
function is recommended and management of laboratory abnormalities should be managed with 
dose interruption and/or dose reduction according to Table 14-1.
14.4.11
Pancreatitis and Lipase or Amylase Elevations
Pancreatitis (symptomatic abdominal pain associated with pancreatic enzyme elevation) and/or 
elevations in lipase and amylase are known AEs associated with both ponatinib.  Most cases of 
pancreatitis or elevated pancreatic enzymes occur within the first 2 months of treatment with 
ponatinib.  The events are generally uncomplicated and reversible and can be managed with a 
brief interruption of treatment and standard medical therapies.  Almost all patients are able to 
continue on with ponatinib treatment at the same or a reduced dose once the event has improved 
to grade 1 or resolved.  Patients with low-grade (1 or 2) elevation in amylase can be continued 
without dose reduction but should be monitored closely with serial enzyme level determinations.  
See Table 14-1 for details.
14.4.12
Fluid Retention and Edema
Ponatinib is associated with edema and occasionally serious fluid retention. Patients should be 
weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected 
rapid weight gain should be carefully investigated and appropriate treatment provided.  Interrupt, 
reduce the dose of, or discontinue ponatinib as outlined in Table 14-1.
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14.4.13
Myelosuppression
Neutropenia, anemia, and thrombocytopenia have been observed in clinical studies of ponatinib 
in patients with CML.  While myelosuppression can occur at any time during treatment, its onset 
in CML patients most commonly occurs within the first month on treatment. Myelosuppression 
can partially be attributed to the CML itself; however, treatment with ponatinib could also 
contribute.  These events can typically be managed with supportive care and, if felt to be 
treatment-related, either a reduction or interruption of treatment with ponatinib should occur.  
Rarely, one or more cytopenias can lead to permanent discontinuation of treatment.  The use of 
hematopoietic growth factors such as granulocyte colony-stimulating factor, and granulocyte-
macrophage colony-stimulating factor is permitted on study; these agents may be used to support 
blood counts as clinically indicated to minimize treatment interruptions or repeated dose 
reductions.
The important clinical AE of febrile neutropenia falls under the broad category of 
myelosuppression. If a patient’s individual risk factors place them at high risk of developing 
febrile neutropenia, primary prophylactic use of colony-stimulating growth factors for the 
prevention or reduction of febrile neutropenia is recommended according to the published NCCN 
guidelines [NCCN Guidelines Version 1, 2012 – Myeloid Growth Factors].
14.4.14
Tumor Lysis Syndrome (TLS)
The patients at risk of tumor lysis syndrome (TLS) are those with high tumor/leukemic burden 
prior to treatment. These patients should be monitored closely, especially at the initiation of 
treatment.  Appropriate TLS precautions and prophylactic treatment (such as aggressive 
hydration with fluids and the initiation of allopurinol 600 mg/day or other appropriate 
treatments) should be initiated prior to the start of therapy for those at risk for TLS.  Rasburicase 
and other appropriate treatments for hyperuricemia or TLS are permitted.
14.4.15
Rash and/or Pruritus
Skin rashes have been commonly reported to be associated with ponatinib.  The vast majority of 
the skin events are nonserious, either self-limiting or manageable with antihistamines or topical 
steroids, and do not result in discontinuation. In more severe cases, a short course of oral 
corticosteroids may be used until the rash has improved or resolved.
In patients treated with ponatinib, the most common skin manifestations are a diffuse 
maculo-papular rash that is non-pruritic or an acneiform dermititis. Occasionally, patients 
treated with ponatinib have been reported to have a dry, flaky or exfoliative type of rash or a 
psoriasiform dermatitis. Rarely, an erythema multiforme type of rash has been associated with 
ponatinib.
Most patients can be maintained on the current dose of ponatinib, uninterrupted, and if necessary
their symptoms can be managed with antihistamines, emollients, or topical steroids.  If dose 
interruption is indicated, patients can resume the same dose of ponatinib typically without 
recurrence of symptoms once the original episode has improved or resolved.  Interrupt 
administration in the case of serious or severe (grade 3 or 4) rash and follow the dose 
modification guidelines for non-hematologic toxicity in Table 14-1.
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14.4.16
Diarrhea, Nausea, and Vomiting
Diarrhea is a common side effect of ponatinib.  The use of anti-diarrhea medications is 
permitted. Patients who experience ≥grade 2 diarrhea may begin loperamide at its standard 
treatment schedule (4 mg orally x 1, then 2 mg orally after each loose stool, up to a maximum of 
16 mg/day).
Nausea and vomiting are also reported as side effects of ponatinib. The use of an antiemetic 
prophylactically is not recommended. However, if a patient is symptomatic, appropriate 
antiemetic medications may be used as clinically indicated.
14.4.17
Constitutional Symptoms/Joint Pain
Certain constitutional symptoms such as myalgia, arthralgia, headache, weakness, fatigue, 
asthenia, and low grade fever have been very commonly reported with ponatinib.  These
symptoms have been reported mainly at the initiation of treatment, are typically short lived 
(<2 weeks), and are seldom, if ever, reported beyond the first month of treatment.  These AEs are 
most commonly low grade (grade 1 and 2) and are self-resolving without the need for dose 
interruption or dose reduction when they do occur. Most patients can be maintained on the 
current dose of ponatinib, uninterrupted, and their symptoms can be managed with a short course 
of oral analagesics, corticosteroids, and/or anti-pyretics as clinically indicated.  If dose 
interruption is indicated, patients can resume the same dose of ponatinib typically without 
recurrence of symptoms once the original episode has improved or resolved.
14.5
Dose Delays and Reductions
Dose delays and/or reductions will be implemented for patients who experience adverse drug 
reactions as indicated in the following sections. 
14.6
Dose Delay and/or Reduction for Adverse Events (AEs) Attributable to the Study 
Drug
Table 14-1 describes guidelines for dose modification due to study-drug-related toxicity, graded 
according to NCI CTCAE v4.0.  These guidelines should be followed by clinical investigators; 
however, for an individual patient, dose interruptions, reductions and treatment discontinuation 
should also be based on the clinical circumstance.  Deviation from these guidelines should be 
documented and communicated with the sponsor.  When the observed toxicity has resolved to 
≤grade 1, the investigator may resume full dosing if clinically indicated.
There will be no dose modifications for grade 1 or 2 non-hematologic toxicities (except for 
pancreatitis and QTcF prolongation) attributable to the study drug that are manageable with 
supportive care or do not interfere with normal daily activities of the patient.  In the event of a 
persistent grade 1 or 2 non-hematologic adverse drug reaction that is 1) intolerable due to clinical 
symptoms or interferes with normal daily activities, or 2) not controlled by optimal supportive 
care, the patient may be managed by dose delay or reduction as described in Table 14-1.  There 
are no suggested dose modifications for grade 1 or 2 hematologic toxicities.
Guidelines for assessment and management of pancreatitis and QTcF prolongation are described 
in Table 14-1 also.
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Pancreatic toxicities may be manifest as an isolated elevation of pancreatic enzymes (amylase, 
lipase) in the absence of symptoms; or by enzyme elevation coupled with clinical symptoms.  In 
the latter case, imaging should be performed, but in the case of isolated enzyme elevations it is 
optional.  Note: the recent update of NCI CTCAE version 4 has changed the grading of 
pancreatitis from the grading system in version 3.  CTCAE version 4 in the Gastrointestinal 
disorder section defines grade 2 pancreatitis as “enzyme elevation or radiologic findings only.”  
Version 4 separately defines toxicity grades for isolated elevation of lipase or serum amylase, 
found in the Investigations section of the guidance.  Refer to Table 14-1 for guidelines on 
management of pancreatitis with or without symptoms, and management of amylase/lipase 
elevations with or without symptoms.
In the event of a grade 3 or 4 AE attributed to study drug, the patient may be managed by dose 
reduction or delay as well.  Guidelines are described in Table 14-1.  Note that grade 3 or 
4 myelosuppression might be attributable to disease rather than study drug. In this case, if dose 
reduction or delay is deemed necessary, it is allowed.
Study drug administration may be delayed for up to 28 days to allow for improvement (to grade 
1 or screening) or resolution of the event.  If longer delays are necessary, the case should be 
discussed with the Medical Monitor of the study.  In the event toxicity is intolerable and not 
controlled, a decision may be made by the Investigator to discontinue the patient from further 
study drug administration.
Table 14-1
Modifications for Adverse Events (AEs) Attributable to Study Drug
Non-hematologic Toxicity
Grade 2
Persistent 7 days with optimal care
First occurrence at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level
Recurrence* at 45 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 30 mg 
Recurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrence at 15 mg:
Discontinue ponatinib 
Grade 3 or 4
Occurrence** at 45 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 30 mg 
Occurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Occurrence at 15 mg:
Discontinue ponatinib 
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Pancreatitis and Elevation of Lipase
Asymptomatic grade 1 or 2 elevation 
of serum lipase
Consider interruption or dose reduction of ponatinib
Asymptomatic grade 3 or 4 elevation 
of lipase (> 2 × ULN) or 
asymptomatic radiologic pancreatitis 
(grade 2 pancreatitis)
Occurrence at 45 mg:
Hold until event is ≤ grade 1 (≤ 1.5 x ULN), or has returned to baseline
Resume at 30 mg 
Occurrence at 30 mg: 
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Occurrence at 15 mg: 
Discontinue ponatinib
Symptomatic grade 3 pancreatitis 
(severe pain, vomiting, medical 
intervention indicated [eg, analgesia, 
nutritional support])
Occurrence at 45 mg:
Hold until complete resolution of symptoms and lipase elevation is ≤ 
grade 1, or has returned to baseline
Resume at 30 mg 
Occurrence at 30 mg:
Hold until complete resolution of symptoms and lipase elevation is ≤ 
grade 1, or has returned to baseline 
Resume at 15 mg 
Occurrence at 15 mg:
Discontinue ponatinib
Grade 4 pancreatitis
Discontinue ponatinib
Hepatic Toxicity
Elevation of liver transaminase > 3 × 
ULN (grade 2 or higher)
Occurrence at 45 mg:
Hold and monitor hepatic function until event is ≤ grade 1 (≤3 × ULN), or 
has returned to baseline
Resume at 30 mg 
Occurrence at 30 mg: 
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Occurrence at 15 mg: 
Discontinue ponatinib
Elevation of AST or ALT ≥3 × ULN 
concurrent with an elevation of 
bilirubin > 2 × ULN and alkaline 
phosphatase < 2 × ULN
Discontinue ponatinib
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LVEF/CHF1
Grade 2 
First occurrence at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level 
Recurrence* at 45 mg:
Hold  until event is ≤ grade 1, or has returned to baseline
Resume at 30 mg 
Recurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrence at 15 mg:
Discontinue ponatinib
Grade 3
Occurrence** at 45 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 30 mg 
Occurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Occurrence at 15 mg:
Discontinue ponatinib
Grade 4
Discontinue ponatinib.
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Skin Rash
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 at 45 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 30 mg 
Recurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrence at 15 mg:
Discontinue ponatinib
Grade 3 persistent despite optimal 
symptomatic therapy
First occurrence at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level 
Recurrence at 45 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 30 mg 
Recurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrence at 15 mg:
Discontinue ponatinib
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Prolonged QTcF
Grade 2 (QTcF 481-500 ms)
First occurrence at any dose level:
Hold ponatinib
Perform serum electrolyte analysis (including potassium, calcium and 
magnesium) and correct with supplements if below normal limits
Review concomitant medications
Repeat ECG as clinically indicated, but at least daily until QTcF returns to 
≤ grade 1 (480 ms)
Resume at 45 mg after recovery to ≤ grade 1
If no contributing reason was identified for QTcF elevation then weekly 
ECG monitoring is recommended for 4 weeks upon resumption of 
ponatinib, then monthly for 6 months, and then every 3 months for the 
remainder of the study, or more frequently as clinically indicated
Recurrence at 45 mg:
Repeat above
Resume at 30 mg after recovery to ≤ grade 1, or until event has returned to 
baseline
Recurrence at 30 mg:
Repeat above
Resume at 15 mg after recovery to ≤ grade 1, or until event has returned to 
baseline 
Recurrence at 15 mg:
Discontinue ponatinib
Grade 3 (QTcF ≥ 501 ms on at least 2 
separate ECGs)
First occurrence at any dose level:
Hold ponatinib
Perform serum electrolyte analysis (including potassium, calcium and 
magnesium) and correct with supplements if below normal limits
Review concomitant medications
Repeat ECG as clinically indicated, but at least daily until QTcF returns to 
≤ grade 1 (480 ms)
Resume at 30 mg after recovery to ≤ grade 1
If no contributing reason was identified for QTcF elevation then weekly 
ECG monitoring is recommended for 4 weeks upon resumption of 
ponatinib, then monthly for 6 months, and then every 3 months for the 
remainder of the study, or more frequently as clinically indicated
Recurrence at 45 mg:
Repeat above
Resume at 30 mg after recovery to ≤ grade 1, or until event has returned to 
baseline
Recurrence at 30 mg:
Repeat above
Resume at 15 mg after recovery to ≤ grade 1, or until event has returned to 
baseline 
Recurrence at 15 mg:
Discontinue ponatinib
Grade 4
Discontinue ponatinib
Consult Sponsor
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Hematologic
ANC/platelets
Grade 3 or 4
First occurrence at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level 
Recurrence at 45 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 30 mg 
Recurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrence at 15 mg:
Discontinue ponatinib
* “Recurrence” means the second time an AE is encountered by a patient at a given dose level. 
** “Occurrence” means the first time an AE is encountered by a patient at a given dose level.
Definitions:  ANC = absolute neutrophil count; CHF = congestive heart failure; CT = computed tomography; LVEF = left 
ventricular ejection fraction.
1Note: CTCAE criteria should be used to interrupt or discontinue study drug for grade 2, 3, or 4 events considered to be study
drug related. 
For grade 2: LVEF < 50% - 40%, grade 3: LVEF < 39 - 20%, grade 4: refractory CHF or LVEF < 20%.
14.6.1
Dose Modifications for Vascular Occlusive Events
If a serious vascular occlusive adverse reaction occurs, treatment should be interrupted.  
Ponatinib should not be re-administered to patients with serious arterial or venous occlusive 
events unless the potential benefit outweighs the risk of recurrent arterial or venous occlusions.
Vascular occlusive events include a broad range of non-specific terms that could meet the criteria 
for diagnosis of a vascular occlusive event. Investigators should use their clinical judgment and
medical knowledge of the specific terms in describing these vascular occlusive events. 
Investigator discretion should be used to judge the event as a vascular pathology when applying 
these dose modifying schemes. 
14.6.1.1
Arterial Thrombotic and Occlusive Events
In patients suspected of developing any arterial thrombotic occlusive event, ponatinib should be 
immediately interrupted. 
Patients should be discontinued from ponatinib in the event of myocardial infarction (MI), 
unstable angina, cerebrovascular accident or transient ischemic attack (TIA), or revascularization 
procedures, unless for that individual patient, the investigator believes the potential benefits of 
ponatinib treatment exceed the risks of continued treatment. 
For all other arterial thrombotic occlusive events, the dose modification guidelines are outlined 
in Table 14-2.
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Table 14-2
Dose Modifications for Arterial Thrombotic Occlusive Events
Vascular Occlusion: Other Cardiovascular and Cerebrovascular Events
Grade 1 
Consider interruption or dose reduction of ponatinib until the event 
resolves.
Grade 2
First occurrence** at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level. 
Recurrence* at 45 mg: Discontinue study drug
Recurrence at 30 mg: Discontinue study drug
Recurrence at 15 mg: Discontinue study drug
Grade 3 and 4
Discontinue ponatinib.
Other Vascular Occlusions including Peripheral Vascular Events
Grade 1 
Consider interruption or dose reduction of ponatinib until the event 
resolves.
Grade 2 
First occurrence at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level 
Recurrence at 45 mg:
Hold  until event is ≤ grade 1, or has returned to baseline
Resume at 30 mg 
Recurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrence at 15 mg:
Discontinue ponatinib
Grade 3
Occurrence at 45 mg:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 30 mg 
Occurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 15 mg 
Occurrence at 15 mg: 
Discontinue ponatinib
Grade 4
Discontinue ponatinib.
* “Recurrence” means the second time any VOE, not necessarily recurrence of the same VOE, is encountered by a patient at any
dose level. 
** “Occurrence” means the first time an AE is encountered by a patient at a given dose level.  
14.6.1.2
Venous Thromboembolic Events
Patients should be discontinued from study drug in the event of life-threatening pulmonary 
embolism and retinal vein thrombosis.
For all other venous thromboembolic events, the dose modification guidelines are outlined in 
Table 14-3.
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Table 14-3
Dose Modifications for Venous Thromboembolic Events
Venous Thromboembolic Events
Grade 1 
Consider interruption or dose reduction of ponatinib until the event 
resolves.
Grade 2 
First occurrence at any dose level: 
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level
Recurrence* at 45 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 30 mg 
Recurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrence at 15 mg:
Discontinue ponatinib
Grade 3
Occurrence** at 45 mg:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 30 mg 
Occurrence at 30 mg:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at 15 mg 
Occurrence at 15 mg: 
Discontinue ponatinib
Grade 4
Discontinue ponatinib.
* “Recurrence” means the second time any VOE, not necessarily recurrence of the same VOE, is encountered by a patient at any
dose level. 
** “Occurrence” means the first time an AE is encountered by a patient at a given dose level.  
14.7
Dose Re-Escalation after Resolution of Adverse Drug Reactions
The dose of ponatinib can be re-escalated from the reduced dose level to the previously 
administered dose level if the following criteria are met:

All ≥ grade 2 non-hematologic toxicities have recovered to ≤ grade 1 for at least 
1 month

Or, all ≥ grade 3 hematologic and non-hematologic toxicities have recovered to ≤grade 
2 and are manageable with supportive therapy
Patients may receive step-wise dose escalations if the above criteria continue to be met (eg, 
15 mg daily to 30 mg daily to 45 mg daily) up to the limitations outlined in Section 13.4.
Note:  patients with grade ≥3 LV dysfunction, CHF, or vascular occlusion events are not eligible 
for dose re-escalation after resolution of their symptoms.
14.8
Formulation, Packaging, and Labeling
Ponatinib drug product is manufactured as tablets. Each tablet contains either 15 mg or 45 mg of 
ponatinib active ingredient.  Other ingredients are typical pharmaceutical excipients (lactose 
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monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, 
magnesium stearate, polyethylene glycol, talc, polyvinyl alcohol, and titanium dioxide). Tablets 
will be supplied as follows:
45 mg tablets: 30 count in 30 cc white high density polyethylene (HDPE) bottles with 
induction-sealed child resistant caps.
15 mg tablets: 60 count in 30 cc white HDPE bottles with induction-sealed child resistant 
caps.  Note: 15 mg tablets will be used for patients reducing dose.
Bottle labels will bear the appropriate label text as required by governing regulatory agencies.  
At a minimum, such text will include product name, product strength, number of tablets, and lot 
number.
14.9
Storage and Stability
The recommended storage condition for ponatinib is room temperature.
14.10
Study Drug Accountability
The study pharmacist or designee at the site will be responsible for handling and dispensing 
study drug, and completing associated documentary paperwork.
Supplies are shipped to the investigative site at appropriate intervals, depending on patient 
accrual.  The site must use an appropriate dispensing log/accountability form provided by the 
Sponsor, or an acceptable substitute approved by the Sponsor.  Each time study medication is 
dispensed for a patient, the following information must be recorded: the patient’s initials, the 
patient’s study number, tablet strength (45 mg or 15 mg), the number of tablets dispensed with 
the corresponding lot number, and the initials of the person dispensing the drug. These logs are 
to be maintained by the study pharmacist in the pharmacy throughout the duration of the study 
and will be periodically verified by a representative of the Sponsor.  The Investigator is 
responsible for ensuring that the patient diary card(s) and study drug provided to the patient and 
returned from the patient are accounted for and noted in source documentation.
14.11
Disposition of Used Supplies
All used bottles of study drug must be destroyed in an appropriate manner according to the 
standard practice at each study center.  Destruction of such supplies will be documented, and a 
representative of the Sponsor will verify disposition records.
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 re-
dispensed.
No other utilization of ponatinib intended for use in this study is authorized by the Sponsor.  The 
Principal Investigator or his/her designee will be responsible for the appropriate handling and 
disposition of residual study drug.  Each site is responsible for proper and careful destruction of 
study drug returned by patients.
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14.12
Inventory of Unused Supplies
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.  Any discrepancies must be investigated and all unused 
study drug must be destroyed on site per the standard operating procedures of the investigative 
site.
15
CONCOMITANT TREATMENT
All concomitant medications administered from the time of informed consent signature through 
the 30-day Follow-up Visit are to be reported on the appropriate eCRF for each patient.
Prior Treatment
Reasonable efforts will be made to collect information on all prior cancer treatments received by 
the patient (chemotherapy, radiotherapy, immunotherapy, biologics, etc.).  The information must 
be obtained from the patient’s medical chart and recorded on the patient’s eCRF.
15.1
Permitted Treatment
All routine and appropriate supportive care (including blood products) will be allowed during 
this study, as clinically indicated, and in accordance with the standard of care practices.  Clinical 
judgment should be utilized in the treatment of any AE experienced by the patient.
Information on all concomitant medications, administered blood products, as well as 
interventions occurring during the study must be recorded on the 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 is permitted. 
●
Where appropriate, patients may be treated with hematopoietic growth factors or 
erythropoietin for limited times.
●
Where appropriate, hydroxyurea or anagrelide are permitted during the first cycle of 
ponatinib administration.  Concomitant use must be discontinued by the end of the third 
week of ponatinib in patients with AP, BP, and Ph+ ALL, and by the end of the first 
cycle in all patients, and is thereafter prohibited.
15.2
Prohibited Treatment
The following concurrent medications and treatments are prohibited: 
●
Any other anticancer therapy including, but not limited to, chemotherapeutic agents, 
immunotherapy, biological response modifiers, radiotherapy, surgery and/or systemic 
hormonal therapy (hematopoietic growth factors are permitted).  However, intrathecal 
therapy for CNS relapse in lymphoid BP or Ph+ ALL is allowed.  NOTE: patients with 
active CNS disease at study entry are excluded (see exclusion criteria 9).
●
Use of any other investigational drug or device.
●
Use of medications with a known risk of Torsades de Pointes (see Attachment B).
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●
Herbal preparations or related over-the-counter preparations containing herbal ingredients 
(eg, St. John’s Wort, Blue Cohosh, Estroven) either during or within 2 weeks prior to the 
first dose of ponatinib.
●
Elective surgery requiring in-patient care.
Medications that are potent inhibitors or inducers of CYP3A4 (see Attachment C) should be 
avoided, but are not prohibited (see Section 15.3).
Medications that prolong the QT interval should be avoided, but are not prohibited. If such 
medications are necessary, and used while a patient is on study, then additional ECG monitoring 
should be performed as clinically indicated.
15.3
Potential Drug Interactions
Based on in vitro studies, drug-drug interactions (DDIs) due to either CYP inhibition or 
induction by ponatinib are highly unlikely in clinical trials using the recommended daily dose of 
45 mg.  In vitro studies also demonstrate that human CYP3A4 is involved in the metabolism of 
ponatinib.  In view of this, a drug interaction study was performed with a strong CYP3A4 
inhibitor in healthy subjects.  Ketoconazole co-administration increased ponatinib Cmax and AUC 
by 47% and 78%, respectively.  Since CYP3A4 contributes to the metabolism of ponatinib, 
strong inducers or inhibitors of CYP3A4 should be used with caution or avoided altogether.  If 
co-administration with strong inhibitors of CYP3A4 is unavoidable, consider reduction of the 
ponatinib dose 1 level from the current (that is, 30 mg for a patient receiving 45 mg; 15 mg for a 
patient receiving 30 mg).  For patients already receiving 15 mg daily due to a prior dose 
reduction, consider an alternative to the strong CYP3A4 inhibitor or, if that is not possible, 
consult the sponsor.
Medicines that are associated with the prolongation of the QT interval may interact with 
ponatinib as well and contribute to QT interval prolongation, which has the potential to 
contribute to ventricular arrhythmia. In addition, some medicines associated with QT 
prolongation also interact with the CYP3A4 cytochrome and an effect on the QT interval might 
thus be exacerbated.  Concomitant administration of medicines with a known risk of Torsades de 
Pointes are prohibited (see Attachment B). Medicines that otherwise prolong the QT interval 
should be avoided.
Concomitant use of ponatinib with anti-platelet agents and anticoagulants should be approached 
with caution in patients who may be at risk of bleeding events (see Section 14.4.6 Hemorrhage
and Section 14.4.13 Myelosuppression).
16
MEASURES TO MINIMIZE/AVOID BIAS
16.1
Patient Registration and Identification
Demographic information on all patients who sign the Informed Consent Form will be recorded 
on the screening log.  Those patients who complete screening procedures and meet all eligible 
criteria may be enrolled into the study using the enrollment procedure established by the 
Sponsor.  At the time of enrollment, the patient will be assigned a unique identification code 
(number), consisting of a study site number and a unique consecutive number.
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17
SAFETY
17.1
Safety Variables
Safety will be assessed by physical examination, interim history, and laboratory assessments.  
Adverse events will be graded according to the NCI CTCAE, v. 4.0 (see Study Reference 
Manual).
17.2
Safety Assessment Methods
Safety will be assessed by physical examination, interim history, and laboratory assessments.  
Adverse events will be graded according to the NCI CTCAE, v. 4.0 (see Study Reference 
Manual).
17.3
Safety Laboratory Assessments
The local laboratory of the institution where the trial is being conducted will be used to process 
the laboratory samples.  Clinically significant laboratory abnormalities (eg, those that lead to 
some sort of intervention) are to be assessed as AEs and recorded on the appropriate eCRF. 
18
EFFICACY
18.1
Efficacy Variables
Primary efficacy endpoints are listed in Section 11.2. The primary endpoints are:
1.
For CML patients in CP at study entry: MCyR, defined as CCyR or PCyR.
CP patients in CCyR are not eligible for this study; as such, they would not be eligible 
for inclusion in the efficacy analysis.
2.
For CML patients in AP at study entry: MaHR, defined as CHR or no NEL.
AP patients in MaHR are not eligible for this study; as such, they would not be eligible 
for inclusion in the efficacy analysis.
3.
For CML patients in BP at study entry or Ph+ ALL patients: MaHR, consisting of CHR or 
NEL.
BP and Ph+ ALL patients in MaHR are not eligible for this study; as such, they would 
not be eligible for inclusion in the efficacy analysis.
Secondary endpoints for efficacy are defined in Section 11.2. They are:
1.
For CML patients in CP:
a.
Hematologic responses: CHR;
b.
Cytogenetic responses: confirmed MCyR; and
c.
Molecular responses: MMR.
2.
For CML patients in AP or BP or Ph+ ALL patients:
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a.
Cytogenetic responses: CCyR, PCyR, confirmed MCyR; and
a.
Molecular responses: MMR.
3.
For all patients: time to response, duration of response, progression free survival, and 
overall survival.
4.
For all patients: safety and tolerability.
The exploratory endpoints of the study are:
1.
For all patients: BCR-ABL sequence collection and analysis
2.
For all patients: ASO PCR for T315I
3.
For all patients: molecular genetic analyses.
Criteria that define the responses that constitute primary and secondary endpoints are included in 
Attachment A.  In addition, criteria to define progression are also listed in Attachment A.
18.2
Efficacy Assessment Methods
Cytogenetic response will be assessed on BM biopsies and aspirations using standard methods 
for quantifying the proportion of Ph+ chromosomes.  The criteria for cytogenetic response are 
derived from Kantarjian et al. (2006) and Talpaz et al. (2006), as well as the National 
Comprehensive Cancer Network (NCCN, 2012) clinical practice guidelines (accessed 21 March 
2014).  Conventional banding must be utilized, preferably on at least 20 metaphase cells.  If BM 
sampling is insufficient and less than 20 metaphases are evaluable, the absolute result should be 
reported and the percentage calculated.  Bone marrow samples will be obtained according to the 
Schedule of Events, Section 8.  A BM sample may be obtained more frequently if clinically 
indicated.
The primary endpoint will be based on an unconfirmed MCyR.  That is, the detection of a 
complete or partial cytogenetic response on a single BM aspirate will qualify as a response for 
the determination of efficacy.  Confirmed MCyR is a secondary endpoint.  In addition, duration 
of response will be measured as described in the statistical analysis plan.
Hematologic responses will be assessed on peripheral blood samples using standard methods to 
obtain a CBC with differential.  Peripheral blood samples will be obtained according to the 
Schedule of Events, Section 8.
Complete hematologic response in CP will be confirmed.  That is, the detection of CHR on a 
CBC at a single time point will require confirmation by CBC at least 4 weeks later to qualify as a 
response.  A concurrent BM aspirate need not be done to assess CHR in CP patients.
Major hematologic response will be confirmed in patients in AP, BP, or with Ph+ ALL.  That is, 
the detection of a CHR or NEL at a single time point will require confirmation at least 4 weeks 
later with a peripheral blood CBC and differential to qualify as a response for the determination 
of the primary endpoint for efficacy. The BM aspirate need not be repeated for confirmation.
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19
STATISTICAL ANALYSIS
19.1
Sample Size and Power
19.1.1
Overview of Trial Design
This is a phase 2, single-arm trial in patients with CML and Ph+ ALL.
Table 19-1 summarizes the number of patients planned to be recruited in each cohort:
Table 19-1
Planned Number of Patients for Each Cohort
Chronic Phase 
(CP)
Accelerated 
Phase (AP)
Blast Phase 
(BP)/Leukemia
Total
Resistant/intolerant to 
dasatinib or nilotinib
100
(Cohort A)
40
(Cohort C)
40
(Cohort E)
180
T315I mutation
60
(Cohort B)
40
(Cohort D)
40
(Cohort F)
140
Total
160
80
80
320
Cohort A will consist of CP CML patients resistant or intolerant to dastinib or nilotinib.  Cohort
B will consist of CP CML patients with T315I mutations.  Cohorts C and E will consist of AP 
and BP/Ph+ ALL respectively, who are resistant or intolerant dasatinib or nilotinib.  Cohorts D 
and F will consist of AP and BP/Ph+ ALL patients, respectively, with the T315I mutation.
Each of the 6 cohorts proposed in this trial are representative of distinct patient populations with 
different primary endpoints.  Each cohort of patients will be analyzed separately for efficacy.  
The safety data from all cohorts will be pooled for the purpose of describing the safety of all 
treated patients as a whole.  These cohorts can be viewed as 6 separate studies that are enrolled 
through a single “umbrella” protocol; therefore, no adjustments for multiplicity are planned.
19.1.2
Sample Size Determination: Cohorts A and B
The primary endpoint for this trial for patients with chronic CML (Cohorts A and B) will be 
MCyR.  The MCyR rate is defined as the proportion of patients who have achieved a CCyR or 
PCyR after the initiation of study treatment.
The primary analysis of the primary endpoint of MCyR will be performed using a 2-sided exact 
95% confidence interval (CI) for MCyR rate among all treated patients in each cohort.
Data on the use of second generation TKIs in patients who have failed dasatinib and nilotinib are 
available in several small studies (Giles et al, 2007; Quintas-Cardama et al, 2007; Garg et al, 
2009).  These 3 studies demonstrate an approximately 30% MCyR in these patients.  However, 
these are highly selected patient populations; they do not include patients who have failed more 
than 2 agents, and responses are typically of short duration. Thus, for the purposes of this trial, 
the null or uninteresting MCyR rate is set at 20% for Cohort A (resistant and intolerant CP 
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patients).  The alternative MCyR rate is set at 35% for Cohort A.  The overall alpha level for 
each cohort will be set at 0.05.  With a cohort size of 100 patients, a minimum of 29 responders 
(ie, those with a CCyR and a PCyR) would need to be observed in Cohort A in order to observe 
an exact 95% CI such that the lower bound exceeds 20% and the upper bound exceeds 35%.  
Therefore, 100 patients will provide at least 85% power to distinguish between a null response 
rate of 20% and an alternative response rate of 35% in Cohort A.  The study will also provide at 
least 98% power to distinguish between 20% and 40%, in which case 29 responses will also be 
required, and at least 78% power to distinguish between 30% and 45%, in which case 40 
responses would be required.
With a cohort size of 100 patients, the maximum width of the exact 95% CI will be 
approximately 20% when the MCyR rate is in the expected range of 20% to 35%.
For Cohort B (T315I CP patients), the null or uninteresting MCyR rate is set at 10% and the 
alternative MCyR rate is set at 35%.  Data on the use of second generation drugs (Muller et al, 
2009; Garg et al, 2009) in these patients suggest that less than 10% of patients achieve MCyR.  
With a cohort size of 60 patients, a minimum of 14 responders would need to be observed in 
Cohort B in order to observe an exact 95% CI such that the lower bound exceeds 10% and the 
upper bound exceeds 35%.  Therefore, 60 patients will provide approximately 98% power to 
distinguish between a null response rate of 10% and an alternative response rate of 35% in 
Cohort B.
With a cohort size of 60 patients, the maximum width of the exact 95% CI will be 25% when the 
MCyR rate is in the expected range of 10% to 35%.
19.1.3
Sample Size Determination: Cohorts C-F
The sample sizes for Cohorts C to F (AP, and BP/Ph+ ALL) are based on similar considerations 
for each cohort (Garg et al, 2009).  The endpoint for these cohorts is the MaHR.  The MaHR rate 
is defined as the proportion of patients achieving a CHR or NEL response.  The null or 
uninteresting MaHR rate is set at 10% and the alternative MaHR 30%.  With a cohort size of 
40 patients, a minimum of 9 responders would need to be observed in cohorts C to F in order to 
observe an exact 95% CI such that the lower bound exceeds 10% and the upper bound exceeds 
30%.  Forty patients in each cohort will provide approximately 89% power to distinguish 
between the null response rate of 10% and an alternative response rate of 30% in these cohorts.
19.1.4
Overall Sample Size
As described in preceding Sections 12.5 and 19.1.1, for each disease phase, after the initiation of 
treatment, patients will be tested for the T315I mutation.  Depending on the outcome of the test, 
patients will be assigned to a resistant/intolerant cohort (cohorts A, C or E, respectively,
depending on disease phase) or a T315I cohort (cohorts B, D, or F).  For example, a CP patient 
will be tested and assigned to cohort A or B, an AP patient will be assigned to cohorts C or D, 
and a BP or Ph+ ALL patient will be assigned to cohort E or F.  Therefore, enrollment and 
assignment to the paired cohorts comprising a disease phase are linked by the relative prevalence 
of T315I patients and the T315I testing scheme.
Early enrollment experience demonstrates that patients whose disease is resistant or intolerant to 
therapy are relatively more common than patients who carry the T315I mutation.
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Thus, the mutation testing schema will lead to a relative over-availability of resistant and 
intolerant patients compared with T315I patients.  Therefore, cohorts A, C, and E may fill before 
the T315I cohorts B, D and F will reach their target sample sizes.  Since the scientific objectives 
of the study require meeting the target accrual goals for the T315I cohorts (and, indeed, all 
cohorts), it is anticipated that the higher relative proportion of resistant/intolerant patients to 
T315I patients will require over-enrollment of the resistant/intolerant cohorts (A,C, and E) to 
ensure full T315I patient enrollment.
Thus, overall enrollment will be determined by the need to fill the T315I cohorts. At the time of 
this amendment, it is anticipated the trial may require up to 450 patients to ensure reaching the 
planned sample sizes of the T315I cohorts. Individual cohorts may be closed by the Sponsor to 
control overall enrollment to the study.
19.2
Statistical and Analytical Plans
19.2.1
Analysis Populations
Treated Population: 
Cohorts A and B
This population includes all patients assigned to Cohort A or B who have received at least 1 dose 
of study drug.  Patients for whom the T315I sample is not received before the first assessment of 
the primary outcome who are resistant to either dasatinib or nilotinib will be assigned to Cohort 
A.  Patients who are not confirmed to have a detectable T315I mutation by direct sequencing 
before the first cytogenetic assessment and are not resistant to dasatinib or nilotinib will not be 
included in the treated population and will be analyzed separately (refer to Section 12.5).  We 
estimate that approximately 10% of patients with a history of a T315I mutation will not be 
resistant or intolerant to dasatinib or nilotinib and lack the mutation by direct sequencing.  We 
also estimate that this situation will most likely apply to the CP candidates, as patients with AP, 
BP and Ph+ ALL will most likely have received more extensive therapy.  Thus, we estimate that 
fewer than 10 patients will fall into this group.
Cohorts C-F
This population includes all patients assigned to one of Cohort C-F who have received at least 
1 dose of study drug.  Patients in AP CML for whom the T315I sample is not received before the 
BM aspirate, and who are resistant to either dasatinib or nilotinib will be assigned to Cohort C.  
Patients in BP CML and Ph+ ALL patients for whom the T315I sample is not received before the 
first BM aspirate, and who are resistant to either dasatinib or nilotinib will be assigned to Cohort 
E.  Patients who are not confirmed to have a detectable T315I mutation by direct sequencing 
before the first BM aspirate and are not resistant to dasatinib or nilotinib will not be included in 
the treated population and will be analyzed separately (refer to Section 12.5).  It is estimated that 
approximately 10% of patients with a history of a T315I mutation will not be resistant or 
intolerant to dasatinib or nilotinib and lack the mutation by direct sequencing.  It also is 
estimated that this situation will most likely apply to the CP candidates, as patients with AP, BP 
and Ph+ ALL will most likely have received more extensive therapy.  Thus, fewer than 
10 patients are expected to fall into this group.
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Safety Population: This population includes all patients who have received at least 1 dose of 
study drug.
19.2.2
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized separately for each cohort and will 
include at a minimum: age, gender, race, weight, country/region, and disease characteristics 
(eg, time since diagnosis, duration of chronic disease, mutation status).
19.2.3
Efficacy Analyses
All efficacy analyses will be performed separately by each cohort (designated A through F) and 
will include all patients in the treated population.
19.2.3.1
Definitions of Efficacy Endpoints
Primary efficacy endpoints for this trial are defined as follows:
●
Major cytogenetic response (MCyR), which is defined as CCyR or PCyR.  Patients 
entering the trial already in PCyR must achieve a CCyR in order to be considered as 
achieving a MCyR.  The criteria for response are given in Attachment A.
●
Major hematologic response (MaHR), which is defined as CHR and NEL.  Major 
hematologic response will be confirmed by a peripheral blood CBC and differential no 
earlier than 28 days later.  The criteria for response are given in Attachment A.
Secondary efficacy endpoints for this trial are defined as follows:
●
Confirmed MCyR, which is defined as 2 assessments of CCyR or PCyR at least 28 days 
apart.  For CP patients entering the trial in PCyR, confirmed MCyR will be defined as 
2 assessments of CCyR at least 28 days apart.
●
Major Molecular Response (MMR) (as defined in Attachment A)
●
Duration of Response, which is defined as the interval between the first assessment at 
which the criteria for response are met until the criteria for progression (as defined in 
Attachment A) are met, censored at the last date at which the criteria for response are 
met.  An additional analysis will be performed defining the duration as the time from the 
first assessment at which the criteria for response are met until the last assessment at 
which the criteria for response are met.
●
Progression-free survival, which is defined as the interval from the first dose of study 
treatment until the criteria for progression (as defined in Attachment A) or death are met, 
censored at the last response assessment.
●
Overall survival, which is defined as the interval from the first dose of study treatment 
until death, censored at the last date at which patient was known to be alive.
●
Time to response, which is defined as the interval from the first dose of study treatment 
until the criteria for response are first met, censored at the last assessment of response.
Exploratory endpoints for this trial are defined as follows:
●
BCR-ABL sequence analysis will be collected and compared with response to therapy.
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●
ASO PCR for T315I will be collected and compared with T315I status by history and by 
direct sequencing during screening, as well as with response to therapy.
●
Molecular genetic analyses will be performed to better understand outcomes.
19.2.3.2
Primary Endpoint Analysis
Cohorts A and B
The primary analysis of the primary endpoint of MCyR will be performed using a 2-sided exact 
95% CI for the MCyR rate and will be based on the total patients enrolled in each cohort.  Major 
cytogenetic response rate is defined as the proportion of patients who have achieved a CCyR or 
PCyR after the initiation of study treatment.  Patients entering the trial already in PCyR must 
achieve a CCyR in order to be considered a success for the MCyR rate.
Cohorts C-F
Major hematologic response rate is defined as the proportion of patients who have achieved a 
confirmed CHR or NEL after the initiation of study treatment.  The primary analysis of the 
primary endpoint of MaHR will be performed using a 2-sided exact 95% CI for MaHR rate and 
will be based on the total patients enrolled in each cohort.
19.2.3.2.1 Data Handling Rules for the Primary Analyses of the Primary Endpoint
The key data handling rules for the primary efficacy analyses are as follows:
●
All CP CML patients (Cohorts A and B) who do not respond by 12 months after the 
initiation of study treatment will be analyzed as non-successes.
●
All AP/BP phase CML patients and Ph+ ALL patients (Cohorts C, D, E and F) who do 
not respond by 6 months after the initiation of study treatment will be analyzed as 
non-successes.
●
Patients who are not confirmed to have a positive T315I mutation testing result by the 
first cytogenetic assessment (CML patients in CP) or BM aspirate (CML patients in AP 
or BP and Ph+ ALL patients) and are resistant or intolerant to either dasatinib or nilotinib 
will be assigned to cohort A, C, or F (resistant/intolerant cohorts).
●
At any given cytogenetic assessment, if fewer than 20 metaphases are examined, that 
assessment will be treated as missing for the determination of MCyR.
●
A BM aspirate is required for a patient to be considered as meeting the criteria for 
MaHR.
●
For a given visit, if all of the data required to support an assessment of response (see 
Attachment A) are not available, the patient will be considered as not a success for that 
particular visit.
19.2.3.3
Secondary Endpoint Analyses
●
Confirmed MCyR:  the confirmed MCyR rate is defined as the proportion of patients who 
have achieved a confirmed CCyR or PCyR after the initiation of study treatment.  
Patients entering the trial already in PCyR must achieve a confirmed CCyR in order to be 
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considered a success for the confirmed MCyR rate.  The analysis will be performed using 
a 2-sided exact 95% CI for the confirmed MCyR rate.
●
Duration of response will be estimated using the Kaplan-Meier method.  The median 
duration of response and 95% CI will be calculated.  An additional analysis will be 
performed defining the duration as the time from the first assessment at which the criteria 
for response are met until the last assessment at which the criteria for response are met.
●
Progression-free survival and overall survival, and time to response will be estimated 
using the Kaplan-Meier method.  The median duration of response and 95% CI will be 
calculated.
1.1.1.1.1 Data Handling Rules for Secondary Endpoint Analyses
In addition to the data handling rules specified in Section 19.2.3.2.1, the following key data 
handling rules for the secondary efficacy analyses will be implemented (note that the definition 
of progression is specified in Attachment A):
●
Loss of MCyR is defined as meeting any of the following criteria:
o
In patients entering the trial in PCyR: 2 consecutive cytogenetic assessments 
≥28 days apart with Ph+ > 0%.  Patients with a single cytogenetic assessment 
with Ph+ > 0% followed by no additional cytogenetic assessments will be also 
considered as meeting the criteria for loss of MCyR.
o
In patients entering the trial not in PCyR: 2 consecutive cytogenetic assessments 
28 days apart with Ph+ > 35%.  Patients with a single cytogenetic assessment with 
Ph+ > 35% followed by no additional cytogenetic assessments will be also 
considered as meeting the criteria for loss of MCyR.
●
Loss of MaHR (Cohorts C through F) is defined as 2 consecutive hematologic 
assessments ≥4 weeks apart at which at the criteria for MaHR are not met.  Patients with 
a single hematologic assessment at which the criteria for MaHR are not met followed by 
no additional hematologic assessments will be also considered as meeting the criteria for 
loss of MaHR.
●
Patients who progress after a single missed or incomplete visit will be considered as 
having progressed at that visit.
●
Patients who progress after 2 or more missed or incomplete visits will be censored at the 
last visit at which the response criteria are met.
19.2.4
Safety Analyses
All patients receiving at least 1 dose of study drug will be considered evaluable for safety.  The 
AE incidence rates as well as the frequency of occurrence of overall toxicity, categorized by 
toxicity grades (severity) will be described for each cohort of the trial.  Listings of laboratory test 
results will also be generated, and descriptive statistics summarizing the changes in laboratory 
tests over time will be presented.
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19.3
Procedures for Reporting Deviations to Original Statistical Analysis Plan
All deviations from the original statistical analysis plan will be provided in the final clinical 
study report.
20
STEERING COMMITTEES
Two steering committees will be constituted prior to the initiation of the trial.  Their purpose will 
be to function in an advisory capacity to: 1) provide input on the conduct of the trial; 2) insure 
scientific and ethical integrity of the trial during its course; and 3) provide ongoing oversight of 
the safety and efficacy components of this open-label study.
The steering committees will be composed of expert clinicians. There will be 2 committees.
The clinical committee will be composed of clinicians most expert in the clinical care and 
investigation of the included patient populations.  It will be responsible for general trial 
oversight. The molecular committee will be charged with oversight of the molecular 
components of the trial, including mutation detection methods, molecular monitoring strategies 
and techniques, and other correlative studies. The Sponsor will take part in both clinical and 
molecular steering committee meetings.
The steering committees will review data at intervals during the trial to evaluate the safety 
profile of the drug, to assess accumulating signals of efficacy, evaluate data quality, and to 
provide input on operational aspects of the study.  They may make recommendations for the 
Sponsor’s consideration based on periodic review.
21
CONTRAINDICATIONS, PRECAUTIONS AND WARNINGS
21.1
Precautions Regarding Conception, Pregnancy, and Nursing
Ponatinib does not induce microbial or mammalian cell gene mutations in vitro, and does not 
produce chromosomal aberrations in vitro or in vivo. Nothing is known about the effects of 
ponatinib on reproductive function.
Female and male patients who are fertile will be informed as to the potential risk of conception 
while participating in this study and will be advised that they must use effective contraception 
from enrollment through at least 4 months after the end of treatment.  A pregnancy test will be
performed on each pre-menopausal female of childbearing potential immediately prior to the first 
dose of ponatinib, and again at treatment discontinuation.  A negative pregnancy test must be 
documented prior to administration of the study drug.
If a patient is confirmed to be pregnant during the trial, study drug administration must be 
discontinued immediately.  Any pregnancy occurring during this study is to be reported as a 
serious adverse event (SAE).  The Investigator must immediately notify the medical monitor 
about the pregnancy and record it as an SAE on the SAE Form as well as on the AE page of the 
eCRF (or other eCRF specifically provided for this purpose).  In addition, the Investigator must 
report follow-up information to the Sponsor regarding the course of the pregnancy, including 
perinatal and neonatal outcome, regardless of whether the patient has discontinued participation 
in the study, unless the patient has received other anticancer therapy.
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Once the newborn is determined to be healthy, as defined by and agreed upon by the 
Investigator(s) and the Sponsor, additional follow-up will no longer be required.
21.2
Overdose
An overdose is defined as the accidental or intentional ingestion of any dose of study treatment 
that exceeds the dose described in the protocol.  Overdoses are not considered AEs; however, all 
overdoses should be recorded on an Overdose Form and forwarded to ARIAD 
Pharmacovigilance and Risk Management, or its designated representative, within 24 hours.  An 
overdose should be reported even if it does not result in an AE.  Overdoses do not need to be 
recorded on the CRF; dosing information is recorded on the CRF.  AEs resulting from overdoses 
should be reported on the CRF. General supportive measures should be provided to manage 
symptoms and signs of overdose.
22
ADVERSE EVENTS
22.1
Adverse Event (AE) Definition
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product whether or not considered related the medicinal product.  Any worsening of a 
preexisting condition, which is temporally associated with the use of the study drug, is also an 
AE.
Adverse events include:
●
Suspected adverse drug reactions;
●
Reactions from study drug overdose, abuse, withdrawal, sensitivity, or toxicity;
●
Significant changes or abnormalities when compared to baseline, in signs, symptoms, 
clinical laboratory results, or physiological testing. This includes any worsening of a pre-
existing condition temporally associated with the use of study drug;
●
Other untoward medical events, regardless of their relationship to the study drug, such as 
injury, events that require surgery, accidents, extensions of symptoms, or apparently 
unrelated illnesses.
Progression of disease is not considered an AE unless it results in hospitalization or death.
22.2
Evaluation of Adverse Events (AEs)
22.2.1
Determination of Seriousness
The Investigator will determine the seriousness of an AE based on the following.
22.2.1.1
Serious Adverse Event (SAE)
An AE is considered an SAE if at least one of the following conditions applies:
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Death:  An AE that results in death during the active study period or within 30 days 
following Study Drug administration.
●
Life-threatening adverse event:  An AE that places the patient, in the view of the 
Investigator, at immediate risk of death from the event as it occurred (ie, this does not 
include a reaction that had it occurred in a more severe form, might have caused death).
●
Permanent, persistent, or significant disability:  A disability is defined as any substantial 
disruption of a person’s ability to conduct normal life functions.
●
Inpatient hospitalization or prolongation of existing hospitalization:  Hospitalization 
refers to admission of a patient into a hospital for any length of time.  Hospitalization for 
an elective or diagnostic procedure, or surgery for a pre-existing condition that has not 
worsened, is not considered and SAE.
●
A congenital anomaly/birth defect:  A fixed, permanent impairment established at or 
before birth.
●
Cancer:  Occurrence or diagnosis of a new cancer during the trial is considered a serious 
event.  A new cancer is one that is histopathologically different than the cancer under 
study in the trial (ie, metastatic or progressive disease would not be considered an SAE).
●
Important medical event: Events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, they jeopardize the patient and require medical or surgical intervention to 
prevent a life-threatening situation, hospitalization or death.
22.2.1.2
Adverse Events of Special Interest (AESIs)
Vascular occlusive events have been identified as AESIs for ponatinib.  These include arterial 
and venous thrombotic and occlusive adverse events that meet the criteria for SAEs, defined 
above in Section 22.2.1.1, and those adverse events that do not meet the SAE criteria.
AESIs require ongoing monitoring by Investigators and rapid identification and communication 
by the Investigator to the sponsor.  All AESIs, whether SAEs or not, must be reported 
immediately (within 24 hours) to the sponsor.  The sponsor has determined that the events listed 
below (whether considered serious or non-serious by Investigators) should be considered AESIs 
and therefore should be reported within 24 hours (see Section 22.6).
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A.
Myocardial infarction:  The Third Universal Definition of Myocardial Infarction 
(Thygesen et al, 2012) is used to define MI (see below)
B.
Angina (newly diagnosed or worsening of existing angina or unstable angina)
C.
Coronary artery disease (CAD) (newly diagnosed or worsening of existing CAD) or 
symptoms that may reflect cardiovascular disease (Thygesen et al, 2012)
D.
Cerebrovascular ischemic disease including ischemic or hemorrhagic stroke, vascular 
stenosis, transient ischemic accident (TIA), cerebrovascular occlusive disease 
documented on diagnostic neuroimaging, or symptoms that may reflect 
cerebrovascular disease (Easton et al, 2009)  
E.
New onset or worsening of peripheral artery occlusive disease (eg, renal artery, 
mesenteric artery, femoral artery) or symptoms that may reflect peripheral vascular 
disease 
F.
Retinal vascular thrombosis, either venous or arterial
G.
Venous thromboembolism, or symptoms that may reflect venous thrombosis, that 
could result in significant compromise of organ function or other significant consequences 
(eg, pulmonary embolism, portal vein thrombosis, renal vein thrombosis) 
22.2.1.2.1 AESIs That May be Non-Serious
Signs/symptoms of vascular occlusive disease that are not fatal or life-threatening, do not require 
hospitalization or prolong hospitalization, and do not meet the definition above of SAEs, but that 
require medical evaluation, are also considered AESIs and must be reported to the sponsor or 
the designated representative by completing the SAE/AESI form within 24 hours of awareness. 
22.3
Determination of Severity
The severity of AEs will be assessed according to the NCI CTCAE, v. 4.0 (see Attachment D
and Study Reference Manual).  If the AE is not defined in the NCI CTCAE, v. 4.0, the 
investigator will determine the severity of an AE based on the following definitions:
●
Mild (Grade 1):  The AE is noticeable to the patient, but does not interfere with routine 
activity.  
●
Moderate (Grade 2):  The AE interferes with routine activity, but responds to 
symptomatic therapy or rest.  
●
Severe (Grade 3):  The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy.  
●
Life Threatening (Grade 4):  The patient is at immediate risk of death.
●
Death (Grade 5):  The patient dies as a direct result of the complication or condition 
induced by the AE.
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22.4
Determination of Relatedness
The Investigator will use medical consideration to determine the relatedness of an AE with the 
study drug based on the following definitions.  Not all criteria in each category of relatedness 
must be present.
Definitely Not Related (not drug related)

The patient did not receive study drug,
OR

The temporal sequence of the AE onset relative to the administration of the study drug is 
not reasonable,
OR

There is another obvious cause of the AE.
Probably Not Related (not drug related)

There is evidence of exposure to study drug.

There is another more likely cause of the AE.

Dechallenge (if performed) is negative or ambiguous.

Rechallenge (if performed) is negative for ambiguous.
Possibly Related (drug related)

There is evidence of exposure to study drug.

The temporal sequence of the AE onset relative to administration of the study drug is 
reasonable.

The AE could have been due to another equally likely cause.

Dechallenge (if performed) is positive.
Probably Related (drug related)

There is evidence of exposure to study drug.

The temporal sequence of the AE onset relative to administration of the study drug is 
reasonable.

The AE is more likely explained by the study drug than by another cause.

Dechallenge (if performed) is positive.
Definitely Related (drug related)

There is evidence of exposure to study drug.

The temporal sequence of the AE onset relative to administration of the study drug is 
reasonable.

The AE is more likely explained by the study drug than by another cause.
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
Dechallenge is positive.

Rechallenge (if feasible) is positive

The AE shows a pattern consistent with previous knowledge of the study drug or study 
drug class
22.5
Documenting AEs
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
patient’s eCRF from the time the patient signs the informed consent until 30 days following the 
last study drug administration or withdrawal from study participation.  Each event will be graded 
for severity, intensity, and relatedness (See “Evaluating Adverse Events”). The date of onset, as 
well as the duration of the event will be recorded.  In addition, the method used to treat the AE 
and the outcome of the AE will also be noted.
AEs ongoing after the reporting period:  Any ongoing AEs thought to be at least possibly 
study drug-related, and all ongoing SAEs and AESIs after this time should be followed at least 
every 4 weeks until they resolve to baseline (or CTCAE grade ≤1), stabilize, or are considered to 
be chronic/irreversible.
22.6
Reporting SAEs, AESIs, and Patient Deaths
Time Frame for Reporting
The following must be reported to the Sponsor or Sponsor’s designee within 24 hours of 
becoming aware of the event: 
Any death, SAE, or AESI experienced by the patient during the on-study period (ie, from the 
signing of informed consent to 30 days after the last dose of study drug).
Any death, SAE, or AESI that the Investigator becomes aware of, and believes to be study drug 
related, that occurs more than 30 days after the patient last received study drug.
Information to be Provided by the Investigator
Within 24 hours of learning about the SAE, AESI, or patient death, the Investigator must notify 
the Sponsor or designee and transmit information to the Sponsor or designee.  Information 
should be provided on an SAE Report form signed and dated by the Investigator.  The Sponsor 
or designee will require all of the following information about the patient and the event:
●
Investigator identification,
●
Patient identification code (eg, sex, age or date of birth),
●
Information on study drug (eg, start/stop date, dose and frequency of Study Drug 
administered),
●
Description of event.
In addition to the above information, the Sponsor will require the Investigator’s assessment of 
the following:
●
Severity of the AE,
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●
Relationship of the AE to the study drug,
●
Outcome of the AE.
22.7
Follow-up Information
Appropriate diagnostic tests should be performed and therapeutic measures, as medically 
indicated, should be instituted.  Appropriate consultation and follow-up evaluations should be 
carried out until the event has resolved or is otherwise explained by the Principal Investigator.
Follow-up data concerning the SAE or AESI (eg, diagnostic test reports, physician's summaries, 
etc.) must be promptly reported (within 24 hours of receipt) to the Sponsor or Sponsor’s 
designee, until resolution of the SAE or AESI.  Should the FDA or National Regulatory 
Authorities require that the Sponsor submit additional data on the event, the Investigator will be 
asked to provide those data to the Sponsor in a timely fashion.
Required Follow-up for SAEs or AESIs
There should be routine follow-up for 30 days after study drug discontinuation or study 
withdrawal in all patients in order to monitor for the occurrence of SAEs or AESIs.  If an SAE or 
AESI continues after the 30-day evaluation period, then the patient must be followed until the 
SAE or AESI resolves or returns to baseline.  The medical monitor may specify a longer period 
of time, if required to assure the safety of the patient.
Sponsor Responsibility for Reporting AEs
All AEs will be reported to regulatory authorities, IRBs/IECs, and Investigators in accordance 
with all applicable global laws and regulations.
22.8
Expectedness of Events
Determinations of expectedness of all AEs and SAEs will be based on the information in the
Investigator’s Brochure.
23
DATA QUALITY ASSURANCE
The Sponsor performs quality control and assurance checks on all clinical studies that it 
sponsors.  Before enrolling any patients into this study, Sponsor personnel or designee and the 
Investigator will review the protocol, the Investigator's Brochure, the eCRFs and instructions for 
their completion, the procedure for obtaining informed consent, and the procedure for reporting 
AEs.  A qualified representative of the Sponsor monitors the conduct of the study by visiting the 
site and by contacting the site by telephone.  During the visits, information recorded in the 
eCRFs is verified against source documents.  The Sponsor’s medical monitor reviews the data 
for safety information.  The Sponsor’s clinical data associates or designees review the data for 
legibility, completeness, and logical consistency.  Additionally, the Sponsor’s clinical data 
associates use automated validation programs to help identify missing data, selected protocol 
violations, out-of-range data, and other data inconsistencies.  Requests for data clarification or 
correction are added to the electronic database and reviewed by the investigational site for 
resolution.  The Sponsor may visit the investigational site and perform a quality check of the 
eCRF against source documents.
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24
INVESTIGATOR’S REGULATORY OBLIGATIONS
24.1
Institutional Review Board (IRB) / Ethics Committee (EC) Approval
The protocol and the informed consent document must have the initial and at least annual (when 
required) approval of an IRB/EC.  The signed IRB/EC approval letter must identify the 
documents approved (ie, list the Investigator’s name, the protocol number and title, the date of 
the protocol and informed consent document, and the date of approval of the protocol and the 
informed consent document).  Any advertisements used to recruit patients also should be 
reviewed by the IRB/EC.  The Sponsor will not ship clinical supplies until a signed approval 
letter from the IRB/EC has been received and a Clinical Trial Agreement has been signed by the 
Sponsor and the clinical site.
24.2
Pre-Study Documentation
The Investigator must provide the Sponsor with the following documents BEFORE enrolling any 
patients:
●
An executed Clinical Trial Agreement,
●
FDA Form 1572,
●
Principal Investigator’s Curriculum Vitae,
●
Documentation of financial disclosure,
●
IRB/EC approval of the protocol,
●
IRB/EC approved consent form.
24.3
Informed Consent
Regulatory agencies have issued regulations to provide protection for human patients in clinical 
investigations and to describe the general requirements for informed consent.
A copy of your proposed informed consent document should be submitted to the Sponsor for 
review and comment before submission to your IRB/EC.  The study should not begin until the 
document has been reviewed by the Sponsor and must not begin until the document has been 
approved by the IRB/EC.  In some instances the study must not begin until the document has 
been approved by a regulatory agency.
The informed consent document shall contain all of the elements of informed consent specified 
in the regulations.  Some regulations may require the disclosure of additional information to the 
patient and/or inclusion of additional information in an informed consent document.
Nothing in this protocol or these regulations is intended to limit the authority of a physician to 
provide emergency medical care under applicable regulations.  In addition, the Investigator 
should be aware that some regulations require that he/she permit regulatory agencies to conduct 
inspections and review records pertaining to this clinical investigation.
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Declaration of Helsinki
This study will be conducted in accordance with the ethical standards that have their origin in the 
Declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) guidelines and 
the applicable regulatory requirements.
24.4
Case Report Forms (CRF)
Study-specific eCRFs will be made available to the Investigative site.  Study data, contained in 
source documentation, will be entered into the eCRFs for all patients enrolled in the trial.  All 
pertinent data records are to be submitted to the Sponsor during and/or at completion or 
termination of the study.
24.5
Adverse Event (AE) Reporting
The Investigator agrees to report all AEs to the Sponsor as described in Section 22.6.  
Furthermore, the Investigator is responsible for ensuring that any co-Investigator or sub-
Investigator promptly brings AEs to the attention of the Investigator.  If applicable, the 
Investigator also is responsible for informing the participating IRB/EC of any SAEs.
24.6
Review of Source Records
The Investigator agrees that qualified representatives of the Sponsor and regulatory agencies will 
have the right, both during and after this study, to conduct inspections and to audit and review 
medical records pertinent to the clinical study as permitted by the regulations.  Patients will not 
be identified by name in any reports stemming from the study, and confidentiality of information 
in medical records will be preserved.  The confidentiality of the patient will be maintained unless 
disclosure is required by regulations. Accordingly, the following statement (or similar statement) 
that permits the release of the patient’s medical records will be included in the informed consent 
document:
Representatives of regulatory agencies, IRB/EC, the Sponsor, and the personal 
physician may review the patient medical records and all information related to 
this study as permitted by law. Patient identity will remain confidential unless 
disclosure is required by law.
24.7
Monitoring of the Study
This study is monitored by a representative of the Sponsor.  Site visits are made before the study 
begins, at regular intervals during the study, and at the study closeout.  Communication by 
telephone, mail and e-mail may be used, as needed, to supplement site visits.  The Investigator 
and study personnel will cooperate with the Sponsor, provide all appropriate documentation, and 
be available to discuss the study.  The purpose of the site visits is to verify:
●
Adherence to the protocol (the Investigator should document and explain any deviation 
from the approved protocol);
●
The completeness and accuracy of the eCRFs and the dispensing and inventory record 
(adequate time and space for these visits should be allocated by the Investigator);
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●
Compliance with regulations (the verification will require comparison of the source 
documents to the eCRFs).
24.8
Protocol Amendments
Any significant change in the study protocol will require an amendment.  The Investigator and 
the appropriate Sponsor’s medical monitor indicate their approval by signing the approval page 
of the amendment.  Once a protocol amendment has received approval from the Sponsor, the 
Investigator submits it to the IRB/EC for written approval.  The approval letter, signed by the 
IRB/EC chair, must refer specifically to the Investigator, the Sponsor’s protocol number, the 
protocol title, the protocol amendment number, and the date of the protocol amendment.  The 
Sponsor submits a copy of the protocol amendment to the appropriate regulatory 
agency/agencies.  A protocol amendment may be implemented after it has been approved by the 
IRB/EC.
A protocol change intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, but the change must then be documented in an amendment and 
reported to the IRB/EC within 5 working days.
24.9
Change in Investigator
If any Investigator retires, relocates, or otherwise withdraws from conducting a study, the 
responsibility for maintaining records may be transferred to another person (Sponsor, IRB/EC, 
other Investigators) who will accept the responsibility.  The Sponsor must be notified in writing 
and must agree to the change.  An updated FDA Form 1572 will be filed with the Sponsor and 
the FDA for any changes in the study personnel reported in the current FDA Form 1572.
24.10
Termination of Study
The Sponsor may terminate the study at any time for any of the following reasons:
●
Failure to enroll patients;
●
Protocol violations;
●
Inaccurate or incomplete data;
●
Unsafe or unethical practices;
●
Questionable safety of the study drug;
●
Suspected lack of efficacy of the study drug;
●
Administrative decision.
In the event of the termination of the Study, by either the Sponsor or an Investigator:
●
The Investigator will return all study drugs, eCRFs, and related study materials to the 
Sponsor;
●
A written statement describing why the study was terminated prematurely will be 
provided by either the Sponsor or the Investigator.
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24.11
Final Study Report
The Investigator must notify the IRB/EC of the conclusion of the clinical trial. This report should 
be made within 3 months of the completion or termination of the Study. The final report sent to 
the IRB/EC is also sent to the Sponsor and, along with the completed eCRFs, constitutes the final 
summary to the Sponsor, thereby fulfilling the regulatory responsibility.
24.12
Confidentiality
All unpublished information that the Sponsor gives to the Investigator and all information 
generated in connection with the study shall be kept confidential and shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor or published prior to 
the Sponsor’s review in accordance with the terms of the Clinical Trial Agreement.  When the 
Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who have contributed significantly to the study will be asked to endorse the final 
report.  The endorsement is required by some regulatory agencies.  The Investigator shall not 
make a patent application based on the results of this study and shall not assist any third party in 
making such an application without the written authorization of the Sponsor.
24.13
Records Retention
Trial documents (including correspondence related to this clinical study, patient records, source 
documents, eCRFs, study drug inventory records, and IRB/EC and Sponsor correspondence 
pertaining to the study original patient, laboratory, and study drug inventory records relating to 
the study) should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications in 
an ICH region (that is at least 15 years or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product).  Trial documents should be retained for 
a longer period if required by applicable regulatory requirements or by agreement with the 
Sponsor. Thereafter, records will not be destroyed without giving the Sponsor prior written 
notice and the opportunity to further store such records, at the Sponsor’s cost and expense.
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25
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Over the Past 40 Years. Cancer. 2008 Oct 1; 113 (7 Suppl): 1933-52. Review.
Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, 
Pasquini R, Nakamae H, Huguet F, Boqué C, Chuah C, Bleickardt E, Bradley-Garelik MB, Zhu 
C, Szatrowski T, Shapiro D, Baccarani M. Dasatinib versus imatinib in newly diagnosed 
chronic-phase chronic myeloid leukemia. N Engl J Med. 2010; 362(24):2260-70.
Khorashad JS, Milojkovic D, Mehta P, Anand M, Ghorashian S, Reid AG, De Melo V, Babb A, 
de Lavallade H, Olavarria E, et al.. In vivo kinetics of kinase domain mutations in CML patients 
treated with dasatinib after failing imatinib. Blood. 2008; 111: 2378-2381.
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LucasCM, Wang L, Austin GM, Knight K, Watmough SJ, Shwe KH, Dasgupta R, Butt NM, 
Galvani D, Hoyle CF, Seale JRC, Clark RE. A population study of imatinib in chronic myeloid 
leukaemia demonstrates lower efficacy than in clinical trials. Leukemia 2008; 22: 1963-1966.
Müller MC, Cortes JE, Kim DW, Druker BJ, Erben P, Pasquini R, Branford S, Hughes TP, 
Radich JP, Ploughman L, Mukhopadhyay J, Hochhaus A. Dasatinib treatment of chronic-phase 
chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. 
Blood. 2009 Dec 3; 114(24):4944-53. Epub 2009 Sep 24.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: 
Myeloid Growth Factors. 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Version 1, 2012 [Accessed 
21 March 2014].
Nicolini FE, Mauro MJ, Martinelli G, Kim DW, Soverini S, Müller MC, Hochhaus A, Cortes J, 
Chuah C, Dufva IH, Apperley JF, Yagasaki F, Pearson JD, Peter S, Sanz Rodriguez C, 
Preudhomme C, Giles F, Goldman JM, Zhou W. Epidemiologic study on survival of chronic 
myeloid leukemia and Ph(+) acute lymphoblastic leukemia patients with BCR-ABL T315I 
mutation. Blood. 2009 Dec 17; 114(26):5271-8. Epub 2009 Oct 20.
O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, 
Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, 
Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, 
Bolton AE, Capdeville R, Druker BJ; IRIS Investigators. Imatinib compared with interferon and 
low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J 
Med. 2003 Mar 13; 348(11):994-1004.
O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Heinrich 
MC, Deininger MWN, Druker BJ. In vitro activity of BCR-ABL inhibitors AMN107 and BMS-
354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 
2005:65 (11) 4500-4505.
O’Hare T, Elde CA, Deininger MWN. BCR-ABL kinase domain mutations, drug resistance, and 
the road to a cure for chronic myeloid leukemia. Blood 110:2242-2249.
O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang 
WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats
JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, 
Dalgarno DC, Deininger MW, Druker BJ, Clackson T. AP24534, a pan-BCR-ABL inhibitor for 
chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based 
resistance. Cancer Cell. 2009 Nov 6; 16 (5): 401-12.
Ottmann O, Wassmann B, Pfeifer H, Giagounidis A, Stelljes M, Duhrsen U, Schmalzing M, 
Wunderle L, Binckebanck A, Hoelzer D; GMALL Study Group. Imatinib Compared With 
Chemotherapy as Front-Line Treatment of Elderly Patients With Philadelphia Chromosome-
Positive Acute Lymphoblastic Leukemia (Ph+ ALL). American Cancer Society. 2007; 109 (10): 
2068-76.
Quintas-Cardama A, Kantarjian HM, Jones D, Nicaise C, O’Brien S, Giles F, Talpaz M and 
Cortes J. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic 
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myelogenous leukemia after imatinib and nilotinib (AMN107) failure. Blood 2007: 109: 497-
499.
Quintas-Cardama A and Cortes J. Therapeutic Options Against BCR-ABL-1 T315I-Positive 
Chronic Myelogenous Leukemia. Clinical Cancer Research. 2008; 14(14): 4392-4399.
Quintas-Cardama A, Kantarjian H, Cortes J. Homoharringtonine, omacetaxine mepesuccinate, 
and chronic myeloid leukemia circa 2009. Cancer. 2009 Dec 1; 115(23):5382-93.
Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, 
Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, 
Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic 
myeloid leukemia.  N Engl J Med. 2010; 362(24):2251-9.
Talpaz M, Shah N, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O’Brien S, Nicaise C, 
Bleickardt E, Blackwood-Chirchir  MA, Iyer V, Chen TT, Huang F, Decillis, AP, Sawyers CL. 
Dasatinib in Imatinib-Resistant Philadelphia Chromosome-Positive Leukemias. New England 
Journal of Medicine. 2006; 354: 2531-2541.
Talpaz M, Cortes JE, Deininger M, Shah N, Flinn I, Mauro M, O'Hare T, Rivera V, Kantarjian 
H, Haluska F. Phase 1 trial of AP24534 in patients with refractory chronic myeloid leukemia 
(CML) and hematologic malignancies. J. Clin. Oncol. 2010; 28 (15S): 6511.
Thygesen K, Alpert JS, Jaffe AS. Third Universal Definition of Myocardial Infarction. 
Circulation. 2012; 126:2020-2035.
Willis SG, Lange T, Demehri S, Otto S, Crossman L, Niederwieser D, Stoffregen EP, 
McWeeney S, Kovacs I, Park B, Druker BJ, Deininger MW. Blood 2005; 106: 2128-2137.
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26
ATTACHMENTS
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Attachment A Response Criteria
Baseline information appropriate to the patient’s specific diagnosis should be collected prior to 
the first dose of ponatinib. The information may be collected as part of this study or from the 
patient’s medical record as long as it is within the time span specified in the Schedule of Events 
in Section 8 of this protocol.
RESPONSE CRITERIA FOR CHRONIC MYELOGENOUS LEUKEMIA (CML) AND 
PHILADELPHIA CHROMOSOME POSITIVE ACUTE LYMPHOBLASTIC 
LEUKEMIA (Ph+ ALL)
Note: These criteria are adapted from Talpaz et al, 2006, O’Brien et al, 2003, and Kantarjian et 
al, 2010.
Hematologic Response
1.
Chronic Phase (CP) Chronic Myelogenous Leukemia (CML)
a.
Complete Hematologic Response (CHR)
i.
White blood cells (WBC) ≤ institutional upper limit of normal
ii.
Platelets < 450,000/mm3
iii.
No blasts or promyelocytes in peripheral blood
iv.
< 5% myelocytes plus metamyelocytes in peripheral blood
v.
Basophils in peripheral blood < 5%
vi.
No extramedullary involvement (including no hepatomegaly or 
splenomegaly)
2.
Accelerated Phase (AP) and Blast Phase (BP) CML and Ph+ ALL
a.
Major Hematologic Response (MaHR)
i.
Complete Hematologic Response (CHR)
a)
WBC ≤ institutional upper limit of normal
b)
Absolute neutrophil count (ANC) ≥ 1000/mm3
c)
Platelets ≥ 100,000/ mm3
d)
No blasts or promyelocytes in peripheral blood
e)
Bone marrow (BM) blasts ≤ 5%
f)
< 5% myelocytes plus metamyelocytes in peripheral blood
g)
Basophils in peripheral blood < 5%
h)
No extramedullary involvement (including no hepatomegaly or 
splenomegaly)
i.
No evidence of Leukemia (NEL)
a)
WBC ≤ institutional upper limit of normal
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b)
No blasts or promyelocytes in peripheral blood
c)
BM blasts ≤ 5%
d)
< 5% myelocytes plus metamyelocytes in peripheral blood
e)
Basophils in peripheral blood < 5%
f)
No extramedullary involvement (including no hepatomegaly or 
splenomegaly)
g)
At least 1 of the following: (i) 20,000/mm3 ≤ Platelets < 
100,000/mm3; (ii) 500/mm3 ≤ ANC <1000/mm3
Cytogenetic Response 
The criteria for cytogenetic response are derived from Kantarjian et al, 2006 and Talpaz et al, 
2006 as well as the National Comprehensive Cancer Network (NCCN, 2012) clinical practice 
guidelines (accessed 21 March 2014).
At least 20 metaphase cells should be examined. If fewer metaphases are available, the absolute 
and percentage values should be reported. Peripheral blood cells may not be used.
Major Response
(MCyR)
Complete Response (CCyR)
No Ph+ cells 
Partial Response (PCyR)
1-35% Ph+ cells
Minor Response
36-65% Ph+ cells
Minimal Response
66-95% Ph+ cells
No Response
96-100% Ph+ cells
Major Molecular Response (Baccarani et al, 2009)
A major molecular response (MMR) is defined as a ratio of reverse transcribed transcript of 
BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in 
transcript). 
Progression Criteria
Progression from CP (O’Brien et al, 2003):
1.
Death
2.
Development of AP or BP
3.
Loss of CHR (in the absence of cytogenetic response)
Confirmed by development in complete blood counts (CBCs) at least 4 weeks apart
4.
Loss of MCyR
5.
Increasing WBC in patient without CHR defined by:
Doubling of WBC to >20K on 2 occasions at least 4 weeks apart (after the first 4 weeks of 
therapy)
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Progression from AP (Apperley et al, 2009)
1.
Death
2.
Development of confirmed BP
3.
Loss of previous major or minor hematologic response over a 2-week period
4.
No decrease from baseline levels in percentage blasts in peripheral blood or BM on all 
assessments over a 4-week period
Progression from BP or Ph+ ALL (Talpaz et al, 2006)
1.
Death
2.
Increasing blasts in peripheral blood or BM over a 4 week period.
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Attachment B Prohibited Drugs with a Risk of Torsades de Pointes
The website http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/ [Accessed: 20 
December 2013] lists 4 categories of QT-prolonging drugs and may be used as a guide for this 
protocol. Categories include “Drugs with Known TdP Risk,” “Drugs with Possible TdP Risk,” 
“Drugs with Conditional TdP Risk,” and “Drugs to be Avoided by Congenital Long QT 
Patients.”  The investigator site should register (under the “For Healthcare Providers” tab) to 
access these categories.  If the investigator site does not wish to register, a composite list, 
including all categories, is available. 
Drugs with a known risk of Torsades de Pointes are listed in the table below, and are the only 
category of QT-prolonging drugs that are prohibited in this study.
Note: The website and table are only to be used as a guideline and are not comprehensive.  It is 
the investigator’s responsibility to ensure that any drugs under consideration have not been 
newly identified as causing Torsades de Pointes.
Table B-1
Drugs Generally Accepted by the QTDrugs.org Advisory Board of the 
Arizona CERT to have a Known Risk of Causing Torsades de Pointes:
Prohibited in this Study
Generic Name
Brand Name
Class/Clinical Use
Amiodarone 
Cordarone®, Pacerone®, 
Nexterone®
Antiarrhythmic / abnormal heart rhythm
Arsenic trioxide 
Trisenox®
Anticancer / Leukemia
Astemizole 
Hismanal®
Antihistamine / Allergic rhinitis
Azithromycin
Zithromax®, Zmax®
Antibiotic / bacterial infection
Bepridil 
Vascor®
Antianginal / heart pain
Chloroquine
Aralen®
Antimalarial / malaria infection
Chlorpromazine 
Thorazine®, Largactil®, 
Megaphen®
Antipsychotic/ Antiemetic / schizophrenia/ 
nausea
Cisapride
Propulsid®
GI stimulant / heartburn
Citalopram
Celexa®
Antidepressant / depression
Clarithromycin
Biaxin®, Prevpac®
Antibiotic / bacterial infection
Cocaine
Cocaine
Local anesthetic / topical anesthetic
Disopyramide 
Norpace®
Antiarrhythmic / abnormal heart rhythm
Dofetilide 
Tikosyn®
Antiarrhythmic / abnormal heart rhythm
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Generic Name
Brand Name
Class/Clinical Use
Domperidone
Motilium®, Motillium®, Motinorm 
Costi®, Nomit®
Antinausea / nausea
Dronedarone
Multaq®
Antiarrhythmic / atrial fibrillation
Droperidol 
Inapsine®, Droleptan®, Dridol®, 
Xomolix®
Sedative;Antinausea / anesthesia adjunct, 
nausea
Erythromycin 
Erythrocin®, E.E.S.®, 
Robimycin®, Erymax®, Ery-Tab®, 
Eryc Ranbaxy®, Erypar®, 
Eryped®, Erythrocin Stearate 
Filmtab®, Erythrocot®, E-Base®, 
Erythroped®, Ilosone®, MY-E®, 
Pediamycin®, Zineryt®, 
Abboticin®, Abboticin-ES®, 
Erycin®, PCE Dispertab®, 
Stiemycine®, Tiloryth®
Antibiotic;GI stimulant / bacterial infection; 
increase GI motility
Escitalopram
Cipralex®, Lexapro®, Nexito®, 
Anxiset-E®, Exodus®, Esto®, 
Seroplex®, Elicea®, Lexamil®, 
Lexam®, Entact®, Losita®, 
Reposil®, Animaxen®, Esitalo®, 
Lexamil®
Antidepressant / major depression, anxiety 
disorders
Flecainide
Tambocor®, Almarytm®, 
Apocard®, Ecrinal®, Flécaine®
Antiarrhythmic / abnormal heart rhythm
Halofantrine 
Halfan®
Antimalarial / malaria infection
Haloperidol 
Haldol®, Aloperidin®, 
Bioperidolo®, Brotopon®, Dozic®, 
Duraperidol®, Einalon S®, 
Eukystol®, Halosten®, Keselan®, 
Linton®, Peluces®, Serenace®, 
Serenase®, Sigaperidol®
Antipsychotic / schizophrenia, agitation
Ibutilide
Corvert®
Antiarrhythmic / abnormal heart rhythm
Levomethadyl
Orlaam®
Opiate agonist / pain control, narcotic 
dependence
Mesoridazine
Serentil®
Antipsychotic / schizophrenia
Methadone
Dolophine®
Opiate agonist / pain control, narcotic 
dependence
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Generic Name
Brand Name
Class/Clinical Use
Methadone
Methadose®, Symoron®, 
Amidone®, Methadose®, 
Physeptone®, Heptadone®
Opiate agonist / pain control, narcotic 
dependence
Moxifloxacin
Avelox®, Avalox®, Avelon®
Antibiotic / bacterial infection
Ondansetron
Zofran®, Anset®, Ondemet®, 
Zuplenz®, Emetron®, Ondavell®, 
Emeset®, Ondisolv®, Setronax®
Somatostatin analog / nausea and vomiting
Pentamidine 
Pentam®, NebuPent®
Antiinfective / pneumocystis pneumonia
Pimozide
Orap® 
Antipsychotic / Tourette's tics
Probucol
Lorelco®
Antilipemic / Hypercholesterolemia
Procainamide 
Pronestyl®, Procan®
Anti-arrhythmic / abnormal heart rhythm
Quinidine
Quinaglute®, Duraquin®, 
Quinact®, Quinidex®, Cin-Quin®, 
Quinora®
Antiarrhythmic / abnormal heart rhythm
Sevoflurane
Ulane®, Sojourn®
Anesthetic, general / anesthesia
Sotalol 
Betapace®, Sotalex®, Sotacor®  
Antiarrhythmic / abnormal heart rhythm
Sparfloxacin 
Zagam® 
Antibiotic / bacterial infection
Terfenadine
Seldane®
Antihistamine / Allergic rhinitis
Thioridazine
Mellaril® , Novoridazine®, 
Thioril®  
Antipsychotic / schizophrenia
Vandetanib
Caprelsa®
Anticancer / thyroid cancer
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Attachment C Medications that Interact with CYP3A4, 5, and 7
The list of drugs that interact with CYP3A4, 5, and 7 can be found online at 
http://medicine.iupui.edu/clinpharm/DDIs/Table.aspx [Accessed: 19 December 2013].  Drugs 
listed as strong inhibitors and inducers of CYP3A should be avoided if possible.
Note:  The website should be used as a guideline and is not necessarily comprehensive. It is the 
investigator’s responsibility to ensure that any drugs under consideration have not been newly 
identified as strong CYP3A4/5 inhibitors or inducers.
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Attachment D National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE)
The United States of America (USA) National Cancer Institute Common Terminology Criteria 
for Adverse Events, version 4.0 (NCI CTCAE, v.4.0) can be found on the following website.
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 [Accessed: 
19 December 2013]
This version of CTCAE is compatible at the AE (Adverse Event) term level where each CTCAE 
term is a MedDRA LLT (Lowest Level Term). CTCAE v4.0 includes 764 AE terms and 26 
'Other, specify' options for reporting text terms not listed in CTCAE. Each AE term is associated 
with a 5-point severity scale. MedDRA v12.0 (Medical Dictionary for Regulatory Activities)
Terminology. 
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SAP_000.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic 
Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
NCT Number: NCT01207440
SAP Approve Date: 14 December 2010
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


ARIAD Pharmaceuticals, Inc.
AP24534-10-201
Statistical Analysis Plan (SAP)
V1.0 14 December 2010
Page 1
STATISTICAL ANALYSIS PLAN
FOR
AP24534-10-201
PROTOCOL TITLE: A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with 
Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
PROTOCOL NUMBER:
AP24534-10-201
IND NUMBER:
78,375
EudraCT NUMBER:
2010-020414-28
SPONSOR:
ARIAD Pharmaceuticals, Inc.
26 Landsdowne Street
Cambridge, MA 02139-4234
Telephone: (617) 494-0400
ORIGINAL ISSUE DATE:
Version 1.0 14 December 2010
REVISION/AMENDMENT HISTORY:
Amendment Number
Version Number
Date
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Statistical Analysis Plan (SAP)
V1.0 14 December 2010
Page 2
TABLE OF CONTENTS
1
Introduction..........................................................................................................................4
2
Study Objectives and Endpoints..........................................................................................4
2.1
Study Objectives ................................................................................................................4
2.1.1
Primary Objectives.......................................................................................................4
2.1.2
Secondary Objectives...................................................................................................4
2.2
Study Design ......................................................................................................................4
2.3
Study Endpoints .................................................................................................................5
2.3.1
Primary Endpoints .......................................................................................................5
2.3.2
Secondary Endpoints ...................................................................................................5
2.3.3
Exploratory Endpoints .................................................................................................6
3
Analysis Populations............................................................................................................6
3.1
Treated Population .............................................................................................................6
3.1.1
Cohorts A and B (CP CML Patients)...........................................................................6
3.1.2
Cohorts C-F (AP CML/BP CML/Ph+ ALL Patients)..................................................6
3.2
Per Protocol Population......................................................................................................7
3.2.1
Per Protocol (Cytogenetic) Population ........................................................................7
3.2.2
Per Protocol (Hematologic) Population.......................................................................7
3.3
Safety Population ...............................................................................................................7
4
Statistical Methods and Determination of Sample Size.......................................................7
4.1
Determination of Sample Size............................................................................................7
4.1.1
Cohorts A and B (Chronic Phase CML Patients) ........................................................7
4.1.2
Cohorts C-F (Accelerated Phase CML/Blast Phase CML/Ph+ ALL Patients)............8
4.2
Statistical Methods.............................................................................................................9
4.2.1
Demographic and Baseline Characteristics .................................................................9
4.2.2
Patient Disposition.......................................................................................................9
4.2.3
Efficacy Analyses ......................................................................................................10
4.2.3.1
Primary Analysis of the Primary Endpoint.......................................................10
4.2.3.2
Data Handling Rules for the Primary Analyses of the Primary Endpoint ........10
4.2.3.3
Sensitivity Analyses of the Primary Endpoint ..................................................11
4.2.4
Key Analyses of the Secondary Endpoints................................................................12
4.2.4.1
Cohorts A and B (CP CML Patients)................................................................12
4.2.4.2
Cohorts C-F (AP CML/BP CML/Ph+ ALL Patients).......................................12
4.2.4.3
All Cohorts........................................................................................................13
4.2.4.4
Data Handling Rules for Secondary Endpoint Analyses ..................................13
4.3
Summaries of Data Handling Rules for Primary and Secondary Efficacy Analyses.......15
4.3.1
Subgroup Analyses of the Primary Endpoints and Key Secondary Endpoints .........22
4.3.2
Treated Patients Not Eligible for Cohorts A-F ..........................................................22
4.3.3
Safety Analyses..........................................................................................................22
4.3.4
Study Drug Exposure.................................................................................................23
4.3.5
Exploratory Analyses.................................................................................................23
5
References..........................................................................................................................24
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Page 3
LIST OF TABLES
Table 1:
Planned Number of Patients for Each Cohort ............................................................4
Table 2:
Sample Size Considerations for Each Cohort ............................................................9
Table 3:
Patient Disposition .....................................................................................................9
Table 4:
MCyR Classification and Baseline Cytogenetic Assessment ..................................10
Table 5:
Determination of PCyR With Assessment of < 20 Metaphases...............................11
Table 6:
Summary of Data Handling Rules for Major Cytogenetic Response (MCyR)........15
Table 7:
Summary of Data Handling Rules for Major Hematologic Response (MaHR).......17
Table 8:
Summary of Data Handling Rules for Analysis of Duration of Response†.............20
Table 9:
Summary of Data Handling Rules for Analysis of Major Molecular Response 
(MMR) .....................................................................................................................21
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1
INTRODUCTION
The AP24534-10-201 Statistical Analysis Plan describes the design characteristics and statistical 
analyses methods for study “A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with 
Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia.”
This document specifies the statistical approaches and data handling conventions for key 
analyses that include the primary analyses for the primary endpoints and the analyses for key 
secondary endpoints.
2
STUDY OBJECTIVES AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objectives
The primary objective of this trial is to determine the efficacy of ponatinib in patients with 
Chronic Myeloid Leukemia (CML) in chronic (CP), accelerated (AP) or blast phase (BP) or with 
Ph+ Acute Lymphoblastic Leukemia (ALL) who either are resistant or intolerant to either 
dasatinib or nilotinib or have the T315I mutation.
2.1.2
Secondary Objectives
Secondary objectives are:
1. To further characterize the anti-leukemia activity of ponatinib in these patients as 
evidenced by clinical responses, molecular responses, and clinical outcomes
2. To characterize the molecular genetic status of patients
3. To examine the safety of ponatinib in these patients
2.2
Study Design
This is a phase 2, single-arm trial in patients with CML and Ph+ ALL.  Table 1 summarizes the 
number of patients planned to be recruited in each cohort:
Table 1:
Planned Number of Patients for Each Cohort
Chronic Phase 
(CP)
Accelerated 
Phase (AP)
Blast Phase 
(BP)/Ph+ ALL
Total
Resistant/intolerant to 
dasatinib or nilotinib
100
(Cohort A)
40
(Cohort C)
40
(Cohort E)
180
T315I mutation
60
(Cohort B)
40
(Cohort D)
40
(Cohort F)
140
Total
160
80
80
320
Cohort A will consist of CP CML patients resistant or intolerant to dastinib or nilotinib.  Cohort 
B will consist of CP CML patients with the T315I mutation.  Cohorts C and E will consist of AP 
and BP/Ph+ ALL, respectively, who are resistant or intolerant to dasatinib or nilotinib.  Cohorts 
D and F will consist of AP and BP/Ph+ ALL patients, respectively, with the T315I mutation.
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Each of the 6 cohorts proposed in this trial are representative of distinct patient cohorts with 
different primary endpoints.  Each cohort of patients will be analyzed separately for efficacy.  
The safety data from all cohorts will be pooled for the purpose of describing the safety of all 
treated patients as a whole.  These cohorts can be viewed as 6 separate studies that are enrolled 
through a single “umbrella” protocol; therefore, no adjustments for multiplicity are planned.
2.3
Study Endpoints
2.3.1
Primary Endpoints
The primary endpoints for the cohorts are:
Cohorts A and B (CP CML Patients)

Major cytogenetic response (MCyR), defined as complete cytogenetic response (CCyR) or 
Partial Cytogenetic Response (PCyR).  Patients entering the trial already in PCyR must 
achieve a CCyR in order to be considered as achieving a MCyR.  The criteria for response 
are provided in Attachment A of the protocol.
Cohorts C-F (AP CML/BP CML/Ph+ ALL Patients)

Major hematologic response (MaHR), defined as complete hematologic response (CHR) and 
no evidence of leukemia (NEL).  MaHR will be confirmed by a peripheral blood complete 
blood count (CBC) and differential no earlier than 28 days after the initial assessment of 
MaHR.  The criteria for response are provided in Attachment A of the protocol.
2.3.2
Secondary Endpoints
Secondary endpoints for this trial are:

Cohorts A and B: CHR as defined in Attachment A of the protocol.

Cohorts C-F: MCyR.

Confirmed MCyR, defined as 2 assessments of CCyR or PCyR at least 28 days apart.  For 
CP patients entering the trial in PCyR, confirmed MCyR will be defined as 2 assessments of 
CCyR at least 28 days apart.

Major Molecular Response (MMR) (as defined in Attachment A of the protocol).

Duration of Response, defined as the interval between the first assessment at which the 
criteria for response were met until the criteria for progression (as defined in Attachment A 
of the protocol) are met, censored at the last date at which the criteria for response are met.  
An additional analysis will be performed in which patients who do not progress will be 
censored at the last dose of study drug.  Duration of response will also be defined and 
analyzed as the time from the first assessment at which the criteria for response are met until 
the last assessment at which the criteria for response are met.

Progression free survival, defined as the interval from the first dose of study treatment until 
the criteria for progression are met (as defined in Attachment A of the protocol) or death, 
censored at the last response assessment.

Overall survival, defined as the interval from the first dose of study treatment until death, 
censored at the last date at which patient was known to be alive.
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or nilotinib will be assigned to Cohort E.  CML patients in BP and Ph+ ALL patients for whom a 
positive baseline T315I mutation result is received will be assigned to Cohort F.  Patients who 
are not confirmed to have a detectable T315I mutation by direct sequencing and who are not 
resistant or intolerant to dasatinib or nilotinib will not be included in the treated population and 
will be analyzed separately, in the same fashion as described for Cohorts A and B.
3.2
Per Protocol Population
3.2.1
Per Protocol (Cytogenetic) Population
This population includes all patients in the treated population who have a baseline cytogenetic 
assessment with at least 20 metaphases examined.  For Cohorts A and B (CP CML Patients), the 
primary analysis will be performed using the per protocol (cytogenetic) population.  For Cohorts 
C-F (AP CML/BP CML/Ph+ ALL Patients), the analysis of the secondary endpoint of MCyR 
will be peformed using the per protocol (cytogenetic) population.
3.2.2
Per Protocol (Hematologic) Population
This population includes all patients in the treated population in Cohorts C-F who have a 
baseline BM assessment for which the percentage of BM blasts can be determined.  For Cohorts 
C-F (AP CML/BP CML/Ph+ ALL Patients), the primary analysis will be performed using the 
per protocol (hematologic) population.
3.3
Safety Population
This population includes all patients who have received at least 1 dose of study drug.
4
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
4.1
Determination of Sample Size
4.1.1
Cohorts A and B (Chronic Phase CML Patients)
As specified in Section 2.3, the primary endpoint for this trial for patients with CP CML 
(Cohorts A and B) is MCyR.  MCyR rate is defined as the proportion of patients who have 
achieved a CCyR or PCyR after the initiation of study treatment.  Patients entering the trial 
already in PCyR must achieve a CCyR in order to be considered as achieving a MCyR.  As 
described above, the determination of PCyR status at baseline for the primary analysis will be 
based on an assessment with an examination of at least 20 metaphases.
The primary analysis of the primary endpoint of MCyR will be performed using a 2-sided exact 
95% confidence interval (CI) for MCyR rate among all patients in the per protocol population in 
each cohort.
Data on the use of second generation tyrosine kinase inhibitors (TKIs) in patients who have 
failed dasatinib and nilotinib are available in several small studies (Giles, 2007; 
Quintas-Cardama, 2007; Garg, 2009), and we have used these data to estimate response rates in 
these historical control populations.  These 3 studies demonstrate an approximately 30% MCyR 
in these patients.  However, these are highly selected patient populations; they do not include 
patients who have failed more than 2 agents, and responses are typically of short duration.  Thus 
for the purposes of this trial, the null or uninteresting MCyR rate is set at 20% for Cohort A 
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(resistant and intolerant CP patients). Here, and with regard to the cohorts discussed below, we 
intend that the specified null or uninteresting response rate defines a result that would not be 
clinically useful for the patient populations for which it is applicable. The alternative MCyR rate 
is set at 35% for Cohort A. The clinical implication of the alternative rate, in contrast, is that it 
would compare favorably with the historical experience for the specified patient populations and 
thus would be clinically beneficial. The overall alpha level for each cohort will be set at 0.05.  
With a cohort size of 100 patients, a minimum of 29 responders (ie, those with a CCyR and a 
PCyR) would need to be observed in Cohort A in order to observe an exact 95% CI such that the 
lower bound exceeds 20% and the upper bound exceeds 35%.  Therefore, 100 patients will 
provide at least 85% power to distinguish between a null response rate of 20% and an alternative 
response rate of 35% in Cohort A.  The study will also provide at least 98% power to distinguish 
between 20% and 40%, in which case 29 responses will also be required, and at least 78% power 
to distinguish between 30% and 45%, in which case 40 responses would be required.
With a cohort size of 100 patients, the maximum width of the exact 95% CI will be 
approximately 20% when the MCyR rate is in the expected range of 20% to 35%.
For Cohort B (T315I CP CML patients), the null or uninteresting MCyR rate is set at 10% and 
the alternative MCyR rate is set at 35%.  Data on the use of second generation drugs (Garg 2009; 
Muller, 2009) in these patients suggest that less than 10% of patients achieve MCyR.  With a 
cohort size of 60 patients, a minimum of 14 responders would need to be observed in Cohort B 
in order to observe an exact 95% CI such that the lower bound exceeds 10% and the upper bound 
exceeds 35%.  Therefore, 60 patients will provide approximately 98% power to distinguish 
between a null response rate of 10% and an alternative response rate of 35% in Cohort B.
With a cohort size of 60 patients, the maximum width of the exact 95% CI will be 25% when the 
MCyR rate is in the expected range of 10% to 35%.
4.1.2
Cohorts C-F (Accelerated Phase CML/Blast Phase CML/Ph+ ALL Patients)
The sample sizes for Cohorts C to F (AP, and BP/Ph+ ALL) are based on similar considerations 
for each cohort (Garg, 2009).  The endpoint for these cohorts is the MaHR.  MaHR rate is 
defined as the proportion of patients achieving a CHR or NEL response.  The null or 
uninteresting MaHR rate is set at 10% and the alternative MaHR 30%.  With a cohort size of 40 
patients, a minimum of 9 responders would need to be observed in Cohorts C to F in order to 
observe an exact 95% CI such that the lower bound exceeds 10% and the upper bound exceeds 
30%.  Forty patients in each cohort will provide approximately 89% power to distinguish 
between the null response rate of 10% and an alternative response rate of 30% in these cohorts.
The sample size considerations for each cohort are summarized in Table 2:
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Table 2:
Sample Size Considerations for Each Cohort
COHORT
Disease Phase
Eligibility 
Criterion
Primary
Endpoint
Sample Size
Effect Size
Power
A
CP
R/I
MCyR
100
35% vs. 20%
40% vs. 20%
45% vs. 30%
≥85%
≥98%
≥78%
B
CP
T315I
MCyR
60
35% vs 10%
25% vs. 10%
98%
85%
C
AP
R/I
MaHR
40
30% vs. 10%
90%
D
AP
T315I
MaHR
40
30% vs. 10%
90%
E
BP/Ph+ALL
R/I
MaHR
40
30% vs. 10%
90%
F
BP/Ph+ALL
T315I
MaHR
40
30% vs. 10%
90%
CP = chronic phase, R/I = resistance and/or intolerant, MCyR = major cytogenetic response, AP = accelerated phase, 
MaHR = major hematologic response, BP = blast phase, Ph+ ALL, Philadelphia chromosome positive acute 
lymphoblastic leukemia.
4.2
Statistical Methods
4.2.1
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized separately for each cohort and will 
include at a minimum: age, gender, race, weight, country/region, and disease characteristics (eg, 
time since diagnosis, mutation status).
4.2.2
Patient Disposition
Patient disposition will be summarized separately for each cohort.  Table 3 below describes the 
anticipated presentation of key patient disposition categories for each cohort:
Table 3:
Patient Disposition
Treated Patients (N=)
Patients still on therapy
Patients discontinued from therapy:
  In survival follow-up
  Died
  Lost to follow-up
  Withdrew consent
Primary reason for discontinuation
  Progressive Disease
  Adverse Event
  Death
  Consent withdrawn
  Noncompliance with study drug
  Protocol violation
  Physician decision
  Lack of Efficacy
  Lost to follow-up
  Pregnancy
  Withdrawal by subject
  Other
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4.2.3
Efficacy Analyses
4.2.3.1
Primary Analysis of the Primary Endpoint
Cohorts A and B (CP CML Patients)
As specified in Section 2.3, the primary endpoint for patients with CP CML in Cohorts A and B 
is MCyR.  MCyR rate is defined as the proportion of patients who have achieved a CCyR or 
PCyR after the initiation of study treatment.  Patients entering the trial in PCyR must achieve a 
CCyR in order to be considered as achieving a MCyR.  Specifically, Table 4 summarizes how 
patient MCyR status will be classified based on baseline cytogenetic assessment:
Table 4:
MCyR Classification and Baseline Cytogenetic Assessment
On-Study Assessment
Baseline Assessment
PCyR
CCyR
Less than PCyR
Less than PCyR
MCyR
MCyR
No MCyR
PCyR
No MCyR
MCyR
No MCyR
PCyR = partial cytogenetic reponse, CCyR = complete cytogenetic response, MCyR = major cytogenetic response.
The primary analysis of the primary endpoint will be performed using an exact 95% CI for the 
MCyR rate, using the per protocol (cytogenetic) population for each cohort.  Patients who do not 
meet the criteria for MCyR will be analyzed as non-successes.
Cohorts C-F (AP CML/BP CML/Ph+ ALL Patients)
The primary endpoint for patients with AP or BP CML or patients with Ph+ ALL in Cohorts C –
F is MaHR.  MaHR rate is defined as the proportion of patients who have achieved a CHR or 
NEL response after the initiation of study treatment.
The primary analysis of the primary endpoint will be performed using an exact 95% CI for the 
MaHR rate using the per protocol (hematologic) population for each cohort.  Patients who do not 
meet the criteria for MaHR will be analyzed as non-successes.
All Cohorts
In the event of over-enrollments beyond 10% of the planned sample size, a sensitivity analysis 
will be performed on the per protocol population when the sample size requirement is first 
realized.
The 6 cohorts will be analyzed separately and no adjustments for multiplicity are planned.
4.2.3.2
Data Handling Rules for the Primary Analyses of the Primary Endpoint
The key data handling rules for the primary efficacy analyses are as follows:

All CP CML patients (Cohorts A and B) will have an opportunity to demonstrate MCyR up 
to 12 months after initiation of study treatment.  Patients in Cohorts A and B who do not 
respond by 12 months after the initiation of study treatment will be analyzed as non-
successes.

All AP/BP phase CML patients and Ph+ ALL patients (Cohorts C, D, E and F) will have an 
opportunity to demonstrate MaHR up to 6 months after initiation of study treatment.  Patients 
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in Cohorts C-F who do not respond by 6 months after the initiation of study treatment will be 
analyzed as non-successes.

For patients entering the trial in less than PCyR, determination of MCyR requires a 
cytogenetic assessment with at least 13 metaphases examined:
o
If 20 or more metaphases are examined, determination of MCyR will be based on 
the %Ph+ cells as specified in Attachment A of the protocol.
o
If 13-19 metaphases are examined, determination of MCyR will be performed as 
follows:
Table 5:
Determination of PCyR With Assessment of < 20 Metaphases
Number of 
metaphases 
examined
≤12
13
14
15
16
17
18
19
Number of Ph+ 
cells
Any 
Number
0
≤1
≤2
≤3
≤4
≤5
≤6
% Ph+
--
0%
≤7%
≤13%
≤19%
≤24%
≤28%
≤32%
Response
Not 
Evaluable*
PCyR
PCyR
PCyR
PCyR
PCyR
PCyR
PCyR
*The minimum of 13 metaphases is based on the threshold for MCyR of 7 Ph+ cells out of 20 metaphases.

For patients entering the trial in PCyR, a CCyR must be observed in order to meet the criteria 
for MCyR; therefore, determination of MCyR requires a cytogenetic assessment with at least 
20 metaphases examined.

The criteria for initial determination of MaHR require the following sources of data:
o
BM Aspirate,
o
CBC with Differential,
o
Physical Exam.
In order to meet the criteria for MaHR, the above assessments must be performed within 
14 days of one another.  At assessments subsequent to the assessment at which the criteria for 
MaHR are first met, a physical exam is not required.

Initial determination of MaHR must be confirmed no earlier than 28 days later; this 
confirmation requires the following source of data:
o
CBC with Differential.
4.2.3.3
Sensitivity Analyses of the Primary Endpoint
Two additional sensitivity analyses of the primary endpoint will be performed as follows:
Sensitivity Analysis 1
Sensitivity Analysis 1 is intended to assess the impact of the use of the per protocol population 
and the timing of when patients first demonstrate the criteria for success.
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
Analysis of the primary endpoint will be performed on the treated population as specified in 
Section 3.

For analyses of MCyR (primary endpoint for Cohorts A and B), all patients in the treated 
population will be included, regardless of the number of metaphases examined for the 
baseline cytogenetic assessment.

The determination of PCyR status at baseline will be based on the percentage of Ph+ cells, 
regardless of the number of metaphases examined.

Determination of success/not a success will be based on all available data in the database, 
regardless of when the criteria for success are met.
Sensitivity Analysis 2
Sensitivity Analysis 2 is intended to assess the impact of patients for whom the baseline T315I 
direct sequencing result is not received until after the first bone marrow assessment.

Patients for whom a positive baseline T315I direct sequencing result is received after the first 
cytogenetic response assessment (CML patients in CP) or BM assessment (CML patients in 
AP or BP and Ph+ ALL patients) will be analyzed as T315I-.

Patients for whom a negative baseline T315I direct sequencing result is received after first 
cytogenetic response assessment (CML patients in CP) or BM assessment (CML patients in 
AP or BP and Ph+ ALL patients) will be analyzed as T315I+.

For analyses of MCyR (primary endpoint for Cohorts A and B), all patients in the treated 
population will be included, regardless of the number of metaphases examined for the 
baseline cytogenetic assessment.

The determination of PCyR status at baseline will be based on the percentage of Ph+ cells, 
regardless of the number of metaphases examined.

Determination of success/not a success will be based on all available data in the database, 
regardless of when the criteria for success are met.
4.2.4
Key Analyses of the Secondary Endpoints 
The key analyses of the secondary endpoints are specified below.  Data handling rules for these 
analyses are specified in Section 4.2.4.4
4.2.4.1
Cohorts A and B (CP CML Patients)

CHR: the CHR rate is defined as the proportion of patients who have achieved a CHR after 
the initiation of study treatment.  Chronic phase CML patients entering the trial in CHR will 
be excluded from this analysis.  The analysis will be performed using a 2-sided exact 95% CI 
for the CHR rate.
4.2.4.2
Cohorts C-F (AP CML/BP CML/Ph+ ALL Patients)

MCyR: the MCyR rate is defined as the proportion of patients who have achieved a CCyR or 
PCyR after the initiation of study treatment.  The analysis will be performed using a 2-sided 
exact 95% CI for the MCyR rate, using the per protocol population.
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4.2.4.3
All Cohorts

Confirmed MCyR:  the confirmed MCyR rate is defined as the proportion of patients who 
have achieved a confirmed CCyR or PCyR after the initiation of study treatment.  Patients 
entering the trial already in PCyR must achieve a confirmed CCyR in order to be considered 
a success for the confirmed MCyR rate.  The analysis will be performed using a 2-sided 
exact 95% CI for the confirmed MCyR rate.

Duration of response will be estimated using the Kaplan-Meier method.  The median 
duration of response and 95% CI will be calculated.  An additional analysis will be 
performed defining the duration as the time from the first assessment at which the criteria for 
response are met until the last assessment at which the criteria for response are met.  
Duration of response will be analyzed for MCyR, MaHR (Cohorts C-F), CHR (Cohorts A 
and B), and MMR.

Progression-free survival, overall survival and time to response will be estimated using the 
Kaplan-Meier method.  The median progression-free survival, overall survival, and time to 
response and 95% CI will be calculated.

Major molecular response rate will be defined as the proportion of patients who meet the 
criteria for MMR at least once after the initiation of study treatment.  The analysis will be 
performed using a 2-sided exact 95% CI for the MMR rate.
4.2.4.4
Data Handling Rules for Secondary Endpoint Analyses
In addition to the data handling rules specified in Section 4.2.3.2, the following key data 
handling rules for the secondary efficacy analyses will be implemented (note that the definition 
of progression is specified in Attachment A of the protocol).

Loss of MCyR is defined as meeting any of the following criteria:
o
Patients entering the trial in PCyR: 2 consecutive cytogenetic assessments ≥28 days 
apart with Ph+ > 0% after achieving a CCyR.  Patients with a single cytogenetic 
assessment with Ph+ > 0% followed by no additional cytogenetic assessments will be 
also considered as meeting the criteria for loss of MCyR.
o
Patients entering the trial not in PCyR: 2 consecutive cytogenetic assessments 28 days 
apart with Ph+ > 35% after achieving a PCyR.  Patients with a single cytogenetic 
assessment with Ph+ > 35% followed by no additional cytogenetic assessments will be 
also considered as meeting the criteria for loss of MCyR.

Loss of MaHR (Cohorts C through F) is defined as 2 consecutive hematologic assessments 
≥28 days apart at which at the criteria for MaHR are not met.  Patients with a single 
hematologic assessment at which the criteria for MaHR are not met followed by no 
additional hematologic assessments will be also considered as meeting the criteria for loss of 
MaHR.

Patients who progress after a single missed or incomplete visit will be considered as having 
progressed at the visit at which progression was documented.

Patients who progress after 2 or more missed or incomplete visits will be censored at the last 
visit at which the response criteria are met.  For Cohorts A and B, 2 missed visits will be 
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defined as more than 182 days between consecutive visits; for Cohorts C-F, 2 missed visits 
will be defined as more than 126 days between consecutive visits.

Determination of MMR will be based on BCR-ABL and ABL reversed transcribed transcript 
levels in peripheral blood assessments for Cohorts A-F and BM assessments for Cohorts E 
and F (BP CML/Ph+ ALL Patients).  MMR will be determined only for patients with the 
b2a2/b3a2 variant of BCR-ABL.
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4.3
Summaries of Data Handling Rules for Primary and Secondary Efficacy Analyses
Table 6:
Summary of Data Handling Rules for Major Cytogenetic Response (MCyR)
Note: all assessments must be after the initiation of study treatment unless otherwise specified.
PRIMARY ANALYSIS
SENSITIVITY ANALYSIS 1
SENSITIVITY ANALYSIS 2
Population
Per Protocol (Cytogenetic) Population
Treated Population (includes patients with 
< 20 metaphases examined for baseline 
cytogenetic assessment)
Treated Population (includes patients with 
< 20 metaphases examined for baseline 
cytogenetic assessment)

Patients for whom a positive baseline 
T315I direct sequencing result is received 
after the first cytogenetic response 
assessment (CML patients in CP) or BM 
assessment (CML patients in AP or BP 
and Ph+ ALL patients) will be analyzed as 
T315I-.

Patients for whom a negative baseline 
T315I direct sequencing result is received 
after first cytogenetic response assessment 
(CML patients in CP) or BM assessment 
(CML patients in AP or BP and Ph+ ALL 
patients) will be analyzed as T315I+.
MCyR
For patients not in PCyR at study entry 
(>35% Ph+ cells): 1 assessment of:

0-35% Ph+ cells with at least 20 
metaphases examined
OR

See Table 5
For patients in PCyR at study entry (>0% 
and ≤35% Ph+ cells): 1 assessment of 0% 
Ph+ cells with at least 20 metaphases 
examined
≤ 12 months after initiation of study 
treatment
For patients not in PCyR at study entry 
(>35% Ph+ cells): 1 assessment of:

0-35% Ph+ cells with at least 20 
metaphases examined
OR

See Table 5
For patients in PCyR at study entry (>0% 
and ≤35% Ph+ cells): 1 assessment of 0% 
Ph+ cells with at least 20 metaphases examined
Any time after initiation of study treatment
For patients not in PCyR at study entry 
(>35% Ph+ cells): 1 assessment of:

0-35% Ph+ cells with at least 20 
metaphases examined
OR

See Table 5
For patients in PCyR at study entry (>0% 
and ≤35% Ph+ cells): 1 assessment of 0% 
Ph+ cells with at least 20 metaphases examined
Any time after initiation of study treatment
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PRIMARY ANALYSIS
SENSITIVITY ANALYSIS 1
SENSITIVITY ANALYSIS 2
Confirmed 
MCyR
For patients not in PCyR at study entry 
(>35% Ph+ cells): 2 consecutive 
assessments at least 4 weeks apart of:

0-35% Ph+ cells with at least 20 
metaphases examined
OR

See Table 5
For patients in PCyR at study entry: 2 
consecutive assessments at least 4 weeks 
apart of 0% Ph+ cells with at least 20 
metaphases examined
≤ 12 months after initiation of study 
treatment
For patients not in PCyR at study entry 
(>35% Ph+ cells): 2 consecutive assessments 
at least 4 weeks apart of:

0-35% Ph+ cells with at least 20 
metaphases examined
OR

See Table 5
For patients in PCyR at study entry: 2 
consecutive assessments at least 4 weeks apart 
of 0% Ph+ cells with at least 20 metaphases 
examined
Any time after initiation of study treatment
For patients not in PCyR at study entry 
(>35% Ph+ cells): 2 consecutive assessments 
at least 4 weeks apart of:

0-35% Ph+ cells with at least 20 
metaphases examined
OR

See Table 5
For patients in PCyR at study entry: 2 
consecutive assessments at least 4 weeks apart 
of 0% Ph+ cells with at least 20 metaphases 
examined
Any time after initiation of study treatment
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Table 7:
Summary of Data Handling Rules for Major Hematologic Response (MaHR)
PRIMARY ANALYSIS
SENSITIVITY ANALYSIS 1
SENSITIVITY ANALYSIS 2
Population
Per Protocol (Hematologic) Population
Treated Population (includes patients with 
baseline bone marrow assessments for which 
percent blast cannot be determined)
Treated Population (includes patients with 
baseline bone marrow assessments for which 
percent blast cannot be determined)

Patients for whom a positive baseline 
T315I direct sequencing result is received 
after the first cytogenetic response 
assessment (CML patients in CP) or BM 
assessment (CML patients in AP or BP 
and Ph+ ALL patients) will be analyzed as 
T315I-.

Patients for whom a negative baseline 
T315I direct sequencing result is received 
after first cytogenetic response assessment 
(CML patients in CP) or BM assessment 
(CML patients in AP or BP and Ph+ ALL 
patients) will be analyzed as T315I+.
MaHR 
(CHR)
1 assessment at which all of the following 
criteria are met:

WBC ≤ ULN

ANC ≥ 1000/mm3

Platelets ≥ 100,000/mm3

No blasts or promyelocytes in 
peripheral blood

BM blasts ≤ 5%

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%

No extramedullary involvement 
(including no hepatomegaly or 
splenomegaly)
≤ 6 months after initiation of study treatment
1 assessment at which all of the following 
criteria are met:

WBC ≤ ULN

ANC ≥ 1000/mm3

Platelets ≥ 100,000/mm3

No blasts or promyelocytes in 
peripheral blood

BM blasts ≤ 5%

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%

No extramedullary involvement 
(including no hepatomegaly or 
splenomegaly)
Any time after initiation of study treatment
1 assessment at which all of the following 
criteria are met:

WBC ≤ ULN

ANC ≥ 1000/mm3

Platelets ≥ 100,000/mm3

No blasts or promyelocytes in 
peripheral blood

BM blasts ≤ 5%

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%

No extramedullary involvement 
(including no hepatomegaly or 
splenomegaly)
≤ 6 months after initiation of study treatment
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PRIMARY ANALYSIS
SENSITIVITY ANALYSIS 1
SENSITIVITY ANALYSIS 2
1 additional assessment at which all of the 
following criteria are met, at least 28 days 
after the first assessment of response:

WBC ≤ ULN

ANC ≥ 1000/mm3

Platelets ≥ 100,000/mm3

No blasts or promyelocytes in 
peripheral blood

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%*
1 additional assessment at which all of the 
following criteria are met, at least 28 days 
after the first assessment of response:

WBC ≤ ULN

ANC ≥ 1000/mm3

Platelets ≥ 100,000/mm3

No blasts or promyelocytes in 
peripheral blood

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%*
1 additional assessment at which all of the 
following criteria are met, at least 28 days after 
the first assessment of response:

WBC ≤ ULN

ANC ≥ 1000/mm3

Platelets ≥ 100,000/mm3

No blasts or promyelocytes in 
peripheral blood

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%*
MaHR 
(NEL)
1 assessment at which all of the following 
criteria are met:

WBC ≤ ULN

No blasts or promyelocytes in 
peripheral blood

BM blasts ≤ 5%

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%

No extramedullary involvement 
(including no hepatomegaly or 
splenomegaly)

At least 1 of the following: (i) 
20,000/mm3 ≤ platelets < 
100,000/mm3; (ii) 500/mm3 ≤ ANC 
<1000/mm3
≤ 6 months after initiation of study treatment
1 additional assessment at which all of the 
following criteria are met, at least 28 days 
after the first assessment of response:
1 assessment at which all of the following 
criteria are met:

WBC ≤ ULN

No blasts or promyelocytes in 
peripheral blood

BM blasts ≤ 5%

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%

No extramedullary involvement 
(including no hepatomegaly or 
splenomegaly)

At least 1 of the following: (i) 
20,000/mm3 ≤ platelets < 
100,000/mm3; (ii) 500/mm3 ≤ ANC 
<1000/mm3
Any time after initiation of study treatment
1 additional assessment at which all of the 
following criteria are met, at least 28 days 
after the first assessment of response:
1 assessment at which all of the following 
criteria are met:

WBC ≤ ULN

No blasts or promyelocytes in 
peripheral blood

BM blasts ≤ 5%

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%

No extramedullary involvement 
(including no hepatomegaly or 
splenomegaly)

At least 1 of the following: (i) 
20,000/mm3 ≤ platelets < 
100,000/mm3; (ii) 500/mm3 ≤ ANC 
<1000/mm3
≤ 6 months after initiation of study treatment
1 additional assessment at which all of the 
following criteria are met, at least 28 days after 
the first assessment of response:
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PRIMARY ANALYSIS
SENSITIVITY ANALYSIS 1
SENSITIVITY ANALYSIS 2

WBC ≤ ULN

No blasts or promyelocytes in 
peripheral blood

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%

At least 1 of the following: (i) 
20,000/mm3 ≤ platelets < 
100,000/mm3; (ii) 500/mm3 ≤ ANC 
<1000/mm3

WBC ≤ ULN

No blasts or promyelocytes in 
peripheral blood

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%

At least 1 of the following: (i) 
20,000/mm3 ≤ platelets < 
100,000/mm3; (ii) 500/mm3 ≤ ANC 
<1000/mm3

WBC ≤ ULN

No blasts or promyelocytes in 
peripheral blood

< 5% myelocytes plus 
metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%

At least 1 of the following: (i) 
20,000/mm3 ≤ platelets < 
100,000/mm3; (ii) 500/mm3 ≤ ANC 
<1000/mm3
*Refer to protocol amendment 1; basophils in peripheral blood changed from <20% to <5%.
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Table 8:
Summary of Data Handling Rules for Analysis of Duration of Response†
CONDITION
ANALYSIS 1
ANALYSIS 2
ANALYSIS 3
ANALYSIS 4
(Duration of Confirmed 
Response)
No progression or loss of 
response
Censored at last date patient 
met criteria for response
Censored at date of last dose 
of study drug
Censored at date of last 
dose of study drug
Censored at last date patient 
met criteria for response
Progression or loss of response*
any time after a single 
(unconfirmed) assessment of 
response
Progression
(Duration = Date of relapse –
Date of first response 
assessment)
Progression
(Duration = Date of relapse –
Date of first response 
assessment)
Progression
(Duration = Date of relapse 
– Date of first response 
assessment)
Excluded
Progression or loss of response 
any time after two consecutive 
assessments of response at least 4 
weeks apart (confirmation of 
response)
Progression
(Duration = Date of relapse –
Date of first response 
assessment)
Progression
(Duration = Date of relapse –
Date of first response 
assessment)
Progression
(Duration = Date of relapse 
– Date of first response 
assessment)
Progression
(Duration = Date of relapse –
Date of second response 
assessment)
Progression or loss of response 
after one missed or incomplete 
assessment
Progression
(Duration = Date of relapse –
Date of first response 
assessment)
Progression
(Duration = Date of relapse –
Date of first response 
assessment)
Progression
(Duration = Date of relapse 
– Date of first response 
assessment)
Censored at last date patient 
met criteria for response
Progression or loss of response 
after two or more missed or 
incomplete assessments
Censored at last date patient 
met criteria for response
Censored at date of last dose 
of study drug
Progression
(Duration = Date of relapse 
– Date of first response 
assessment)
Censored at last date patient 
met criteria for response
Initiation of prohibited anti-
leukemia therapy (including stem 
cell transplant) prior to loss of 
unconfirmed response
Censored at date of initiation 
of new therapy
Censored at date of initiation 
of new therapy
Censored at date of 
initiation of new therapy
Excluded
Initiation of prohibited anti-
leukemia therapy (including stem 
cell transplant) prior to loss of 
confirmed response
Censored at date of initiation 
of new therapy
Censored at date of initiation 
of new therapy
Censored at date of 
initiation of new therapy
Censored at last date patient 
met criteria for response
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CONDITION
ANALYSIS 1
ANALYSIS 2
ANALYSIS 3
ANALYSIS 4
(Duration of Confirmed 
Response)
Cohorts A and B:
Failure to respond by 12 months 
after the initiation of study 
treatment 
Cohorts C, D, E, and F:
Failure to respond by 6 months 
after the initiation of study 
treatment
Excluded
Excluded
Included if patient meets 
criteria for response
Excluded
† An additional analysis will be performed defining the duration as the time from the first assessment at which the criteria for response are met until the last 
assessment at which the criteria for response are met.
Table 9:
Summary of Data Handling Rules for Analysis of Major Molecular Response (MMR)
CONDITION
ANALYSIS 1
ANALYSIS 2
ANALYSIS 3
No baseline result obtained
Non-success
Excluded
Analyze as observed
MMR at baseline
Non-success
Excluded
Analyze as observed
Detectable levels of BCR-ABL and ABL at 
baseline followed by Not Detectable levels of 
BCR-ABL post-baseline 
Success
Success
Success
Measurement of BCR-ABL or ABL considered 
to be aberrant upon medical review
Data point will be used for 
determination of MMR
Data point will be excluded for 
determination of MMR
Data point will be excluded for 
determination of MMR
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4.3.1
Subgroup Analyses of the Primary Endpoints and Key Secondary Endpoints
For the primary endpoint and selected key secondary endpoints, subgroup analyses will be 
performed by key baseline potential prognostic factors. Subgroups will include: 

Age

Gender

Race

Eastern Cooperative Oncology Group (ECOG) performance status

Geographic Region (US vs. Rest of World [ROW])

Time Since Diagnosis

Mutation Status
o
Via Direct Sequencing method

T315I mutation

Kinase Domain (KD) mutations other than T315I

No detectable KD mutations
o
Via allele-specific oligonucleotide (ASO) method

T315I+ vs. T315I-
o
T315I status by history

T315+ vs. T315I-

Prior TKI Exposure
o
2nd line (1 prior TKI) vs. 3rd line (any 2 prior TKIs) vs. >3rd line (any 3 or more 
prior TKIs)
o
Nilotinib Exposure (Yes/No)
o
Dasatinib Exposure (Yes/No)
o
Intolerant vs. Resistant (to Dasatinib or Nilotinib)

BCR-ABL/ABL transcript ratio

PCyR at baseline

High-enrolling investigational sites (if applicable)

Other Disease-Related Prognostic Factors

T315I and Resistant-Intolerant patients will be pooled within disease groups where 
applicable (eg, pooling of Cohorts A and B)
4.3.2
Treated Patients Not Eligible for Cohorts A-F
Patients who receive study treatment but who are not confirmed to have a detectable baseline 
T315I mutation by direct sequencing and who are not resistant or intolerant to dasatinib or 
nilotinib will be analyzed separately according to the data handling rules for primary and 
secondary efficacy analyses, if applicable.
4.3.3
Safety Analyses
All safety analyses will be performed on the safety population, which will include all patients 
who have received at least one dose of study drug.  The safety data from all cohorts will be 
pooled.
The adverse event incidence rates, as well as the frequency of occurrence of overall toxicity 
categorized by toxicity grades (severity), will be described.  All adverse events starting on or 
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 22"%; %/ ! /,!*!!:
2&!- !B" /  & !! :! *!
  !!#! 22 %!!2 %/!*! / 
"!%; 
%!!/ "%  ;  &  ! &!=!$
$!!)!!&/$:! 232 2! ,=$$)$3 2 -
"**%$&:!%!"!! /"%; 
:!  ; &!:%!!/"!%& :!
%!!/ ! 

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 !! !-"%; */:!!!$!*"!%
;   &*!*  %!:*" ! /! !
 !
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da: For non-commercial use only and 


ARIAD Pharmaceuticals, Inc.
AP24534-10-201
Statistical Analysis Plan (SAP)
V1.0 14 December 2010
Page 24
5
REFERENCES
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resistant chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or 
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2. Quintas-Cardama A, Kantarjian H, et al. (2007). Dasatinib (BMS-354825) is active in 
Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and 
nilotinib (AMN107) therapy failure. Blood 109(2): 497-499.
3. Garg RJ, Kantarjian H, et al. (2009). The use of nilotinib or dasatinib after failure to 2 prior 
tyrosine kinase inhibitors: long-term follow-up.  Blood 114(20): 4361-4368.
4. Muller MC, Cortes J, et al. (2009). Dasatinib treatment of chronic-phase chronic myeloid 
leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood
114(24): 4944-4953.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use