Clinical trial NCT01667133
Conditions: Chronic Myeloid Leukemia (CML) Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Keywords: Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases
Sponsor: Ariad Pharmaceuticals
Start date: 2012-08-31; Completion date: 2018-08-02
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and efficacy of ponatinib in Japanese patients with chronic myeloid leukemia (CML) who have experienced failure of dasatinib or nilotinib or with Ph+ acute lymphoblastic leukemia (ALL) following failure of prior tyrosine kinase inhibitors (TKIs).

Detailed description:
This multi-center, phase 1/2, open-label study will consist of two phases. The first will be a dose escalation phase employing a modified 3+3 design with two dose cohorts (30mg and 45mg). After 6 patients complete the first cycle in a cohort, safety events will be evaluated before opening the next dose cohort. Patients will continue on treatment as long as it is tolerated and disease progression has not occurred. Phase 2 will occur at the recommended dose determined in phase 1 in an additional 25 patients. Another 3 patients will be dosed at 15mg for collection of pharmacokinetic data. These patients may also escalate to the recommended dose and be assessed for efficacy and safety as phase 2 patients.

Efficacy measures include molecular, cytogenetic, and hematologic response rates at various time points; time to response; duration of response; and survival follow-up. Safety measures include routine physical and laboratory evaluations, adverse event monitoring, and ECGs. Other measures include mutation testing and molecular genetic assessment. Accrual is expected to take approximately 12 months, and patients will be followed for survival for up to 60 months from the last dose of study drug; therefore, the estimated duration of the trial is 72 months.

Arms: arm 1: Phase 1 arm 2: Phase 2
Interventions: intervention 1: ponatinib - Phase 1 intervention 2: ponatinib - Phase 2
Intervention descriptions: intervention 1: 30 mg dose of ponatinib taken orally once daily for at least the first 6 patients. If no dose-limiting toxicities are observed, the next patients will receive 45 mg dose of ponatinib taken orally once daily. Once the recommended dose is confirmed, all patients may receive the recommended dose, at the investigators' discretion. intervention 2: Recommended dose of ponatinib as determined in the dose escalation phase. In addition, 3 patients will receive 15 mg dose once daily for 8 days for PK testing. These PK patients may be allowed to receive the recommended dose after PK testing is complete, at the investigators' discretion.

Protocol documents:
Prot_000.pdf: 



Title: A phase I/II multi-center, open-label study of ponatinib in Japanese patients with chronic 
myeloid leukemia (CML) who have failed dasatinib or nilotinib or Philadelphia chromosome-
positive (Ph+) acute lymphoblastic leukemia (ALL) who have failed prior tyrosine kinase 
inhibitors (TKIs)
NCT Number: NCT01667133
Protocol Approve Date: 21 November 2013
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.


ARIAD Pharmaceuticals, Inc.
AP24534-11-106
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1
CLINICAL STUDY PROTOCOL
Study Title:
A phase I/II multi-center, open-label study of ponatinib in 
Japanese patients with chronic myeloid leukemia (CML) 
who have failed dasatinib or nilotinib or Philadelphia 
chromosome-positive (Ph+) acute lymphoblastic leukemia 
(ALL) who have failed prior tyrosine kinase inhibitors 
(TKIs)
Protocol Number:
AP24534-11-106
Study Phase:
I/II
Product Name:
AP24534
Sponsor:
In-Country Clinical Caretaker 
(ICCC):
ARIAD Pharmaceuticals, Inc
26 Landsdowne Street
Cambridge, MA 02139-4234
Telephone: +1 (617) 494-0400
Protocol Issue Date:
21 November 2013
Version Number:
Version 3.0
PROTOCOL REVISION HISTORY
Amendment Number
Protocol Version Number
Date
First Version
Version 1.0
08 May 2012
Revision in line with PMDA Advice 
raised during the CTN inquiry 
Version 1.1
31 May 2012
Revision for appropriate writing
Version 1.2
11 Jun 2012
Revision for appropriate writing
Version 1.3
04 Jul 2012
Amendment 1
Version 2.0
26 June 2013
Amendment 2
Version 3.0
21 November 2013
PPD
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3.0
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for appr
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CONTACT INFORMATION
Sponsor
In-Country Clinical Caretaker 
(ICCC):
ARIAD Pharmaceuticals, Inc
26 Landsdowne Street
Cambridge, MA 02139-4234
Telephone: +1 (617) 494-0400
Monitor:
PPD
PPD
Property of Takeda: For Non-Commercial Use Only and Su
nd
App
Ap
ble Terms of Use
of
pplicabl
Subject to the Ap


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PROTOCOL SYNOPSIS
Study Title
A phase I/II multi-center, open-label study of ponatinib in Japanese patients with 
chronic myeloid leukemia (CML) who have failed dasatinib or nilotinib or 
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who 
have failed  prior tyrosine kinase inhibitors (TKIs)
Study Treatment
AP24534 (Ponatinib 15 mg or 45 mg white tablets; once daily)
Phase
Phase I/II
Eligible Population
Japanese patients with CML who have experienced a failure of dasatinib or nilotinib 
because of resistance or intolerance, or Ph+ ALL patients who have experienced a 
failure of  prior TKIs because of resistance or intolerance
Summary and Study 
Rationale
Chronic myeloid leukemia is a clonal myeloproliferative disorder that represents about 
15% of adult leukemias (Deininger et al, 2000).  The underlying cause of CML is the 
Breakpoint Cluster Region-Abelson (BCR-ABL) fusion oncoprotein, which results 
from a reciprocal (9;22) chromosomal translocation in hematopoietic stem cells.  This 
chromosomal abnormality (Ph+) is present in about 95% of all patients with CML, as 
well as about 40% of adult patients with Ph+ ALL.  The translocation leads to the 
fusion of the BCR coding sequence with the tyrosine kinase coding region of ABL.  
This fusion event results in the constitutive activation of ABL kinase activity, which is 
both necessary and sufficient for induction of CML or ALL (Deininger et al, 2000).
Imatinib was the first small molecule TKI approved by the Food and Drug 
Administration (FDA; United States) to treat CML patients.  At 8 years of follow-up, 
the pivotal study of imatinib (IRIS: International Randomized Study of Interferon and 
ST1571 trial) in newly diagnosed chronic phase (CP)-CML patients has reported 81% 
event-free survival (EFS) and 85% overall survival (OS; Cortes et al, 2011).  However, 
despite the success of imatinib, 45% of patients in the IRIS trial discontinued imatinib 
therapy.  A substantial fraction of patients either initially fail to respond to imatinib or 
progress after a period of therapy.  BCR-ABL point mutations in the ABL kinase 
domain that impair imatinib binding are the main cause of resistance to imatinib 
therapy, and account for approximately 40% to 50% of resistant cases of disease 
(Branford et al, 2003; Jabbour et al, 2006; Jones et al, 2009; Terasawa et al, 2010; 
O’Hare et al, 2011).
Second-generation small-molecule inhibitors, dasatinib and nilotinib, are more potent 
than imatinib and inhibit many, but not all, imatinib-resistant point mutants, as well as 
native BCR-ABL (Talpaz et al, 2006; Kantarjian et al, 2006).  Dasatinib and nilotinib 
were approved in Japan in 2009.  Both are approved for use in patients who have 
experienced a failure of imatinib therapy, based on phase II clinical trials, in which 
approximately 40% to 45% of CP-CML patients achieved major cytogenetic responses 
(MCyRs) (Pinilla-Ibarz et al, 2008; Kantarjian et al, 2007).  However, the remainder of 
patients, many of whom carry resistance mutations, remained refractory.  Of note, both 
dasatinib and nilotinib are ineffective against the uniformly resistant T315I BCR-ABL 
mutation, which represents 15% to 20% of all clinically observed mutations (O’Hare et 
al, 2007).
To address the problem of resistance to the first- and second-generation BCR-ABL 
TKIs, ARIAD Pharmaceuticals, Inc (ARIAD) has developed ponatinib.  Ponatinib is a 
novel synthetic orally active TKI, specifically developed to inhibit BCR-ABL, the 
fusion protein that is the product of the Philadelphia chromosome in CML and in a 
subset of 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 
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is a pan-BCR-ABL inhibitor.
In vitro assays have demonstrated that ponatinib potently inhibits the enzymatic 
activity of the T315I ABL kinase domain, as well as that of the native (unmutated) 
enzyme.  In leukemia cell lines expressing these BCR-ABL variants, ponatinib 
potently inhibited BCR-ABL signaling, leading to inhibition of cellular proliferation 
and induction of apoptosis.  Ponatinib also inhibits the proliferation of cell lines 
expressing other major clinically observed imatinib-resistant mutants of BCR-ABL.  In 
an in vitro mutagenesis screen designed to characterize the resistance profile of 
ponatinib, no mutations in BCR-ABL were identified that alone could confer 
resistance to 40 nM ponatinib.  Based on the promising preclinical activity profile of 
ponatinib, initial human clinical studies were conducted.
The phase I study of ponatinib included patients diagnosed with a hematologic 
malignancy who relapsed or were refractory to standard care, or for whom no standard 
care was available.  The primary objective was to determine the maximum tolerated 
dose (MTD) or a recommended dose of daily oral ponatinib.  
The phase II PACE study (Ponatinib Ph+ ALL and CML Evaluation) was initiated in 
September 2010 and is ongoing.  The objective of this international, single-arm, 
open-label study is to establish the efficacy and safety of ponatinib in patients with 
refractory CML in CP, accelerated phase (AP) or blast phase (BP), or Ph+ ALL 
resistant or intolerant to dasatinib or nilotinib or with the T315I mutation.  The primary 
endpoints are MCyR for CP-CML and major hematologic response (MaHR) for AP, 
BP, or Ph+ ALL.
Findings from the phase I study of ponatinib show evidence of clinical antileukemic 
activity in patients with resistance to approved second-generation TKIs, dasatinib and 
nilotinib, including patients with the T315I mutation of BCR-ABL.  Based on the 
phase I safety, pharmacokinetic (PK), pharmacodynamics (PD), and antileukemic
activity, 45 mg was chosen as the recommended dose for further study in adults.  In 
addition, data emerging from the pivotal, international, phase II study are promising, 
with a safety profile similar to that reported for the phase I study and early efficacy 
signals showing substantial antileukemic activity in heavily pretreated patients and 
those with refractory T315I, even after a short follow-up period.  Results from these 
clinical studies, taken together with the strong preclinical data that characterize 
ponatinib, provide the rationale for investigation of ponatinib in Japanese patients with 
CML or Ph+ ALL.
Study Design
This will be a phase I/II, multi-center, open-label study of ponatinib in Japanese 
patients with CML who have experienced a failure of dasatinib or nilotinib therapy, or 
Ph+ ALL who have experienced a failure of prior TKIs because of resistance or 
intolerance.  The study will consist of two components, a phase I component followed 
by a phase II component.  The phase I component will be an open-label, dose-
escalation study of two dose cohorts, 30 mg and 45 mg.  At least 6 patients will be 
enrolled in each cohort to confirm the safety of the recommended dose (45 mg) of 
ponatinib in Japanese patients.
The phase I component will employ a modified 3+3 design.  After 6 patients complete 
their first cycle (1 cycle = 28 days) in a cohort and are evaluable for dose-limiting 
toxicities (DLTs), safety events, including any DLTs, will be reviewed in conference 
between the sponsor and the investigators.  These discussions will occur prior to 
opening the next dose level.  Patients who are not evaluable for DLTs will be replaced.  
Definitions of DLT and MTD, and rules for escalation to the next dose level are 
provided in Section 5.2.
The second dose cohort (45 mg) will be enrolled once the 30 mg dose cohort is 
completed and all patients have received 1 full cycle (28 days) of ponatinib.  Patients 
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are expected to receive study drug over at least 1 cycle of study treatment, unless an 
unacceptable drug reaction or disease progression occurs.  Patients who give their 
consent to remaining in the study for ongoing treatment may continue to receive 
additional cycles of study treatment as long as treatment is tolerated and disease 
progression has not occurred.  The recommended phase II dose of ponatinib in 
Japanese patients will be determined (in conference between the investigator and 
sponsor) based on the evaluation of DLTs and safety in the 30 mg and 45 mg cohorts.
Once the safety of the recommended dose of ponatinib in Japanese patients is 
confirmed, the phase II component will be initiated.  This will be a phase II, 
single-arm, open-label study of ponatinib at the recommended dose (determined in 
phase I) in an additional 25 patients.
An additional 3 patients will be dosed at 15 mg for collection of PK data. PK 
parameters at the 15-mg dose level will be modeled, along with the 30-mg and 45-mg 
dose levels for determination of PK linearity in Japanese patients. After PK samples 
collection on Day 1 and Day 8 in Cycle 1, patients at 15 mg will be allowed to 
dose-escalate to the recommended phase II dose (determined in the phase I component 
of the trial) at the investigators’ discretion and will be assessed for efficacy and safety 
as phase II patients.
Study Objectives
Primary

Phase I: To examine the safety of the recommended dose of oral ponatinib in 
Japanese patients with CML who are resistant or intolerant to dasatinib or 
nilotinib, or with Ph+ ALL who are resistant or intolerant to prior TKIs

Phase II: To confirm the antileukemic activity of ponatinib in Japanese 
patients with CML who are resistant or intolerant to dasatinib or nilotinib, or
with Ph+ ALL who are resistant or intolerant to prior TKIs, as evidenced by 
clinical responses, molecular responses, and clinical outcomes
Secondary

To examine the PK of ponatinib in Japanese patients with CML who are 
resistant or intolerant to dasatinib or nilotinib, or with Ph+ ALL who are 
resistant or intolerant to prior TKIs

To describe potential pharmacogenomic markers of ponatinib antileukemic 
activity and to characterize the molecular status of patients
Study Endpoints
Primary Endpoints
Phase I:  Safety of the dose recommended in the previous foreign study of oral 
ponatinib in Japanese patients with CML who are resistant or intolerant to dasatinib or 
nilotinib, or with Ph+ ALL who are resistant or intolerant to prior TKIs
Phase II:  In the phase II component, the primary efficacy endpoints will be:

For CML patients in CP at study entry: MCyR, defined as complete 
cytogenetic response (CCyR) or partial cytogenetic response (PCyR)
o
CP patients in CCyR are not eligible for this study.

For CML patients in AP, BP, or Ph+ ALL at study entry: MaHR, defined as 
complete hematologic response (CHR) or no evidence of leukemia (NEL)
o
AP, BP, and Ph+ ALL patients in MaHR are not eligible for this study.
Secondary Endpoints

For CML patients in CP:
o
Hematologic responses: CHR
o
Cytogenetic responses: confirmed MCyR
o
Molecular responses: major  molecular response (MMR)

For CML patients in AP or BP or Ph+ ALL patients:
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AP24534-11-106
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o
Cytogenetic responses: CCyR, PCyR, confirmed MCyR
o
Molecular responses: MMR
!
For all patients: time to response (TTR), duration of response, 
progression-free survival (PFS), and OS
Exploratory Endpoints
!
!
Diagnosis and Inclusion 
Criteria
1.
Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ 
ALL (defined in Sections 4.3 and 4.4).
!
All patients must have screening bone marrow (BM) cytogenetics with 
conventional banding performed within 42 days prior to beginning 
treatment.
!
Examination of at least 20 metaphases is required in patients in CP.  If less 
than 20 metaphases are examined, the BM aspirate must be repeated.
!
Adequate BM aspirate with differential cell counts is required in patients 
with AP, BP, or Ph+ ALL.  If an adequate aspirate is not obtained, the 
aspirate must be repeated.
2.
Be previously treated with and resistant or intolerant to either dasatinib or nilotinib 
for CML or at least oe TKI for Ph+ ALL
2.1
Resistance is defined for CP-CML patients (CP at the time of initiation of 
dasatinib or nilotinib therapy) as follows.  Patients must meet at least one 
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 (see 
Appendix A)
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 AP-CML 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 an MaHR
b.
At any time after the initiation of therapy, the loss of an 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 
CCI
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ARIAD Pharmaceuticals, Inc.
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BCR-ABL kinase domain mutations in the absence of an MaHR
2.3
Resistance is defined for BP-CML 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 an MaHR
b.
At any time after the initiation of therapy, the loss of an 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 an MaHR
2.4
Intolerance 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), irrespective of the absence of a CCyR for CP patients or an 
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 the 
manufacturer, irrespective of the absence of a CCyR for CP patients or 
MaHR for AP, BP, or Ph+ ALL patients
NOTE: Although the above criteria define the failure of dasatinib or 
nilotinib therapy (mostly according to Baccarani et al., 2009), CML 
patients who have gone on to later-line therapy are eligible, having 
experienced a failure of dasatinib or nilotinib.  Similarly, Ph+ ALL 
patients who have gone on to another TKI having experienced a failure 
of one prior TKI are eligible.
Patients must meet all of the remaining criteria to be eligible for the study:
3.
Must be ≥18 years old
4.
Provide written informed consent
5.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
6.
Minimum life expectancy of 3 months or more
7.
Adequate renal function defined as serum creatinine <1.5 × upper limit of normal 
(ULN) for institution
8.
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 <1.5 × ULN
9.
Normal pancreatic status defined as:
a.
Lipase ≤1.5 × ULN for institution
b.
Amylase ≤1.5 × ULN for institution
10. Normal QT interval corrected (Fridericia) (QTcF) interval on screening 
electrocardiogram (ECG) evaluation, defined as QTcF of ≤450 ms in males or 
≤470 ms in females
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11. For females of childbearing potential, a negative pregnancy test must be 
documented prior to enrollment
12. Female and male patients who are fertile must agree to use an effective form of 
contraception with their sexual partners from enrollment through at least 4 months 
after the end of treatment
13. Ability to comply with study procedures, in the investigator’s opinion
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 2 by National Cancer Institute Common 
Terminology Criteria for Adverse Events, version 4.0 [NCI CTCAE v.4.0]) from 
adverse events (AEs) (except alopecia) due to agents previously administered
2.
Received other therapies as follows:
a.
For CP and AP patients, received 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 7 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 and other chemotherapy within 7 days prior to the first 
dose of ponatinib; otherwise, 2a applies
3.
Underwent autologous or allogeneic stem cell transplant <60 days prior to 
receiving the first dose of ponatinib; any evidence of ongoing graft versus-host 
disease (GVHD) or GVHD requiring immunosuppressive therapy
4.
Take medications that are known to be associated with Torsades de Pointes
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 CP-CML are excluded if they are in CCyR
8.
Patients with CP-CML are excluded if a baseline BM aspirate adequate for 
conventional cytogenetic analysis with 20 metaphases examined is not available.
9.
Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if they are in MaHR.
10. Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if a baseline BM 
aspirate adequate for cell count and differential report is not available.  Patients 
with a fibrotic marrow or dry tap that does not yield adequate cell counts for 
diagnosis are not evaluable for classification, and endpoints are not eligible.
11. 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.
12. Have significant, uncontrolled, or active cardiovascular disease, specifically 
including, but not restricted to:
a.
Myocardial infarction (MI) within 6 months prior to enrollment
b.
Unstable angina within 6 months prior to enrollment
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c.
Congestive heart failure (CHF) within 6 months prior to enrollment
d.
History of clinically significant atrial arrhythmia as determined by the treating 
physician
e.
Any history of ventricular arrhythmia
f.
Cerebrovascular accident or transient ischemic attack (TIA) within 6 months 
prior to enrollment
g.
Any history of peripheral arterial occlusive disease requiring revascularization
Any history of venous thromboembolism, including deep venous thrombosis 
or pulmonary embolism within 6 months prior to enrollment
13. Have a significant bleeding disorder unrelated to CML or Ph+ ALL
14. Have a history of pancreatitis or alcohol abuse
15. Have uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)
16. Have malabsorption syndrome or other gastrointestinal illness that could affect 
absorption of orally administered ponatinib
17. 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)
18. Are pregnant or lactating.  Females and males who are fertile must agree to use an 
effective form of contraception from enrollment through at least 4 months after the 
end of treatment.  Women who stopped breastfeeding before the initial dose of 
ponatinib are eligible for inclusion (forbidden period: the day of the initial 
ponatinib dose until 6 months from the last dosing).
19. 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
20. 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.
21. 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
22. Have uncontrolled hypertension (diastolic blood pressure >90 mm Hg; systolic 
blood pressure >140 mm Hg).  Patients with hypertension should be under 
treatment on study entry to effect blood pressure control.
Approximate Number of 
Patients
At least 34 patients with CML who are resistant or intolerant to dasatinib or nilotinib 
or Ph+ ALL who have failed prior TKIs because of resistance or intolerance will be 
enrolled (at least 12 patients in the phase I dose escalation component and 3 patients at 
15 mg for determination of PK linearity). For the entire study (phase I and phase II
combined), 17 CP CML patients and 17 CML patients other than CP-CML patients 
(AP-CML, BP-CML or Ph+ALL patients) are targeted (See Section 9.4).
Approximate Duration of 
Patient Participation
The duration of each patient’s study participation will be up to 60 months, plus up to 
3 weeks for screening and a 30-day follow-up period.
Approximate Duration of 
Study
The estimated duration of the study is approximately 72 months, including 12 months 
of enrollment and 60 months of follow-up.  All patients who discontinue prematurely 
from the study will be followed for survival every 12 weeks ± 2 weeks starting after 
the last dose of study drug for up to 60 months from the initiation of therapy.
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Approximate Number of 
Study Centers
Approximately 10-12 centers
Dosage and 
Administration
Ponatinib will be administered orally once daily at two dose levels, 30 mg and 45 mg, 
during the phase I dose escalation phase.  Based on the recommended dose determined 
in the phase I component, 30 mg or 45 mg will be administered in the phase II
expansion phase of the trial.  For determination of PK, 3 additional patients will be 
given 15 mg orally once daily.
Dose Recommendations Based on Updated Data
Before Amendment 2 (Version 3.0), the recommended phase II dose of ponatinib for 
Japanese patients was determined to be 45 mg given once daily.  However, an increase 
in the cumulative incidence of cardiovascular events has been noted in the phase II 
PACE trial over time (N=449).  With a median follow up of 24 months, serious arterial 
thrombosis occurred in 11.8% of patients: cardiovascular events in 6.2% of patients, 
cerebrovascular events in 4.0% of patients, and peripheral vascular events in 3.6% of 
patients (some patients had more than one type of event).  This compares to 8.0% after 
11 months of follow up. At 24 months, serious venous occlusion occurred in 2.9% of 
patients, compared to 2.2% after 11 months of follow-up. Furthermore, 2 of 28 
patients in AP24534-11-106 had cardiovascular events at a 45-mg dose.  These results 
have prompted the need for reducing risk while maintaining the potential benefit of 
ponatinib.  
Recent multivariate analyses performed on data from the phase II PACE trial found 
significant relationships between dose intensity and the occurrence of ≥grade 3 
adverse events including vascular occlusion, thrombocytopenia, pancreatitis, 
neutropenia, rash, ALT, AST, lipase, and myelosuppression in CML patients treated 
with ponatinib.  These data support the conclusion that lowering the daily dose of 
ponatinib can reduce the risk of serious adverse events and ischemia.
Data from the phase II PACE trial also indicate that patients can achieve and maintain 
responses on lower doses.  After a median follow-up of 24 months, 110/190 CP-CML 
patients with dose reductions had achieved MCyR, and over 90% maintained response 
(100/110).  Of 87 patients who achieved response while on 45 mg, 44 had a dose 
reduction after response (14 patients had dose reductions to 15 mg).  All 44 patients 
have maintained their response.  Of 46 patients who achieved response while on 
30 mg, 20 had a dose reduction after response.  Of these, 18 maintained response; the 
2 patients who lost response had a dose reduction to 15 mg that lasted only 1 day.  To 
summarize, 62 of 64 patients who had a dose reduction after response maintained the 
response, including all 35 who had reduced doses for more than 90 days.  This result 
suggests that for CP-CML patients, reduction to 15 mg once daily after achievement of 
a cytogenetic response can sustain that response.  Among the patients with advanced 
disease (179 patients with AP-CML, BP-CML, or Ph+ ALL), 56 % achieved MaHR at 
the 45-mg dose.  Of these, 19 had a dose reduction, and 9 of these 19 have lost 
response.  Of the 10 who remain in response, 7 have had dose reductions lasting longer 
than 90 days:  3 patients with BP-CML (2 at 15 mg, 1 at 30 mg) and 4 patients with 
AP-CML (2 each at 15-mg and 30-mg doses).  Fifteen patients achieved MaHR at 30 
mg.  Of these, 7 had a subsequent dose reduction, and 6 lost response.  One patient 
with AP-CML remains in response, generally taking 15 mg every other day.
Therefore, the following dose regimen is recommended:

For patients with CP-CML who achieve MCyR, consider reducing the 
ponatinib dose to 15 mg once daily, 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 justifies 
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treatment with a higher dose.  Escalate to 30 mg if response is lost.
!
All CP-CML patients currently on trial who have not yet achieved MCyR 
should consider ponatinib dose reduction to 30 mg/day 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 justifies treatment with a higher or lower dose.
!
All Advanced phase (AP- or BP-CML or Ph+ALL) patients currently on trial 
should have their dose reduced to 30 mg/day 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 justifies treatment with a higher dose.
For all patients, document in the patient’s chart and in the study drug administration 
page of the study case report form (CRF) the dosing changes based on the above 
recommendations or the justification not to change the patient from his or her current 
dose.
Concomitant 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.
!
Use of any other investigational drug or device
!
Use of medications that are known to be associated with the development of 
Torsades de Pointes (see Appendix B)
!
Herbal preparations or related over-the-counter preparations containing herbal 
ingredients (eg, St. John’s wort, black cohosh, Estroven) either during or 
within 2 weeks prior to the first dose of ponatinib
!
Elective surgery requiring in-patient care
The following medications should be avoided, but are not prohibited:
!
Medications that are strong inhibitors or inducers of cytochrome P450 (CYP)
3A (see Appendix C)  
!
Medications that prolong the QT interval.  If such medications are necessary 
and used while a patient is on study, then additional (ECG monitoring should 
be performed as clinically indicated (see Appendix B).
Efficacy Evaluation
Hematologic response, cytogenetic response, and molecular response will be assessed 
according to standard criteria (see Appendix A).
Safety Evaluation
Safety will be assessed by routine physical and laboratory evaluations, ECGs, and 
AEs, and will be recorded, and the severity will be graded according to the NCI 
CTCAE v.4.0 (see Appendix D).
Pharmacokinetic 
Evaluation
Blood samples will be collected at specified time points to study the PK of ponatinib.  
Pharmacokinetic parameters such as time of maximum concentration (Tmax), maximum 
plasma concentration (Cmax), area under the curve (AUC), and elimination half-life 
(t1/2) will be determined, where possible.
Other Assessments
Other assessments include 
 
and survival.
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ARIAD Pharmaceuticals, Inc.
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Statistical Analysis
Descriptive statistics and analyses will be provided for each dose level, and for patients 
combined across dose levels, where applicable.  Data from patients in the 
phase 2 expansion phase will be summarized together with data from patients in the 
dose escalation cohorts, as appropriate within disease group, with each disease type 
summarized separately (CP-CML, AP-CML, BP-CML, Ph+ALL), and with the 
advanced phases (AP-CML, BP-CML, and Ph+ALL) pooled.  Descriptive statistics 
(such as means, medians, standard deviations, ranges for continuous data, and 
percentages for categorical data) will be used to summarize patient characteristics, 
treatment administration/compliance, efficacy, safety, and PK parameters.  Data will 
also be displayed graphically, where appropriate.
All efficacy analyses will include all patients in the treated population.
CP-CML Patients: The primary analysis of the primary efficacy endpoint of MCyR 
will be performed using a 1-sided exact 95% confidence interval (CI) for the MCyR 
rate and will be based on the total number of CP-CML patients enrolled in the 
dose-escalation phase and expansion phase.  Major cytogenetic response rate is defined 
as the proportion of patients who have achieved a CCyR or PCyR after initiation of 
study treatment.  Patients entering the study already in PCyR must achieve a CCyR in 
order to be considered a success for the MCyR rate.
AP-CML, BP-CML, Ph+ ALL Patients: Major hematologic response rate is defined 
as the proportion of patients who have achieved a confirmed CHR or NEL after 
initiation of study treatment.  The primary analysis of the primary efficacy endpoint of 
MaHR will be performed using a 1-sided exact 95% CI for MaHR rate and will be 
based on the total number of patients enrolled in the dose-escalation phase and 
expansion phase for each group and combined across the disease groups (AP-CML, 
BP-CML and Ph+ ALL).
All patients receiving at least 1 dose of study drug will be considered evaluable for 
safety.
Rationale for Number of 
Patients
Six patients will be enrolled at each dose level of 30 mg and 45 mg to allow for 
adequate assessment of tolerability and evidence of clinical activity.  The number of 
patients at each dose level is consistent with phase I dose-finding studies. An 
additional 3 patients will be included at 15 mg for the purposes of PK sample 
collection during Cycle 1 in order to determine PK linearity in Japanese patients.  
These patients will be allowed to dose escalate to the recommended phase II dose (at 
the discretion of the investigator) and will be assessed for efficacy and safety as phase 
II patients.  The phase II portion of the study will allow confirmation of the overall 
tolerability of ponatinib and an estimate of its antileukemic activity in Japanese 
patients.
For the phase II component, combined data from phase I and phase II will be 
evaluated.  It is assumed that a 40% efficacy rate (MCyR rate for CP-CML and MaHR 
rate for others) and a 10% uninteresting rate for both groups are set.  Sixteen patients 
per group are needed to retain 80% power for testing, using a 5% 1-sided significance 
level. Assuming 1 ineligible patient per group would be included, 17 patients per group 
(total of 34 patients) will be enrolled.
Medical Institutions and 
Investigators
Medical institutions and investigators are shown in a separate pamphlet.
Study Administrative 
Structure
Study administrative structure (project manager, auditors, data management, 
biostatistics, etc.) is shown in a separate pamphlet. 
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Medical Specialist
Professor Tomoki Naoe,  President, National Hospital Organization, Nagoya Medical 
Center
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TABLE OF CONTENTS
PROTOCOL REVISION HISTORY ..........................................................................................1
DISCLOSURE STATEMENT .....................................................................................................2
CONTACT INFORMATION.......................................................................................................3
PROTOCOL SYNOPSIS..............................................................................................................4
LIST OF ABBREVIATIONS .....................................................................................................19
DEFINITIONS OF TERMS .......................................................................................................22
1
INTRODUCTION............................................................................................................24
1.1
Background ..........................................................................................................24
1.2
Rationale...............................................................................................................27
2
STUDY OBJECTIVES....................................................................................................28
2.1
Primary Objectives..............................................................................................28
2.2
Secondary Objectives...........................................................................................28
3
INVESTIGATIONAL PLAN .........................................................................................28
3.1
Overall Study Design and Plan...........................................................................28
3.2
Description of Treatment(s)................................................................................29
3.3
Study Duration.....................................................................................................29
3.4
Study or Site Termination...................................................................................29
4
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................30
4.1
Inclusion Criteria.................................................................................................30
4.2
Exclusion Criteria................................................................................................33
4.3
Classification of Chronic Myeloid Leukemia Patients .....................................36
4.4
Philadelphia-Positive Acute Lymphoblastic Leukemia Patients.....................36
4.5
Subject Discontinuation ......................................................................................36
5
STUDY TREATMENT(S) ..............................................................................................37
5.1
Study Treatment(s)..............................................................................................37
5.1.1
Treatment Administration .................................................................37
5.1.2
Dose Selection and Schedule ..............................................................37
5.2
Phase I Dose-Escalation Scheme.........................................................................38
5.2.1
Intra-patient Dose Escalation ............................................................39
5.2.2
Replacements.......................................................................................39
5.2.3
Definition of Maximum Tolerated Dose and Dose Limiting 
Toxicity.................................................................................................39
5.2.4
Dose Recommendations Based on Updated Data.............................39
5.2.5
Management of Adverse Drug Reactions .........................................41
5.2.6
Management of Selected Adverse Events .........................................45
5.3
Prior and Concomitant Treatment(s)/Therapy.................................................49
5.4
Permitted Treatment ...........................................................................................50
5.5
Prohibited Treatment(s)/Therapy......................................................................50
5.6
Potential Drug Interactions.................................................................................51
5.7
Phototoxicity Study..............................................................................................51
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5.8
Treatment Compliance........................................................................................51
5.9
Treatment(s) Supply............................................................................................52
5.9.1
Formulation, Packaging, and Labeling.............................................52
5.9.2
Preparation and Dispensing...............................................................52
5.9.3
Treatment(s) Storage and Accountability.........................................52
6
EFFICACY AND SAFETY ASSESSMENTS...............................................................53
6.1
Efficacy Assessments ...........................................................................................53
6.1.1
Bone Marrow Aspirate and Cytogenetics.........................................53
6.1.2
BCR-ABL Molecular Response Assessment.....................................53
6.2
Safety Assessments...............................................................................................54
6.2.1
Adverse Events ....................................................................................54
6.2.2
Vital Signs ............................................................................................54
6.2.3
Physical Examination .........................................................................54
6.2.4
Clinical Laboratory Safety Assessments...........................................54
6.2.5
Electrocardiogram ..............................................................................55
6.2.6
Echocardiogram..................................................................................55
6.3
Other Assessments ...............................................................................................56
6.3.1
Additional Disease Assessments.........................................................56
6.3.2
BCR-ABL Mutation Testing..............................................................56
6.3.3
Molecular Genetic Assessment...........................................................56
6.3.4
Survival ................................................................................................56
6.4
Pharmacokinetics.................................................................................................56
7
STUDY PROCEDURES .................................................................................................57
7.1
Screening Period Procedures, Medical History, and Demographics ..............62
7.1.1    Screen Failures.........................................................................................64
7.2
Treatment Period Procedures.............................................................................64
7.3
End of Treatment or Early Termination Procedures.......................................65
7.4
Follow-up ..............................................................................................................65
7.5
Survival Follow-up...............................................................................................66
8
ADVERSE EVENT REPORTING ................................................................................66
8.1
Adverse Events.....................................................................................................66
8.1.1
Adverse Event Definition....................................................................66
8.1.2
Abnormal Test Findings.....................................................................66
8.1.3
Performing Adverse Event Assessments...........................................67
8.1.4
Reporting Period.................................................................................67
8.1.5
Adverse Event Severity.......................................................................67
8.1.6
Causality ..............................................................................................68
8.1.7
Expectedness........................................................................................69
8.2
Serious Adverse Events and Adverse Events of Special Interest ....................69
8.2.1
Serious Adverse Event Definition......................................................69
8.2.2
Identification of Adverse Events of Special Interest........................71
8.2.3
Reporting Serious Adverse Events and Adverse Events of 
Special Interest ....................................................................................72
8.2.4
Information to be Provided by the Investigator for a Serious 
Adverse Event or Adverse Event of Special Interest.......................73
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8.2.5
Follow-up Information on a Serious Adverse Event or Adverse 
Event of Special Interest.....................................................................73
8.3
Other Safety Issues ..............................................................................................74
8.3.1
Pregnancy ............................................................................................74
8.3.2
Overdose ..............................................................................................74
9
PLANNED STATISTICAL METHODS.......................................................................75
9.1
General Considerations.......................................................................................75
9.2
Analysis Populations............................................................................................75
9.3
Study Endpoints...................................................................................................75
9.3.1
Primary Endpoints..............................................................................75
9.3.2
Secondary Endpoints ..........................................................................76
9.3.3
Exploratory Endpoints .......................................................................76
9.4
Determination of Sample Size.............................................................................76
9.5
Efficacy Analysis..................................................................................................77
9.5.1
Definitions of Efficacy Endpoints ......................................................77
9.5.2
Primary Efficacy Endpoint Analysis.................................................78
9.5.2.1
Data Handling Rules for the Primary Analyses of the 
Primary Efficacy Endpoint......................................................78
9.5.2.2
Secondary Endpoint Analyses .................................................79
9.6
Safety Analysis .....................................................................................................79
9.7
Interim Analysis...................................................................................................79
9.8
Protocol Deviations/Violations............................................................................79
10
QUALITY CONTROL AND QUALITY ASSURANCE.............................................79
10.1
Investigators and Study Administrative Structure...........................................80
10.2
Study Monitoring.................................................................................................80
11
ETHICAL CONDUCT OF THE STUDY .....................................................................80
11.1
Institutional Review Board Approval................................................................80
11.2
Patient Information and Consent.......................................................................80
11.3
Patient Confidentiality.........................................................................................81
12
DATA HANDLING AND RECORD KEEPING..........................................................81
12.1
Case Report Forms and Study Records.............................................................81
12.2
Access to Source Documentation........................................................................81
12.3
Retention of Data .................................................................................................81
12.4
Termination of Study...........................................................................................82
13
PUBLICATION AND DISCLOSURE POLICY..........................................................82
14
REFERENCES.................................................................................................................83
15
APPENDICES..................................................................................................................85
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TABLE OF TABLES
Table 1
Chronic Myeloid Leukemia Phase Classification ....................................................36
Table 2
Phase I Dose-Escalation Decision Rules....................................................................38
Table 3
Modifications for Adverse Events Attributable to Study Drug..............................42
Table 4
Study Flow Chart........................................................................................................57
Table 5
Schedule of Events for Chronic Phase Patients........................................................58
Table 6
Schedule of Events for Accelerated Phase, Blast Phase, and Ph+ ALL Patients..59
LIST OF APPENDICES
APPENDIX A Response Criteria ..............................................................................................86
APPENDIX B Prohibited Drugs Affecting the QT Interval...................................................89
APPENDIX C Medications that are Strong Inhibitors or Inducers of CYP3A4/5/7............90
APPENDIX D National Cancer Institute Common Terminology Criteria for Adverse 
Events..................................................................................................................91
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LIST OF ABBREVIATIONS
Abbreviation
Term
ABL
Abelson
AE
adverse event
AESI
adverse event of special interest
ALL
acute lymphoblastic leukemia, also known as acute lymphocytic 
leukemia
ALT
alanine aminotransferase
AML
acute myelogenous leukemia, also known as acute myeloid leukemia
ANC
absolute neutrophil count
AP
accelerated phase
ARIAD
ARIAD Pharmaceuticals, Inc
AST
aspartate aminotransferase
AUC
area under the curve
β-HCG
beta-human chorionic gonadotropin
BCR
Breakpoint Cluster Region
BCR-ABL
Breakpoint Cluster Region-Abelson
BM
bone marrow
BP
blast phase
BUN
blood urea nitrogen
CBC
complete blood count
CCyR
complete cytogenetic response
CHF
congestive heart failure
CHR
complete hematologic response
CI
confidence interval
Cmax
maximum plasma concentration
CML
chronic myelogenous leukemia, also known as chronic myeloid leukemia
CNS
central nervous system
CP
chronic phase
CTCAE
Common Terminology Criteria for Adverse Events
cTn
cardiac troponin
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EFS
event-free survival
FDA
Food and Drug Administration (United States)
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GM-CSF
granulocyte-macrophage colony-stimulating factor
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Abbreviation
Term
GVHD
graft versus-host disease
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICMJE
International Committee of Medical Journal Editors
INR
International Normalized Ratio
IRB
Institutional Review Board
IRIS
International Randomized Study of Interferon and ST1571
LBBB
left branch bundle block
LV
left ventricular
LVEF
left ventricular ejection fraction
MaHR
major hematologic response
MCyR
major cytogenetic response
MHLW
Ministry of Health, Labor, and Welfare (Japan)
MI
myocardial infarction
MMR
major molecular response
MRI
magnetic resonance image/imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network (United States)
NCI
National Cancer Institute (of the United States)
NEL
no evidence of leukemia
OS
overall survival
PACE
Ponatinib Ph+ ALL and CML Evaluation
PCR
polymerase chain reaction
PCyR
partial cytogenetic response
PD
pharmacodynamics
PFS
progression-free survival
Ph+
Philadelphia chromosome-positive
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PT
prothrombin time
PTT
partial thromboplastin time
QD
daily
QT
QT interval; a measure of the time between the start of the Q wave and 
the end of the T wave in the heart's electrical cycle
QTc
heart rate-corrected QT interval (calculated)
QTcF
QT interval corrected (Fridericia)
R/I
resistant/intolerant
SAE
serious adverse event
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
t1/2
terminal elimination half-life
TIA
transient ischemic attack
TKI
tyrosine kinase inhibitor
Tmax
time to reach maximum plasma concentration
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Abbreviation
Term
TTR
time to response
ULN
upper limit of normal
URL
upper reference limit
WBC
white blood cell
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DEFINITIONS OF TERMS
Term
Definition
30 Days After 
End-of-Treatment
At 30 days after the end of treatment, a patient completes all 
post-treatment discontinuation assessments.
Active Study 
Period
The active study period for a patient begins with administration of the first 
dose of study drug and continues through 30 days following 
discontinuation of study drug.
Suspected Adverse 
Reaction
A suspected adverse reaction is any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  For the 
purposes of study safety reporting, "reasonable possibility" means there is 
evidence to suggest a causal relationship between the drug and the adverse 
event.
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-Treatment
The end of treatment occurs when a patient receives final dose of study 
drug or discontinues taking study drug and completes the end-of-treatment
assessments
End-of-Study
The end-of-study (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, and has received study drug.
Evaluable for 
Efficacy
Any eligible patient who receives study drug is considered evaluable for 
efficacy analyses.
Evaluable for 
Safety
Any patient who receives study drug is considered evaluable for safety
analyses.
Follow-up Period
The follow-up period for a patient begins after the last completed 
assessment during the active study period and continues until patient 
contact discontinues.
Institutional 
Review Board
Throughout this document the term Institutional Review Board (IRB) 
refers to all appropriate properly constituted committees or boards 
recognized by the head of institute for approving clinical studies.  These 
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Term
Definition
include independent ethics committees (ECs) and IRBs.
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 (United States); Ethical Guidelines for Clinical 
Research (Ministry of Health, Labor, and Welfare [MHLW] in Japan); 
Good Clinical Practice (GCP) Guidelines (MHLW); Japan 
Pharmaceuticals Affairs Law; the International Conference on 
Harmonisation Guideline for GCP; 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 Ministry of Health, 
Labor, and Welfare (Japan), Pharmaceuticals and Medical Devices 
Agency (PMDA), and the Food and Drug Administration (FDA; United 
States).
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 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.
Study Start Date
The study start date is the date that the first patient signs the informed 
consent form.
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1
INTRODUCTION
1.1
Background
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that represents about 
15% of adult leukemias (Deininger et al, 2000).  The underlying cause of CML is the Breakpoint 
Cluster Region-Abelson (BCR-ABL) fusion oncoprotein, which results from a reciprocal (9;22) 
chromosomal translocation in hematopoietic stem cells.  This chromosomal abnormality 
(Philadelphia chromosome-positive [Ph+]) is present in about 95% of all patients with CML, as 
well as about 40% of adult patients with Ph+ acute lymphoblastic leukemia (ALL).  The 
translocation leads to the fusion of the BCR coding sequence with the tyrosine kinase coding 
region of ABL.  This fusion event results in the constitutive activation of ABL kinase activity, 
which is both necessary and sufficient for induction of CML or ALL (Deininger et al, 2000).
Imatinib was the first small molecule tyrosine kinase inhibitor (TKI) approved by the Food and 
Drug Administration (FDA) (United States) to treat CML patients.  At 8 years of follow-up, the 
pivotal study of imatinib (IRIS: International Randomized Study of Interferon and ST1571 trial) 
in newly diagnosed chronic phase (CP)-CML patients has reported 81% event-free survival 
(EFS) and 85% overall survival (OS) (Cortes et al, 2011).  However, despite the success of 
imatinib, 45% of patients in the IRIS trial discontinued imatinib therapy.  A substantial fraction 
of patients either initially fail to respond to imatinib or progress after a period of therapy.  BCR-
ABL point mutations in the ABL kinase domain that impair imatinib binding are the main cause 
of resistance to imatinib therapy, and account for approximately 40% to 50% of resistant cases of 
disease (Branford et al, 2003; Jabbour et al, 2006; Jones et al, 2009; Terasawa et al, 2010; 
O’Hare et al, 2011).
Second-generation small-molecule inhibitors, dasatinib and nilotinib, are more potent than 
imatinib and inhibit many, but not all, imatinib-resistant point mutants, as well as native 
BCR-ABL (Talpaz et al, 2006; Kantarjian et al, 2006).  Dasatinib and nilotinib were approved in 
Japan in 2009.  Both are approved for use in patients who have experienced a failure of imatinib 
therapy, based on phase II clinical trials, in which approximately 40% to 45% of CP-CML 
patients achieved major cytogenetic responses (MCyRs) (Pinilla-Ibarz et al, 2008; Kantarjian et 
al, 2007).  However, the remainder of patients, many of whom carry resistance mutations, 
remained refractory.  Of note, both dasatinib and nilotinib are ineffective against the uniformly 
resistant T315I BCR-ABL mutation, which represents 15% to 20% of all clinically observed 
mutations (O’Hare et al, 2007).
To address the problem of resistance to the first- and second-generation BCR-ABL TKIs, 
ARIAD Pharmaceuticals, Inc (ARIAD) has developed ponatinib.  Ponatinib is a novel synthetic 
orally active TKI, specifically developed to inhibit BCR-ABL, the fusion protein that is the 
product of the Philadelphia chromosome in CML and in a subset of 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.
In vitro assays have demonstrated that ponatinib potently inhibits the enzymatic activity of the 
T315I ABL kinase domain, as well as that of the native (unmutated) enzyme.  In leukemia cell 
lines expressing these BCR-ABL variants, ponatinib potently inhibited BCR-ABL signaling, 
leading to inhibition of cellular proliferation and induction of apoptosis.  Ponatinib also inhibits 
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the proliferation of cell lines expressing other major clinically observed imatinib-resistant 
mutants of BCR-ABL.  In an in vitro mutagenesis screen designed to characterize the resistance 
profile of ponatinib, no mutations in BCR-ABL were identified that alone could confer resistance 
to 40 nM ponatinib.  Based on the promising preclinical activity profile of ponatinib, initial 
human clinical studies were conducted.
Phase I Clinical Study of Ponatinib
The phase I study of ponatinib included patients diagnosed with a hematologic malignancy who 
relapsed or were refractory to standard care, or for whom no standard care was available.  The 
primary objective was to determine the maximum tolerated dose (MTD) or a recommended dose 
of daily oral ponatinib.  Secondary objectives included safety and pharmacokinetics (PK) of 
ponatinib, along with characterization of antileukemic activity, pharmacodynamic (PD) activity, 
and potential pharmacogenomic markers of activity.  Patients (≥18 years) were administered 
ponatinib orally once daily.  Dosing began at 2 mg and extended up to 60 mg.  Enrollment closed 
in October 2010.  Data are presented through 22 July 2011.
In total, 81 patients (54% male) received ponatinib and were followed for a median duration of 
377 (range 11 to 977) days; at the time of analysis, 35 (43%) patients were ongoing.  Diagnoses 
included 60 CML (43 CP, 17 advanced), 5 Ph+ ALL, 12 acute myeloid leukemia (AML), and 
4 other.  Prior therapies in Ph+ patients included imatinib (97%), dasatinib (89%), nilotinib 
(55%); 94% experienced a failure of ≥2, and 63% experienced a failure of ≥3 prior TKIs; 51% 
experienced failure of imatinib, dasatinib, and nilotinib.  At entry, 65% had BCR-ABL 
mutations, including 29% T315I and 11% F317L.
The maximum administered dose was 60 mg, at which point dose-limiting toxicities (DLTs) of 
increased amylase and increased lipase, concurrent with grade 2 pancreatitis were reported.  
Additional DLTs included rash, fatigue, and alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) elevation.  All DLTs were reversible.  Some patients were able to 
tolerate 60 mg and remain on study at this dose, but overall, 60 mg was declared to exceed the 
MTD.  Based on this observation, as well as on PK, PD, and antileukemia activity, 45 mg was 
chosen as the recommended dose for further study in adults.
Ponatinib was found to have an acceptable safety profile at therapeutic dose levels.  
Constitutional symptoms were the most common drug-related adverse events (AEs) reported, 
including rash (30%), arthralgia (16%), fatigue (16%), headache (15%), nausea (15%), dermatitis 
acneiform (14%), dry skin (14%), myalgia (12%), and abdominal pain (10%).  Elevated lipase 
(15%), pancreatitis (12%), hypertriglyceridemia (12%), and ALT increased (10%) were also 
observed.  The most common treatment-related hematologic events were thrombocytopenia 
(27%), neutropenia (12%), and anemia (11%).  Treatment-related serious adverse events (SAEs) 
were reported for 12 (15%) patients; the most common of which was pancreatitis (9%; grade 3: 
3%).  There were 10 deaths on study, none of which were treatment-related. Twelve patients 
(15%) discontinued due to AEs.
A subgroup analysis of the heart rate-corrected QT interval (QTc) of patients who received 
ponatinib 30 mg or higher revealed there was no significant effect of ponatinib on cardiac 
repolarization in this refractory population.
Of 43 evaluable CP-CML patients, 42 (98%) experienced a complete hematologic response 
(CHR) and 31 (72%) experienced a MCyR, including 27 (63%) complete cytogenetic responses
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(CCyR). Of the 12 CP-CML T315I patients, 100% experienced a CHR and 11 (92%) a MCyR, 
including 9 CCyR (75%).  The median duration of follow-up for CP-CML patients was 
511 (range 51 to 977) days.  Overall, 19/43 (44%) CP-CML evaluable patients achieved major 
molecular response (MMR), as did 8/12 (67%) CP-CML T315I patients.  Responses were also 
observed in patients with other mutations and in refractory patients with no detectable mutations.
For 22 evaluable advanced CML (accelerated phase [AP]-CML, blast phase [BP]-CML) or 
Ph+ALL patients, 9 (41%) experienced a major hematologic response (MaHR) and 7 (32%) 
experienced an MCyR.  Of this advanced group, 7 had T315I mutation, 2 (29%) of which had 
MaHR and MCyR. 
In summary, the phase I data suggest that ponatinib has a tolerable safety profile in a population 
of patients with advanced hematologic malignancies.  Substantial evidence of clinical 
antileukemic activity was observed in heavily pretreated patients, including refractory patients 
with the T315I mutation, patients with other mutations, and those with no mutations.
Phase II Clinical Study of Ponatinib
The phase II PACE study (Ponatinib Ph+ ALL and CML Evaluation) was initiated in 
September 2010.  The objective of this international, single-arm, open-label study is to establish 
the efficacy and safety of ponatinib in patients with refractory CML in CP, AP, or BP, or 
Ph+ ALL, resistant or intolerant (R/I) to dasatinib or nilotinib, or with the T315I mutation.  
Patients received 45 mg ponatinib orally once daily in 1 of 6 cohorts: CP R/I; CP T315I; AP R/I; 
AP T315I; BP/ALL R/I; BP/ALL T315I.  The primary endpoints are MCyR for CP-CML and 
MaHR for AP, BP, or Ph+ ALL.  The study is ongoing; enrollment closed in September 2011.
As of 02 December 2011, 449 patients were enrolled and treated.  Diagnoses included 207 CP 
R/I, 64 CP T315I, 60 AP R/I, 19 AP T315I, 48 BP/ALL R/I, and 46 BP/ALL T315I.  Prior TKIs 
included imatinib only (4%), imatinib + dasatinib or nilotinib (39%), imatinib + dasatinib + 
nilotinib (53%); 94% experienced failure of ≥2 prior TKIs, and 59% experienced failure of ≥3 
prior TKIs.  Overall, 129 patients had the T315I mutation.  Of the 315 R/I patients, 120 (38%) 
had non-T315I BCR-ABL mutations.  At the time of analysis, 301 (67%) patients remained on 
therapy, and 148 (33%) discontinued (73 BP/ALL).  The reasons for discontinuation included 
50 (11%) progressive disease (35 BP/ALL), 35 (8%) AE, 16 (4%) death, and 35 (8%) other.
Substantial antileukemic activity was observed in this heavily pretreated population.  For 
CP-CML, 116 (47%) of 248 evaluable patients had MCyR; response rates were 41% (79/191) for 
CP R/I and 65% (37/57) for CP T315I.  For AP-CML, 37 (67%) of 55 evaluable patients had 
MaHR; response rates were 74% (31/42) for AP R/I and 46% (6/13) for AP T315I.  For 
BP-CML and Ph+ ALL, 33 (37%) of 89 evaluable patients had MaHR; response rates were 
identical for BP/ALL R/I and BP/ALL T315I patients.  
The most common treatment-related AEs (≥10% any grade) were rash (32%), thrombocytopenia 
(31%; 25% grade 3/4), dry skin (24%), abdominal pain (19%; 5% grade 3/4), headache (17%), 
fatigue (15%), neutropenia (15%; 14% grade 3/4), myalgia (14%), arthralgia (14%), lipase 
increased (14%), constipation (12%), anemia (12%; 7% grade 3/4), and nausea (11%).  Based on 
this analysis of the pivotal phase II PACE trial, ponatinib has a safety profile nearly similar to 
that observed in phase I, but with a lower incidence of pancreatitis.  
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1.2
Rationale
Findings from the phase I study of ponatinib show evidence of clinical antileukemic activity in 
patients with resistance to approved second-generation TKIs, dasatinib and nilotinib, including 
patients with the T315I mutation of BCR-ABL.  In addition, data emerging from the pivotal,
international, phase II study are promising, with a safety profile similar to that reported for the 
phase I study, and early efficacy signals showing substantial antileukemic activity in heavily 
pretreated patients and those with refractory T315I, even after a short follow-up period.  The 
results from these clinical studies, taken together with the strong preclinical data that characterize 
ponatinib provide the rationale for investigation of ponatinib in Japanese patients with CML or 
Ph+ ALL. 
This is a phase I/II study of oral ponatinib.  The study is a non-randomized, multi-center, 
dose-escalation study to evaluate and confirm the safety and tolerability of the recommended 
dose, PK, and efficacy of ponatinib in Japanese patients with CML who are resistant or intolerant 
to therapy with dasatinib or nilotinib, or with Ph+ ALL who are resistant or intolerant to therapy 
with TKIs.  The study consists of two components, a phase I (dose-escalation) component 
followed by a phase II component.
The dose-escalation portion of the study is designed to ascertain, by clinical and PK criteria, the 
safety and antileukemic activity of doses of ponatinib that have been demonstrated to be safe and 
to possess antileukemic activity in phase I and phase II studies.  In the initial phase 1 study of 
ponatinib (discussed in Section 1.1), the recommended dose was determined as 45 mg once 
daily.  This study will start at a lower dose level (30 mg) and increase to a 45 mg dose level once 
safety is established.  The recommended phase II dose of ponatinib for Japanese patients will be 
determined (in conference between the investigator and sponsor) based on the evaluation of 
dose-limiting toxicities (DLT) and safety in 30 mg and 45 mg cohorts.
Once the safety of the recommended dose of ponatinib in Japanese patients is confirmed, the 
phase II component will be initiated.  This will be a phase II, single-arm, open-label study of 
ponatinib at the recommended dose (determined in phase I) in an additional 25 patients.  The 
phase II portion of the study will allow for further characterization of ponatinib with regard to 
overall tolerability, and provide an estimate of its antileukemic activity in Japanese patients.
An additional 15-mg dose level will be included for the purposes of determining PK linearity in 
3 Japanese patients.  After collection of PK samples during Cycle 1, patients at 15 mg will be 
allowed to dose-escalate to the recommended phase II dose (determined in the phase I
component of the trial) at the investigator’s discretion, and will be assessed for efficacy and 
safety as phase II patients.
The study will be conducted in compliance with the protocol, the standards specified under 
Article 14, Paragraph 3 and Article 80-2 of the Japan Pharmaceuticals Affairs Law (PAL, 2006), 
and Good Clinical Practice (GCP).
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2
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objectives of this study are:
●
phase I component: examine the safety of the recommended dose of oral ponatinib in 
Japanese patients with CML who are resistant or intolerant to dasatinib or nilotinib, or 
with Ph+ ALL who are resistant or intolerant to prior TKIs 
●
phase II component: confirm the antileukemic activity of ponatinib in Japanese patients 
with CML who are resistant or intolerant to dasatinib or nilotinib, or with Ph+ ALL who 
are resistant or intolerant to prior TKIs, as evidenced by clinical responses, molecular 
responses, and clinical outcomes
2.2
Secondary Objectives
The secondary objectives of this study are:
●
To examine the PK of ponatinib in Japanese patients with CML who are resistant or 
intolerant to dasatinib or nilotinib, or with Ph+ ALL who are resistant or intolerant to 
prior TKIs
●
To describe potential pharmacogenomic markers of ponatinib antileukemic activity and 
to characterize the molecular status of patients
3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
This will be a phase I/II, multi-center, open-label study of ponatinib in Japanese patients with 
CML who have experienced failure of dasatinib or nilotinib therapy, or with Ph+ ALL who have 
experienced failure of prior TKIs because of resistance or intolerance.
The study will consist of 2 components, a phase I component followed by a phase II component.  
The phase I component will be an open-label, dose-escalation study of 2 dose cohorts, 30 mg and 
45 mg.  At least 6 patients will be enrolled in each cohort to confirm the safety of the 
recommended dose of ponatinib in Japanese patients.
The phase I component will employ a modified 3+3 design.  After 6 patients complete their first 
cycle (1 cycle = 28 days) in a cohort and are evaluable for DLTs, safety events including any 
DLTs will be reviewed in conference between the sponsor and the investigators.  These 
discussions will occur prior to opening the next dose level.  Patients who are not evaluable for 
DLTs will be replaced (see Section 5.2).  Definitions of DLT and MTD, and rules for escalation 
to the next dose level are provided in Section 5.2.
The second dose cohort (45 mg) will be enrolled once the 30 mg dose cohort is completed and all 
patients have received 1 full cycle (28 days) of ponatinib.  Patients are expected to receive study 
drug over at least 1 cycle of study treatment, unless an unacceptable drug reaction or disease 
progression occurs.  Patients who give their consent to remaining in the study for ongoing 
treatment may continue to receive additional cycles of study treatment for efficacy and safety 
assessment, as long as treatment is tolerated and disease progression has not occurred.  The 
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recommended phase II dose of ponatinib in Japanese patients will be determined (in conference 
between the investigator and sponsor) based on the evaluation of DLTs and safety in the 30 mg 
and 45 mg cohorts.
Once the safety of the recommended dose of ponatinib in Japanese patients is confirmed, the 
phase II component will be initiated.  This will be a phase II, single-arm, open-label study of 
ponatinib at the recommended dose (determined in phase I) in an additional 25 patients.
An additional 3 patients will be dosed at 15 mg for collection of PK data. PK parameters at the 
15-mg dose level will be modeled, along with the 30-mg and 45-mg dose levels for 
determination of PK linearity in Japanese patients. After PK collection on Day 1 and Day 8 
during Cycle 1, patients at 15 mg will be allowed to dose-escalate to the recommended phase II
dose (determined in the phase I component of the trial), at the investigators’ discretion, and be 
assessed for efficacy and safety as phase II patients.
For the entire study (phase I and phase II combined), approximately 15 CP-CML patients and 
approximately 8 patients each in AP-CML, BP-CML, and Ph+ALL are targeted, although the 
numbers may vary from these targets (see Section 9.4).
Disease assessments will be performed on a defined schedule in accordance with defined 
efficacy criteria specific to a patient’s type of malignancy (see Appendix A).
Safety will be assessed by routine physical and laboratory evaluations, electrocardiograms 
(ECGs), and AEs, and will be recorded and the severity will be graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE 
v.4.0) (see Appendix D).
Each patient will be followed for up to 60 months after his/her first dose of ponatinib.  Patients 
will be evaluated according to the Schedule of Events in Table 5 and Table 6.  
3.2
Description of Treatment(s)
Ponatinib (15-mg, 30-mg, and 45-mg dose levels) will be administered orally once daily in 
4-week cycles (1 cycle = 28 days).
3.3
Study Duration
It is expected to take approximately 12 months to complete enrollment in the study.  The 
duration of each patient’s study participation will be up to 60 months, plus 3 weeks for screening 
and a 30-day follow-up period.  The duration of therapy will be determined by the patient’s 
response and toxicity, and patients will remain on ponatinib if responding.  Patients will be 
followed for response, progression, and survival up to 60 months following initiation of 
treatment.  In addition, all patients who discontinue prematurely from the study will be followed 
for survival every 12 weeks ± 2 weeks starting after the last dose of study drug for up to 
60 months from initiation of therapy.
3.4
Study or Site Termination
If the sponsor, investigator, medical monitor, or regulatory agencies discover conditions during 
the study that indicate that the study or site should be terminated, this action may be taken after 
appropriate consultation between the sponsor, investigator, and medical monitor.
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Conditions that may warrant termination of the study include, but are not limited to:
●
The discovery of a serious, unexpected, or unacceptable risk to subjects enrolled in the 
study
●
The decision on the part of the sponsor to suspend or discontinue testing, evaluation, or 
development of the study treatment
●
Submission of knowingly false information from the research facility to the sponsor, 
medical monitor, or regulatory authorities
●
Insufficient adherence to protocol requirements
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the guidelines for GCP, International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use.
4
SELECTION AND WITHDRAWAL OF SUBJECTS
At least 34 patients with CML who are resistant or intolerant to dasatinib or nilotinib, or with 
Ph+ ALL who have failed prior TKIs because of resistance or intolerance will be enrolled 
(at least 12 patients in the phase I dose-escalation component and 3 patients at 15 mg for 
determination of PK linearity). For the entire study (phase I and phase II combined), 17 CP 
CML patients and 17 CML patients other than CP-CML (AP-CML, BP-CML, or Ph+ALL) are 
targeted. Patients must meet the inclusion and exclusion criteria to be enrolled in the study.
4.1
Inclusion Criteria
1.
Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL 
(defined in Sections 4.3 and 4.4).

All patients must have screening bone marrow (BM) cytogenetics with 
conventional banding performed within 42 days prior to beginning treatment.

Examination of at least 20 metaphases is required in patients in CP.  If less than 
20 metaphases are examined, the BM aspirate must be repeated.

Adequate BM aspirate with differential cell counts is required in patients with AP, 
BP, or Ph+ ALL.  If an adequate aspirate is not obtained, the aspirate must be 
repeated.
2.
Be previously treated with and resistant, or intolerant, to either dasatinib or nilotinib 
for CML or at least one TKI for Ph+ ALL:
2.1 Resistance is defined for CP-CML patients (CP at the time of initiation of 
dasatinib or nilotinib therapy) as follows.  Patients must meet at least one 
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 partial cytogenetic 
response (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 (see 
Appendix A)
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 AP-CML 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 an MaHR
b.
At any time after the initiation of therapy, the loss of an 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 an MaHR
2.3 Resistance is defined for BP-CML 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 an MaHR
b.
At any time after the initiation of therapy, the loss of an 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 an MaHR
2.4 Intolerance 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) irrespective of the absence of a CCyR for CP patients or an 
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 the manufacturer,
irrespective of the absence of a CCyR for CP patients or MaHR for AP, BP, 
or Ph+ ALL patients
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NOTE: Although the above criteria define failure after dasatinib or nilotinib 
(mostly according to Baccarani et al, 2009), CML patients who have gone 
on to later-line therapy are eligible, having experienced failure of dasatinib 
or nilotinib.  Similarly, Ph+ ALL patients who have gone on to another TKI,
having experienced failure of 1 prior TKI are eligible.
Patients must meet all of the remaining criteria to be eligible for the study:
3.
Must be ≥18 years old
4.
Provide written informed consent
5.
Eastern Cooperative Oncology Group (ECOG) performance status ≤2
6.
Minimum life expectancy of 3 months or more
7.
Adequate renal function defined as serum creatinine < 1.5 × upper limit of normal 
(ULN) for institution
8.
Adequate hepatic function defined as:
a.
Total bilirubin < 1.5 × ULN
b.
ALT (SGPT) and AST (SGOT) < 2.5 × ULN for institution (< 5 × ULN if liver 
involvement with leukemia)
c.
Prothrombin time (PT) < 1.5 × ULN
9.
Normal pancreatic status defined as:
a.
Lipase ≤1.5 × ULN for institution
b.
Amylase ≤1.5 × ULN for institution
10.
Normal QT interval corrected (Fridericia) (QTcF) interval on screening ECG 
evaluation, defined as QTcF of ≤ 450 ms in males or ≤470 ms in females
11.
For fertile females, a negative pregnancy test must be documented prior to enrollment
12.
Female and male patients who are fertile must agree to use an effective form of 
contraception with their sexual partners from enrollment through at least 4 months 
after the end of treatment.
13.
Ability to comply with study procedures, in the investigator’s opinion
< Reasons for setting up the above inclusion criteria > 
1. To specify the target patient population of CP, AP, and BP-CML and Ph+ALL
2. To define patients with CML who have experienced failure of dasatinib or nilotinib 
because of resistance or intolerance, or with Ph+ALL who have experienced failure of
prior TKIs because of resistance or intolerance
3. 18 was set up as the age of patients who can fully understand this trial and follow the 
protocol.
4. To confirm that each patient participates in this trial with his/her own intention
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5. ～6. To properly evaluate safety and efficacy of investigational drug
7. ～8. To select patients with substantially no marked damage in the function of liver,
kidney, and hematological condition
9. To ensure the safety of patients against potential adverse reactions
10. Due to the uncertainty of QT/QTC prolongation by ponatinib
11. Due to the uncertainty of safety of ponatinib against fetus and infant
12. Due to the uncertainty of safety of ponatinib against fetus and infant, and due to 
insufficient data for the safety regarding spermatotoxicity
13. To secure safety of patients and to avoid patients who will not be able to obey the 
protocol.
4.2
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 2 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 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 7 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 and other chemotherapy within 7 days prior to the first dose of 
ponatinib; otherwise, 2a applies
3.
Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving 
the first dose of ponatinib; any evidence of ongoing graft versus-host disease (GVHD) 
or GVHD requiring immunosuppressive therapy
4.
Take medications that are known to be associated with Torsades de Pointes
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 CP-CML are excluded if they are in CCyR
8.
Patients with CP-CML are excluded if a baseline BM aspirate, adequate for 
conventional cytogenetic analysis with 20 metaphases examined, is not available.
9.
Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if they are in MaHR.
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10.
Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if a baseline BM aspirate 
adequate for cell count and differential report is not available.  Patients with a fibrotic 
marrow or dry tap that does not yield adequate cell counts for diagnosis are not 
evaluable for classification, and endpoints are not eligible.
11.
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.
12.
Have significant, uncontrolled, or active cardiovascular disease, specifically 
including, but not restricted to:
a.
Myocardial infarction (MI) within 6 months prior to enrollment
b.
Unstable angina within 6 months prior to enrollment
c.
Congestive heart failure (CHF) within 6 months prior to enrollment
d.
History of clinically significant atrial arrhythmia as determined by the treating 
physician
e.
Any history of ventricular arrhythmia
f.
Cerebrovascular accident or transient ischemic attack (TIA) within 6 months 
prior to enrollment 
g.
Any history of peripheral arterial occlusive disease requiring revascularization
h.
Any history of venous thromboembolism, including deep vein thrombosis or 
pulmonary embolism within 6 months prior to enrollment
13.
Have a significant bleeding disorder unrelated to CML or Ph+ ALL
14.
Have a history of pancreatitis or alcohol abuse
15.
Have uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)
16.
Have malabsorption syndrome or other gastrointestinal illness that could affect 
absorption of orally administered ponatinib
17.
Have been diagnosed with another primary malignancy within the past 3 years (except 
for non-melanoma skin cancer, cervical cancer in situ, or controlled prostate cancer, 
which are allowed within 3 years)
18.
Are pregnant or lactating.  Females and males who are fertile must agree to an 
effective contraception from enrollment through at least 4 months after the end of 
treatment. Women who stopped breastfeeding before the initial dosing of ponatinib 
are eligible for inclusion (forbidden period: the day of the initial ponatinib dosing 
until 6 months from the last dosing).
19.
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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20.
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.
21.
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
22.
Have uncontrolled hypertension (diastolic blood pressure > 90 mm Hg; systolic blood 
pressure > 140 mm Hg).  Patients with hypertension should be under treatment on 
study entry to effect blood pressure control.
< Reasons for setting up the above exclusion criteria > 
1. ～2. To pay attention to safety of patients and to eliminate the effect to the evaluation of 
safety of investigational drug
3. ～5. To pay sufficient attention to safety of patients
6. To eliminate the effect to the evaluation of safety and efficacy of investigational drug
7. ～10. To properly evaluate the efficacy of investigational drug
11. To pay attention to safety of patients and to eliminate the effect to the evaluation of
safety of investigational drug
12. To pay sufficient attention to safety of patients
13. ～15. To pay attention to safety of patients and to eliminate the effect to the evaluation 
of safety of investigational drug
16. To eliminate the effect to the evaluation of efficacy of investigational drug
17. To eliminate the effect to the evaluation of safety and efficacy of investigational drug
18. Due to the uncertainty of safety of ponatinib against fetus and infant
19. ～20. To pay sufficient attention to safety of patients
21. To pay attention to safety of patients and to eliminate the effect to the evaluation of
safety of investigational drug
22. To pay attention to safety of patients and to eliminate the effect to the evaluation of 
safety of investigational drug
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4.3
Classification of Chronic Myeloid Leukemia Patients
Patients with CML who enroll in the study will be classified according to Talpaz and colleagues 
in their studies of dasatinib (Talpaz et al, 2006).  See Table 1 below.
Table 1
Chronic Myeloid Leukemia Phase Classification
CML Phase
Criteria
Chronic Phase (CP)
The following conditions are all observed:
<15% blasts in peripheral blood or bone marrow
<20% basophils in peripheral blood
<30% blasts + promyelocytes in peripheral blood or bone marrow
>100 x 109 platelets/L in peripheral blood
No extramedullary disease other than hepatosplenomegaly 
Accelerated Phase 
(AP)
At least 1 of 5 conditions (1-5) and 6 are observed.
1. >15% and < 30% blasts in peripheral blood or bone marrow
2. >20% basophils in peripheral blood or bone marrow
3.>30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts)
4. <100 x 109 platelets/L in peripheral blood unrelated to therapy
5. Cytogenetic, genetic evidence of clonal evolution
6. No extramedullary disease other than hepatosplenomegaly
Blast Phase (BP)
≥30% blasts in peripheral blood or bone marrow
or
Extramedullary disease other than hepatosplenomegaly
4.4
Philadelphia-Positive Acute Lymphoblastic Leukemia 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.
4.5
Subject Discontinuation
In the event that a patient is withdrawn from the study, every effort will be made by the 
investigator to document and report the reason(s) for withdrawal as thoroughly as possible.  The 
reason(s) for termination must be clearly reported on the appropriate page of the patient’s 
electronic case report form (eCRF).
If a patient is discontinued from the study for any reason, every effort must be made by the 
investigator 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.
Patients will be discontinued from further study drug administration in the event of any of the 
following: 
●
Intolerable toxicity, as determined by the investigator
●
Progression of disease requiring an alternate therapy, in the opinion of the investigator
●
Entry into another therapeutic clinical study or start of additional anticancer therapy
●
Significant deviation from the protocol or eligibility criteria, in the opinion of the medical 
monitor or investigator
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●
Noncompliance with study or follow-up procedures
●
Patient withdrawal of consent and decision to discontinue participation
●
Patient with beta-human chorionic gonadotropin (β-HCG) test positive (pregnant)
●
Termination of the study by the sponsor
●
Any other reason that, in the opinion of the investigator, would justify removal of the 
patient from the study
Once a subject is taken off treatment, toxicity assessments will be performed at least every 
4 weeks until all study-related toxicities resolve to baseline (or CTCAE grade ≤1), stabilize, or 
are considered to be chronic/irreversible.
All patients who are discontinued prematurely from the study will be followed for survival every 
12 weeks ± 2 weeks starting after the last dose of study drug, for up to 60 months from initiation 
of therapy.
Patients who experience a DLT or drug-related AE and come off study during the first 28 days of 
participation will NOT be replaced for purposes of patient accrual. Any patient who is enrolled 
in the study but is discontinued for reasons other than a DLT or drug-related safety event prior to 
receiving at least 75% of scheduled doses in the first 28 days (Cycle 1) will be replaced.
5
STUDY TREATMENT(S)
5.1
Study Treatment(s)
Ponatinib tablets will be administered orally once daily at 2 dose levels, 30 mg and 45 mg, 
during the phase I dose-escalation phase.  Based on the recommended dose determined in the 
phase I component, 30 mg or 45 mg will be administered in the phase II expansion phase of the 
trial. For determination of PK, 3 additional patients will be given 15 mg orally once daily.
5.1.1
Treatment Administration
Study drug will be administered only to eligible enrolled patients at participating centers.  
Patients do not need to continuously meet the eligibility criteria in order to continue on study 
drug.
Patients will take the prescribed number of tablets with water, with or without food, at 
approximately the same time each day. Patients who forget to take their dose should not make 
up the missed dose.  Missed doses should be recorded in an appropriate source record (eg, 
hospital chart), patient diary card, and study drug administration eCRF.  When possible, patients 
should take the study drug under observation during scheduled study visits to the clinic.
5.1.2
Dose Selection and Schedule
The starting dose for phase I is 30 mg (two 15-mg tablets) taken orally once daily.  Once the 
safety of the 30-mg dose is confirmed, the second dose cohort will be enrolled and administered 
45 mg (one 45-mg tablet) taken orally once daily.  Based on the phase I results, 30 mg or 45 mg 
will be administered in phase II (expansion phase).  In addition, a 15-mg dose level (one 15-mg 
tablet taken orally once daily) will be included (3 patients only) for determination of PK 
linearity.
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Patients will begin taking study drug on Day 1 up to 60 months of treatment.  Patients are 
expected to receive study drug over at least 1 cycle (28 days) of study treatment unless an 
unacceptable drug reaction or disease progression occurs. Patients who give their consent to the 
ongoing treatment in phase I portion may continue receiving the treatment in the following 
cycles.
5.2
Phase I Dose-Escalation Scheme
The dose-escalation scheme is described below.  The investigators and sponsor will review 
safety data on an ongoing basis and make decisions regarding the advisability of continuing 
accrual or escalating to the next dose level cohort.  The investigators and sponsor will consider 
the nature of the DLTs that occurred when making dose-escalation decisions.
Table 2
Phase I Dose-Escalation Decision Rules
Number of Patients with a DLT at a Given
Dose Level
Escalation Decision Rule
0 out of 6
If 0 of 6 patients experience a DLT, the MTD has not been 
reached.  Proceed to the next dose level or proceed to 
phase 2 (expansion phase) of the study as applicable.
≤1 out of 6
If 1 of 6 patients experiences a DLT, the MTD has not been 
reached.  Proceed to the next dose level or proceed to 
phase 2 (expansion phase) of the study as applicable.
2 out of 6
If 2 of 6 patients experience a DLT, enroll an additional 
6 patients (total 12).
If none of the additional 6 patients experiences a DLT, the 
MTD has not been reached.  Proceed to the next dose level 
or proceed to phase II (expansion phase) of the study, if 
applicable.
If 1 of the additional 6 patients experiences a DLT, the MTD 
has been reached.
If 2 or more of the additional 6 patients experience a DLT, 
the MTD has been exceeded.
>2 out of 6
If more than 2 of 6 patients experience a DLT, the MTD has 
been exceeded.
Definitions: DLT = dose-limiting toxicity; MTD = maximum tolerated dose.
If no patient, or 1 out of the 6 patients has a DLT (defined below) during Cycle 1 of study 
treatment at the 30-mg dose, enrollment into the second dose level cohort (45 mg) will 
commence.  Enrollment into the second dose level cohort will proceed only after all 6 evaluable 
patients have completed one full cycle (28 days) of study treatment.  Patients who are not 
evaluable for DLTs will be replaced, ie, the sponsor may permit enrollment of additional patients 
in the cohort to ensure that there are 6 evaluable patients to complete the first cycle.
In the event that 2 of 6 patients experience a DLT, the cohort will be expanded to 12 patients.  If 
no further DLTs are observed for 6 additional evaluable patients, and these patients complete a 
full cycle, enrollment to the next dose level will commence, or the study will continue into 
phase 2 (expansion phase) if this occurs at 45 mg.  If 1 or more of the additional evaluable 
patients experience a DLT, the MTD will have been reached.
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In the event that > 2 of 6 patients (or > 3 of 12 patients, if a dose level has been expanded)
experience a DLT, the MTD has been reached.
5.2.1
Intra-patient Dose Escalation
During the dose-escalation phase I component of the trial, patients at 30 mg will continue at that 
dose while 45 mg is being evaluated.  If 45 mg is selected as the recommended dose, patients 
will be allowed to escalate to 45 mg at the discretion of the investigator, provided that safety,
such as dose reduction/drug withdrawal, must be assured before the dose escalation.
5.2.2
Replacements
Patients who experience a DLT or drug-related AE and come off study during the first 28 days of 
participation will NOT be replaced for purposes of patient accrual.  Any patient who is enrolled 
in the study, but is discontinued for reasons other than a DLT or drug-related safety event prior 
to receiving at least 75% of scheduled doses in the first 28 days (Cycle 1) will be deemed not 
evaluable for DLTs and replaced.
5.2.3
Definition of Maximum Tolerated Dose and Dose Limiting Toxicity
The MTD is defined as the highest dose at which ≤1 of 6 (or ≤3 of 12, in the instance that a 
dose level has been expanded from 6 to 12 patients) evaluable patients experience a DLT.  
Evaluable patients must complete at least 75% of scheduled doses in Cycle 1.  A cohort may be 
expanded to better define tolerability at a dosage level.
For the purposes of this protocol, the following AEs are considered to be DLTs that count for the 
determination of the MTD.  Toxicity grades are defined in the NCI CTCAE v.4.0.

Grade ≥3 non-hematologic, with the exception of medically controllable toxicities 
(eg, nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting 
≤3 days, but excluding alopecia

Missed doses: > 25% of planned ponatinib doses over 28 days due to AEs in the first 
cycle

Febrile neutropenia (the occurrence of an ANC < 500/µL concurrently with a temperature 
elevation of > 101 ºF), when neutropenia is not related to underlying acute leukemia, as 
defined below

Hematologic toxicity: Dose-limiting hematologic toxicity is the occurrence of a 
grade 4 cytopenia > 28 days, not related to underlying disease according to the 
investigator.  Bone marrow examination must demonstrate < 5% cellularity.
When there is ambiguity about whether an AE is related to the underlying disease as opposed to 
the study drug, the most conservative approach will be taken and the AE will be considered 
study drug-related.
5.2.4
Dose Recommendations Based on Updated Data
Before Amendment 2 (Version 3.0), the recommended phase II dose of ponatinib for Japanese 
patients was determined to be 45 mg given once daily.  However, an increase in the cumulative 
incidence of cardiovascular events has been noted in the phase II PACE trial over time (N=449).  
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With a median follow up of 24 months, serious arterial thrombosis occurred in 11.8% of patients: 
cardiovascular events in 6.2% of patients, cerebrovascular events in 4.0% of patients, and 
peripheral vascular events in 3.6% of patients (some patients had more than one type of event).  
This compares to 8.0% after 11 months of follow up.  At 24 months, serious venous occlusion 
occurred in 2.9% of patients, compared to 2.2% after 11 months of follow-up. Furthermore, 2 of 
28 patients in AP24534-11-106 had cardiovascular events at a 45-mg dose.  These results have 
prompted the need for reducing risk while maintaining the potential benefit of ponatinib.  
Recent multivariate analyses performed on data from the phase II PACE trial found significant 
relationships between dose intensity and the occurrence of ≥grade 3 adverse events including 
vascular occlusion, thrombocytopenia, pancreatitis, neutropenia, rash, ALT, AST, lipase, and 
myelosuppression in CML patients treated with ponatinib.  These data support the conclusion 
that lowering the daily dose of ponatinib can reduce the risk of serious adverse events and 
ischemia.
Data from the phase II PACE trial also indicate that patients can achieve and maintain responses 
on lower doses.  After a median follow-up of 24 months, 110/190 CP-CML patients with dose 
reductions had achieved MCyR, and over 90% maintained response (100/110).  Of 87 patients 
who achieved response while on 45 mg, 44 had a dose reduction after response (14 patients had 
dose reductions to 15 mg).  All 44 patients have maintained their response.  Of 46 patients who 
achieved response while on 30 mg, 20 had a dose reduction after response.  Of these, 18 
maintained response; the 2 patients who lost response had a dose reduction to 15 mg that lasted 
only 1 day.  To summarize, 62 of 64 patients who had a dose reduction after response maintained 
the response, including all 35 who had reduced doses for more than 90 days.  This result suggests 
that for CP-CML patients, reduction to 15 mg once daily after achievement of a cytogenetic 
response can sustain that response.  Among the patients with advanced disease (179 patients with 
AP-CML, BP-CML, or Ph+ ALL), 56 achieved MaHR at the 45-mg dose.  Of these, 19 had a 
dose reduction, and 9 of these 19 have lost response.  Of the 10 who remain in response, 7 have 
had dose reductions lasting longer than 90 days:  3 patients with BP-CML (2 at 15 mg, 1 at 30 
mg) and 4 patients with AP-CML (2 each at 15-mg and 30-mg doses).  Fifteen patients achieved 
MaHR at 30 mg.  Of these, 7 had a subsequent dose reduction, and 6 lost response.  One patient 
with AP-CML remains in response, generally taking 15 mg every other day.
Therefore, the following dose regimen is recommended:

For patients with CP-CML who achieve MCyR, consider reducing the ponatinib dose to 
15 mg once daily, 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 justifies treatment with a higher dose.  Escalate to 30 mg if
response is lost.

All CP-CML patients currently on trial who have not yet achieved MCyR should 
consider ponatinib dose reduction to 30 mg/day 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 justifies 
treatment with a higher dose.

All advanced phase (AP- or BP-CML or Ph+ALL) patients currently on trial should have 
their dose reduced to 30 mg/day unless, in the judgment of the investigator, the 
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benefit/risk analysis taking into account the patient’s CML characteristics, BCR-ABL 
mutation status, and the patient’s cardiovascular risk justifies treatment with a higher 
dose.
For all patients, document in the patient’s chart and in the study drug administration page of the 
study case report form (CRF) the dosing changes based on the above recommendations or the 
justification not to change the patient from his or her current dose.
5.2.5
Management of Adverse Drug Reactions
Comprehensive assessments of any study drug-related AEs (adverse drug reactions) experienced 
by the patient will be performed throughout the study.  Anticipated adverse drug reactions that 
may be experienced are described in the Clinical Investigator 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 study.
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.
Dose Modification(s)
Phase I portion Cycle 1 is intended for DLT assessment and no dose change is planned. In phase 
I Cycle 1, and the phase II portion, dose delays and/or reductions will be implemented for 
patients who experience adverse drug reactions, as described below.
Table 3 describes guidelines for dose modification due to study-drug-related toxicity, graded 
according to NCI CTCAE v.4.0.  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 must 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) 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 3.  There are no 
suggested dose modifications for grade 1 or 2 hematologic toxicities.
Guidelines for assessment and management of pancreatitis are also described in Table 3.  
Pancreatic toxicities may 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: NCI CTCAE v.4.0 in the Gastrointestinal disorders System Organ Class defines 
grade 2 pancreatitis as “enzyme elevation or radiologic findings only.”  Version 4.0 separately 
defines toxicity grades for isolated elevation of lipase or serum amylase, which are found in the 
Investigations section of the guidance.  Refer to Table 3 for guidelines on management of 
pancreatitis with or without symptoms, and management of amylase/lipase elevations with or 
without symptoms.
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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 3.  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 3
Modifications for Adverse Events Attributable to Study Drug
Non-hematologic Toxicity
Grade 1 or transient Grade 2
No intervention
Grade 2
Lasting >7 days with optimal care
When the initial dose is 45 mg:
Hold ponatinib
Resume at 45 mg after recovery to ≤grade 1
Recurrence at 45 mg:
Hold ponatinib
Resume at 30 mg after recovery to ≤grade 1
When the initial dose is 30 mg, or recurrence at 30 mg:
Hold ponatinib
Resume at 15 mg after recovery to ≤grade 1
When the initial dose is 15 mg, or recurrence at 15 mg:
Hold ponatinib
Resume at 15 mg every other day after recovery to ≤grade 1
Upon recurrence at 15 mg every other day:
Consider discontinuing ponatinib
Grade 3 or 4
When the initial dose is 45 mg:
Hold ponatinib
Resume at 30 mg after recovery to ≤grade 1
When the initial dose is 30 mg, or recurrence at 30 mg:
Hold ponatinib
Resume at 15 mg after recovery to ≤grade 1
When the initial dose is 15 mg, or recurrence at 15 mg:
Hold ponatinib
Resume at 15 mg every other day after recovery to ≤grade 1
Upon recurrence at 15 mg every other day:
Consider discontinuing ponatinib
Non-hematologic Toxicity
Pancreatitis
Grade 2 (elevated amylase or lipase 
only)
See amylase/lipase section below
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Grade 2 (mild or moderate symptoms 
or radiologic findings)
When the initial dose is 45 mg:
Hold ponatinib
Perform ultrasound or abdominal CT scan with contrast
If imaging is positive, continue holding ponatinib and repeat according to 
clinical care
If imaging is negative, or after resolution by imaging, resume at 45 mg 
after recovery to ≤grade 1
Recurrence at 45 mg:
Repeat above, except resume at 30 mg after recovery to ≤grade 1
When the initial dose is 30 mg, or recurrence at 30 mg:
Repeat above, except resume at 15 mg after recovery to ≤grade 1
When the initial dose is 15 mg, or recurrence at 15 mg:
Hold ponatinib
Resume at 15 mg every other day after recovery to ≤grade 1
Upon recurrence at 15 mg every other day:
Consider discontinuing ponatinib
Grade 3 (severe pain, vomiting, 
medication intervention indicated [eg, 
analgesia, nutritional support])
When the initial dose is 45 mg:
Hold ponatinib
Perform ultrasound or abdominal CT scan with contrast
If imaging is positive, continue holding ponatinib and repeat according to 
clinical care
If imaging is negative, or after resolution by imaging, resume at 30 mg 
after recovery to ≤grade 1
When the initial dose is 30 mg, or recurrence at 30 mg:
Repeat above, except resume at 15 mg after recovery to ≤grade 1
When the initial dose is 15 mg, or recurrence at 15 mg:
Repeat above, except resume at 15 mg every other day after recovery to 
≤grade 1
Upon recurrence at 15 mg every other day:
Consider discontinuing ponatinib
Grade 4
Hold ponatinib
Consult sponsor
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Amylase/Lipase
Grade ≤2 
No intervention, monitor closely
Grade 3 with no radiologic findings
When the initial dose is 45 mg:
Hold ponatinib
Resume at 45 mg after recovery to ≤grade 1
Recurrence at 45 mg:
Hold ponatinib
Resume at 30 mg after recovery to ≤grade 1
When the initial dose is 30 mg, or recurrence at 30 mg:
Hold ponatinib
Resume at 15 mg after recovery to ≤grade 1
When the initial dose is 15 mg, or recurrence at 15 mg:
Hold ponatinib
Resume at 15 mg every other day after recovery to ≤grade 1
Upon recurrence at 15 mg every other day:
Consider discontinuing ponatinib
Grade 3 with radiologic findings or 
Grade 4
When the initial dose is 45 mg:
Hold ponatinib
Repeat imaging according to clinical care
After resolution by imaging, resume at 30 mg after recovery to ≤grade 1
When the initial dose is 30 mg, or recurrence at 30 mg:
Repeat above
Resume at 15 mg after recovery to ≤grade 1
When the initial dose is 15 mg, or recurrence at 15 mg:
Repeat above, except resume at 15 mg every other day after recovery to 
≤grade 1
Upon recurrence at 15 mg every other day:
Consider discontinuing ponatinib
LV dysfunction/CHF
Grade 2 or 3 
When the initial dose is 45 mg:
Hold ponatinib
Resume at 45 mg after recovery to ≤grade 1
Recurrence at 45 mg:
Hold ponatinib
Resume at 30 mg after recovery to ≤grade 1
When the initial dose is 30 mg, or recurrence at 30 mg:
Hold ponatinib
Resume at 15 mg after recovery to ≤grade 1
When the initial dose is 15 mg, or recurrence at 15 mg:
Hold ponatinib
Resume at 15 mg every other day after recovery to ≤grade 1
Upon recurrence at 15 mg every other day:
Consider discontinuing ponatinib
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Grade 4
Hold ponatinib
Consult sponsor
Hematologic Toxicity
Drug-related ANC/Platelets
Grade 1 or 2
No dose adjustment
Grade 3 or 4
When the initial dose is 45 mg:
Hold ponatinib
Resume at 45 mg after recovery to ≤grade 1
Recurrence at 45 mg:
Hold ponatinib
Resume at 30 mg after recovery to ≤grade 1
When the initial dose is 30 mg, or recurrence at 30 mg:
Hold ponatinib
Resume at 15 mg after recovery to ≤grade 1
When the initial dose is 15 mg, or recurrence at 15 mg;
Hold ponatinib
Resume at 15 mg every other day after recovery to ≤grade 1
Upon recurrence at 15 mg every other day:
Consider discontinuing ponatinib
Definitions: ANC = absolute neutrophil count; CHF = congestive heart failure; CT = computed tomography; LV = left 
ventricular. 
5.2.6
Management of Selected Adverse Events 
Dose reduction guidelines are outlined in Section 5.2.5.  This section provides additional 
guidance for management of selected AEs for ponatinib.
Comprehensive assessments of any study drug-related AEs (adverse drug reactions) experienced 
by the patient will be performed throughout the study.  Anticipated adverse drug reactions that 
may be experienced are described in the ponatinib Investigator Brochure.  Event severity as well 
as clinical judgment will be utilized to determine appropriate management of the patient for any 
AE experienced while participating in this study.
Any medications, 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.
Vascular Occlusion
Arterial and venous thrombosis and occlusions, 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 occlusion adverse events were more frequent with increasing age and in 
patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia.
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Arterial Occlusion and Thrombosis 
Serious arterial thrombosis occurred in ponatinib-treated patients with some patients 
experiencing events of more than one type.  Serious cardiovascular thrombosis events included 
myocardial infarction and coronary artery disease.  Some patients developed congestive heart 
failure concurrent or subsequent to the myocardial ischemic event.
Serious cerebrovascular 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 events were reported in ponatinib-treated patients; some patients 
developed digital or distal extremity necrosis with complications of diabetes mellitus and 
peripheral arterial disease which required amputations.  
Monitor and aggressively treat factors that increase cardiovascular risk, such as hypertension, 
hypercholesterolemia, and hyperglycemia.  Interrupt and consider discontinuation of study drug 
in patients who develop arterial thrombotic 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.
Venous Thromboembolism
Venous thromboembolic 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 thromboembolism.
Neuropathy
Peripheral and cranial neuropathy has occurred in ponatinib-treated patients.  In clinical trials, 
peripheral neuropathies 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, neuropathic discomfort, a burning sensation, 
neuropathic pain or weakness. Consider interrupting ponatinib and evaluate if suspected.
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 laboratory abnormalities should be managed with dose interruption 
and/or dose reduction, according to Table 3.
Congestive Heart Failure and Left Ventricular Dysfunction
Severe 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.
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Hypertension
Blood pressure should be monitored at each visit.  Hypertension, as confirmed by at least 2 blood 
pressure measurements, should be graded according to CTCAE version 4.0, which defines 
hypertension as a disorder characterized by a pathological increase in blood pressure (a repeated 
elevation in blood pressure exceeding 140 mm Hg for systolic and exceeding 90 mm Hg for 
diastolic).  For patients who develop hypertension or worsening hypertension during study 
treatment, aggressive antihypertensive medication should be initiated or optimized, at the 
discretion of the investigator, to achieve target blood pressure before interruption or dose 
reduction of study treatment.  If hypertension is persistent, despite additional antihypertensive
medications, or if grade 4 hypertension develops, dose interruption and reduction is 
recommended, according to dose modification guidelines for general non-hematologic AEs, as 
described in Section 5.2.5.  
Ocular Toxicity
Serious ocular 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 
cataract, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye 
exams at baseline and periodically during treatment.
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 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 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 3 for details.
Hemorrhage
Hemorrhagic events have occurred in patients receiving ponatinib.  Most hemorrhagic events 
occurred in patients with grade 4 thrombocytopenia.  Interrupt ponatinib administration in the 
case of serious or severe hemorrhage.
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 Section 5.2.5. 
Cardiac Arrhythmias
Supraventricular tachyarrhythmias and symptomatic bradyarrhythmias were reported in patients 
treated with ponatinib.  Advise patients to report signs and symptoms of rapid heart rate 
(palpitations, dizziness) or those suggestive of slow heart rate (fainting, dizziness, or chest pain).
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Myelosuppression
Myelosuppression is a common AE in patients with CML and occurs in CP patients as well as 
those in the accelerated and blast phases. The etiology for myelosuppression can be attributed to 
CML itself, the drugs used to treat CML, such as TKIs, or a combination of both. Neutropenia, 
anemia, and thrombocytopenia have all been commonly reported, either together or individually,
in patients treated with ponatinib.  While myelosuppression can occur any time during treatment, 
its onset most commonly occurs within the first month on treatment. 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 (Table 3) 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 (G-CSF) or granulocyte-macrophage
colony-stimulating factor (GM-CSF) 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 him/her at high risk of developing 
febrile neutropenia, primary prophylaxis use of colony-stimulating growth factors for the 
prevention or reduction of febrile neutropenia is recommended, according to the published 
National Comprehensive Cancer Network (NCCN) guidelines [NCCN Guidelines Version 
1.2012 – Myeloid Growth Factors].
Tumor Lysis Syndrome
Clinically significant tumor lysis syndrome has been reported at initiation of treatment with TKIs 
in CML patients. The patients at risk of tumor lysis syndrome are those with high 
tumor/leukemic burden prior to treatment. These patients should be monitored closely, 
especially at the initiation of treatment.  Appropriate tumor lysis syndrome 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 tumor lysis syndrome.  Rasburicase and other appropriate treatments for 
hyperuricemia or tumor lysis syndrome are permitted.
Rash and/or Pruritus
Skin rashes have been commonly reported to be associated with ponatinib. The vast majority of 
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 dermatitis. 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.
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 
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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. The use of an antiemetic prophylactically is not 
recommended. However, if a patient is symptomatic, appropriate antiemetic medications may be 
used as clinically indicated.
Constitutional Symptoms/Joint Pain
Certain constitutional symptoms such as myalgia, arthralgia, headache, weakness, fatigue, 
asthenia, and low-grade fever have been 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 analgesics, corticosteroids, and/or antipyretics 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.
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.
Prolonged QTcF
If a prolongation of QTcF is observed, it is important to perform serum electrolyte analysis 
(including potassium, calcium, and magnesium) and correct any significant abnormalities with 
supplements if below normal limits.  It is also necessary to review all concomitant medications 
the patient is on and discontinue medications that are known or suspected to cause QT 
prolongation.
If no contributing reason is identified, and the reason for QTcF prolongation is believed to be 
due to study medication, dose interruption and reduction guidelines for general non-hematologic 
toxicities in Table 3 should be followed.  Additionally, weekly ECG monitoring is recommended 
for 4 weeks upon resumption of study drug, then monthly for 6 months, and then every 3 months 
for the remainder of the study, or more frequently as clinically indicated.
5.3
Prior and Concomitant Treatment(s)/Therapy
Prior and concomitant medications will be recorded from 21 days prior to the start of study 
treatment, at study entry, and during the study (the 30-day Follow-up Visit after the last dose of 
the study drug) on the appropriate eCRF for each patient.
Reasonable efforts will be made to collect information on all prior cancer treatments received by 
the patient (chemotherapy, radiotherapy, immunotherapy, biologics, etc.).  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 of or intolerance to each regimen.  
Stem cell transplant or experimental therapy history will also be recorded.
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All information must be obtained from the patient’s medical chart and recorded on the patient’s 
eCRF.
5.4
Permitted Treatment
All routine and appropriate supportive care (including blood products) will be provided during 
this study, as clinically indicated, and in accordance with 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 (eg, 
colony-stimulating factors such as G-CSF or GM-CSF) per institutional guidelines.
●
Where appropriate, hydroxyurea is 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 (including CP-CML), and is thereafter prohibited.
5.5
Prohibited Treatment(s)/Therapy
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.
●
Use of any other investigational drug or device
●
Use of medications that are known to be associated with the development of Torsades de 
Pointes (see Appendix B)
●
Herbal preparations or related over-the-counter preparations containing herbal ingredients 
(eg, St. John’s Wort, black cohosh, Estroven) within 2 weeks prior to the first dose of 
ponatinib
●
Elective surgery requiring in-patient care
The following medications should be avoided, but are not prohibited:
●
Medications that are potent inhibitors or inducers of cytochrome P450 (CYP)3A (see 
Appendix C) Medications that prolong the QT interval.  If such medications are 
necessary and used while a patient is on study, additional ECG monitoring should be 
performed as clinically indicated (see Appendix B).
Once the patient has withdrawn from the study, concomitant medications and treatments should 
be recorded for 30 days after last dose or until all study drug-related toxicities have resolved, 
whichever is later.
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5.6
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 studies using the recommended daily dose 
of 45 mg.  In vitro studies demonstrated that ponatinib is primarily metabolized by CYP3A. In 
view of this, a drug interaction study was performed with a strong CYP3A inhibitor in healthy 
subjects. Recent data from this ketoconazole–ponatinib drug-drug interaction (DDI) study 
indicate that maximum plasma concentration (Cmax) and area under the curve (AUC) of ponatinib 
are approximately 47% and 78% higher (when dosed at 15 mg), respectively, in the presence of a 
strong CYP3A inhibitor, classifying ponatinib as a weak substrate of CYP3A (Clinical Study 
Report AP24534-11-103).  Therefore, there is a possibility for a clinically relevant DDI if 
ponatinib is administered with strong inhibitors or inducers of CYP3A.  Investigators should 
have patients discontinue strong inhibitors or inducers of CYP3A within 2 weeks of the first dose 
of ponatinib, if at all possible.  If coadministration of ponatinib with a strong inhibitor of CYP3A
is unavoidable, consider reduction of the ponatinib dose 1 level from the current (eg, 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 CYP3A inhibitor, 
or, if that is not possible, consult the sponsor.  If patients are required to receive prolonged 
(>7 days) concomitant administration of an inducer of CYP3A with ponatinib, patient response 
should be monitored closely.  
Medications that are associated with prolongation of the QT interval may interact with ponatinib
and contribute to QT interval prolongation, which has the potential to contribute to ventricular 
arrhythmia.  In addition, some medications associated with QT prolongation also interact with 
the CYP3A cytochrome, and an effect on the QT interval might thus be exacerbated.  
Concomitant administration of medications that are associated with a risk for Torsades de 
Pointes are prohibited (see Appendix B).  Medications that otherwise prolong the QT interval 
should be avoided (see Appendix A).
A list of strong inhibitors or inducers of CYP3A is identified in Appendix C.
5.7
Phototoxicity Study
In a phototoxicity study of ponatinib in eyes and skins of pigmented rats, skin inflammation, 
dermal reaction on the darkly pigmented skin site, and ocular findings were noted.  Therefore,
the phototoxic properties of ponatinib were demonstrated, and the investigator should warn 
patients to protect their eyes and skin from direct sunlight exposure.
5.8
Treatment Compliance
Patients will be provided a diary card or equivalent where the date of ponatinib administration 
will be recorded. Any missing doses should be recorded in an appropriate source record (eg, 
hospital chart), patient diary card, and study drug administration eCRF.  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.  
The Investigator is responsible for ensuring that the patient diary card(s) are accounted for and 
noted in the source documentation.
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5.9
Treatment(s) Supply
Upon receipt of clinical study materials and/or study drug, the investigational product 
administrator must verify that the shipment was received as stated on the clinical supply 
shipment form, enclosed within each shipment. If there are any discrepancies with the shipment, 
the sponsor should be contacted immediately (contact information is listed on the clinical supply 
shipment form).  A copy of this form must be retained in the site files.
5.9.1
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 
monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, 
magnesium stearate, polyethylene glycol, talc, polyvinyl alcohol, and titanium dioxide).  
Ponatinib product is provided as 60 tablets of 15 mg in a bottle and 30 tablets of 45 mg in a 
bottle of a white density polyethylene (6.5 cm tall, 3.5 cm diameter, and 30 cc volume).
Container labels will bear the appropriate label text, as required by the J-GCP and the Japanese 
Regulatory Agency. J-GCP requires the following description on the label:
  1). For Clinical Trial Use Only 
  2). Name and address of sponsor (ARIAD) &
Name and address of ICCC 
  3). Chemical name or drug code (AP24534 or ponatinib)
4). Batch Number
5). Storage condition, expiring date, and other necessary information.
5.9.2
Preparation and Dispensing
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, 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.
5.9.3
Treatment(s) Storage and Accountability
The recommended storage condition for ponatinib is controlled at 10°C – 30°C.
The investigator is responsible for ensuring that the study drug provided to the patient and 
returned from the patient is accounted for and noted in source documentation.
CCI
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During the study and at termination, patients must return all unused study drug supplies, and the 
return of these unused study drug supplies must be recorded.  Returned supplies must not be 
re-dispensed.
No other utilization of ponatinib intended for use in this study is authorized by the sponsor. The 
sponsor will be responsible for the appropriate handling and disposition of residual study drug. 
Periodically, throughout and at the conclusion of the study, a representative of the sponsor will 
conduct an inventory of unused study drug.  At the completion of the study, a final study drug 
accountability review will be conducted. 
The sponsor (ICCC) should prepare the records of delivery and withdrawal of the test drug and 
records of disposition of residual test drug.
6
EFFICACY AND SAFETY ASSESSMENTS
The following sections describe the procedures/tests required for this study.
6.1
Efficacy Assessments
Patients will be assessed for hematologic response, cytogenetic response, and molecular response 
every 2-3 cycles, according to criteria established and published for specific hematologic 
malignancies (Talpaz et al, 2006; O’Brien et al, 2003; Kantarjian et al, 2010, described in 
Appendix A).  All patients will be followed for up to 60 months after the first dose of ponatinib.
6.1.1
Bone Marrow Aspirate and Cytogenetics
BM aspirate results must list the components required for assessing patient response.  Results of 
any BM aspirate or biopsy, whether scheduled or unscheduled, should be recorded in the 
patient’s eCRF.  All BM examinations must include blast count and cytogenetic assessment by 
conventional banding.
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 patient response, as delineated in 
Appendix 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 must be repeated.
BM aspirate is required every 3 months for CP patients, at the end of Cycle 1 and Cycle 2, and 
then every 2 months for AP, BP, and Ph+ ALL patients.  A BM aspirate is performed at the 
End-of-Treatment Visit if it has been ≥12 weeks for CP and ≥8 weeks for AP or BP or Ph+ 
ALL since the last BM aspirate.  Bone marrow aspirates and biopsies may be performed at other 
times when clinically indicated.
6.1.2
BCR-ABL Molecular Response Assessment
A quantitative real-time polymerase chain reaction (PCR) assay will be used to measure 
BCR-ABL transcript levels in peripheral blood samples collected from all patients, and in BM 
samples collected from BP and Ph+ ALL patients.  Samples must be collected at screening, 
during the treatment period at the same time as BM aspirates (ie, at least every 3 months for CP 
and at least every 2 months for AP, BP, and Ph+ ALL), and at the End-of-Treatment Visit.  This 
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test quantifies the molecular response to therapy and will be reported to the participating 
investigator.
6.2
Safety Assessments
Safety will be assessed by routine physical and laboratory evaluations, ECGs, and AEs, and will 
be recorded and the severity will be graded according to the NCI CTCAE v.4.0 (see 
Appendix D).
6.2.1
Adverse Events
Type, incidence, severity (graded in accordance with the NCI CTCAE v.4.0), timing, seriousness 
and relatedness, outcome, action taken with study drug, and treatment will be assessed and 
documented by the investigator throughout the study (see Section 8).
Baseline malignancy-related signs and symptoms will be recorded as AEs during the study if 
they worsen in severity or increase in frequency.
6.2.2
Vital Signs
Vital signs include temperature, pulse rate, respiratory rate, and blood pressure (when patient is 
seated).  Height and weight are required only at screening.
6.2.3
Physical Examination
All physical examinations should address the presence or absence of hepatosplenomegaly and 
ECOG performance status.  The extent of the physical examination should be consistent with the 
medical history and the patient’s underlying disease.  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 examinations defined in the protocol.
A complete physical examination (including comprehensive eye exams at baseline and 
periodically during treatment) will be performed at screening, on Cycle 1 Day 1 prior to the first 
administration of study drug, and at the End-of-Treatment Visit.  Physical examinations at other 
time points may be directed to relevant findings in the patient.  The Follow-up Visit physical 
examination may be directed to any relevant findings. ECOG status must be assessed during all 
physical examinations.
6.2.4
Clinical Laboratory Safety Assessments
Complete blood count (CBC) with differential, and PT and partial thromboplastin time (PTT) 
will be performed to assess patient safety, as well as hematologic response.  Serum chemistry 
tests and pregnancy tests will be performed to assess patient safety.  The following clinical 
laboratory safety assessments will be performed:
Complete Blood Count with Differential
Complete blood count with differential is defined as peripheral blood total white blood cell 
(WBC) count, hemoglobin, hematocrit, platelet count, ANC, and WBC differential reported 
individually for each cell type, including immature cells such as metamyelocytes, promyelocytes, 
and blasts, when present.
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Serum Chemistry, Including Amylase and 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), glucose (including fasting glucose levels), albumin, creatinine, total bilirubin (direct and 
indirect), AST (SGOT), ALT (SGPT), alkaline phosphatase, magnesium, phosphorous, calcium, 
amylase, and lipase.
Serum Triglycerides
The fasting or non-fasting serum triglyceride level must be collected during screening (including 
fasting total and LDL cholesterol levels).  If a patient is ineligible based on a non-fasting level, 
the test may be repeated with a fasting level to determine eligibility.
Prothrombin Time and Partial Thromboplastin Time
A peripheral blood sample will be collected during screening to measure PT and PTT.  The PT 
may be expressed as an International Normalized Ratio (INR) or in seconds.
Pregnancy Test
A pregnancy test must be performed on fertile females. The pregnancy test must be a β-HCG 
test, and either urine or serum can be used.  The test must be known to be negative prior to study 
drug administration and must be performed within 7 days prior to the first study drug 
administration.  Women of childbearing potential at study start must also complete the pregnancy 
test at the End-of-Treatment Visit.
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, except those 
with chemical menopause diagnosed by an investigator]) do not need to have the test performed.
Thyroid function test (T3, T4, and TSH)
Thyroid function test will measure the levels of TSH, free T3 and free T4. The test will be 
performed at screening and Day 1 of Cycle 3.
6.2.5
Electrocardiogram
All ECGs must be 12-lead.  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 calculations of QTc intervals, and the QTcF interval must be normal on screening as specified 
in the eligibility criteria (Section 4).  If other medications known to prolong the QTcF interval 
are used while a patient is on study, additional ECG monitoring should be performed as 
clinically indicated.
6.2.6
Echocardiogram
An echocardiogram (ECHO) for assessment of left ventricular ejection fraction (LVEF) must be 
performed within the 21-day screening window.  An ECHO should be performed at the end of 
Cycle 3 only if clinically indicated, and at the End-of-Treatment or Follow-up Visit only if 
abnormality develops during study.
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6.3
Other Assessments
6.3.1
Additional Disease Assessments
Additional examination, laboratory studies, or imaging must be performed as appropriate to fully 
assess disease status.  This may include documentation of hepatosplenomegaly or, in patients 
with extramedullary involvement, imaging the site(s) of involvement.  The sites of involvement 
must be assessed at screening and in subsequent disease evaluations with appropriate laboratory 
tests or procedures.
6.3.2
BCR-ABL Mutation Testing
6.3.3
Molecular Genetic Assessment
6.3.4
Survival
All patients should be followed-up for survival every 12 weeks ± 2 weeks starting after the last 
dose of study drug for up to 60 months from initiation of therapy.  These data do not need to be 
obtained during a visit, and phone contact is acceptable.
6.4
Pharmacokinetics
Blood samples will be collected at specified time points to study the PK of ponatinib.  
Pharmacokinetic parameters such as time of maximum concentration (Tmax), Cmax, AUC, and 
elimination half-life (t1/2) will be determined where possible.
During both Cycle 1 and Cycle 2, blood samples will be collected immediately prior to the first 
dose (time 0), and 0.5, 1, 2, 4, 6, 8, and 24 hours after the first dose.  The 24-hour sample will be 
collected prior to dosing on Day 2 for both cycles.  Blood samples will also be collected prior to 
dosing on Cycle 1 Days 8, 15, and 22.  An additional sample will be collected for AP, BP, and 
Ph+ ALL patients prior to dosing on Cycle 1 Day 28.
For the Phase II portion patients, PK samples will not be collected.
Regarding PK sample collection for patients who will be given 15 mg ponatinib daily in order to 
investigate PK linearity in Japanese patients, sampling time will be 0 (just before administration), 
0.5, 1, 2, 4, 6, 8, and 24 hours after intake on Day 1 and Day 8 in Cycle 1, respectively.
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7
STUDY PROCEDURES
Table 4 illustrates the planned flow of clinical study procedures.  Concomitant treatments and 
AEs will be collected throughout the study.
Table 4
Study Flow Chart
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.
Cycle 1
End of 
Treatment
30 Days After 
End of 
Treatment
The follow-up period for 
a patient begins after the 
last completed assessment 
during the active study 
period and continues until 
patient contact 
discontinues.
Patient 
receives first 
dose of study 
drug and is 
then 
considered an 
enrolled 
patient
Patient 
continues to 
receive study 
drug and/or 
undergo 
study 
procedures/
assessments 
as described 
in the 
protocol
Patient 
receives final 
dose of study 
drug or 
discontinues 
taking study 
drug and 
completes end-
of-treatment 
assessments
Patient completes 
all post-treatment 
discontinuation
assessments
On-Study Period
Follow-Up 
Period
Screening
Period
Active Study Period
In addition, in the phase I portion, before initiating Cycle 2, patients should be checked for their 
willingness to continue receiving treatment, and consent must be obtained.
The “on-study period” begins with signing the informed consent form and ends approximately 
30 days following the last dose of study drug.  The “active study period” begins with 
administration of the first dose of study drug and continues through approximately 30 days 
following discontinuation of study drug (ie, at the follow-up visit).  The “follow-up period” (to 
collect survival data) begins after the last dose of study drug and continues for up to 60 months 
from initiation of therapy.
The Schedule of Events for the safety and efficacy assessments to be performed at each visit is 
provided in Table 5 (CP patients) and Table 6 (AP, BP, and Ph+ ALL patients).
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Table 5
Schedule of Events for Chronic Phase Patients
Active Study Period
Cycle
(1 cycle = 28 days)
Screening
Cycle 1
Cycle 2
Cycle 3
Cycles
4 to 13
End of 
Cycles 6, 
9, 12
End of 
Every Third 
Cycle (15 to 
60)
End-of-
Treatment 
Visit1
Follow-
up 
Visit1
Survival 
Follow-
up2
Day
-21 to 1
1
8
15
22
1
15
1
15
28
1
28
28
Procedure
Informed Consent
X
X14
Medical/Surgical History & Demographics3
X
Cancer Diagnosis & Prior Cancer Therapy4
X
BCR-ABL Mutation History
X
Vital Signs5
X
X
X
X
X
X
X
X
X
Physical Exam including Hepato-
splenomegaly & ECOG Performance 
Status6
X
X
X
X
X
X
X
X
X
Complete Blood Count with Differential
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry15, Amylase, Lipase
X
X
X
X
X
X
X
X
X
X
X
Thyroid Function Test7
X
X
Serum Triglycerides8
X
PT & PTT
X
Pregnancy Test (if applicable)
X
X
12- lead Electrocardiogram
X
X
X
X
X
Echocardiogram9
(X)
(X)
(X)
(X)
Adverse Events
Throughout study
Concomitant Medications
Throughout study
Response Assessment
Bone Marrow Aspirate & Cytogenetic 
Response10
X
X
X
X
X
Molecular Response11
X
X
X
X
X
Additional Disease Assessments12
X
X
X
X
Exploratory Tests
Pharmacokinetics
PK Sampling13
X
X
X
X
X
Survival Follow-Up
Survival2
X
See footnotes after Table 6.
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Table 6
Schedule of Events for Accelerated Phase, Blast Phase, and Ph+ ALL Patients
Active Study Period
Cycle
(1 cycle = 28 days)
Screening
Cycle 1
Cycle 2
Cycle 3
Cycles 
4 to 26
End of 
Even 
Cycles 
4 to 60
End-of-
Treatment 
Visit1
Follow-
up 
Visit1
Survival 
Follow-
up2
Day
-21 to 1
1
8
15
22
28
1
15
28
1
15
28
1
15
28
Procedure
Informed Consent
X
X14
Medical/Surgical History & Demographics3
X
Cancer Diagnosis & Prior Cancer Therapy4
X
BCR-ABL Mutation History
X
Vital Signs5
X
X
X
X
X
X
X
X
X
Physical Exam including Hepatosplenomegaly 
& ECOG Performance Status6
X
X
X
X
X
X
X
X
X
Complete Blood Count with Differential
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry15, Amylase, Lipase
X
X
X
X
X
X
X
X
X
X
Thyroid Function Test7
X
X
Serum Triglycerides8
X
PT & PTT
X
Pregnancy Test (if applicable)
X
X
12- lead Electrocardiogram
X
X
X
X
X
Echocardiogram9
(X)
(X)
(X)
(X)
Adverse Events
Throughout study
Concomitant Medications
Throughout study
Response Assessment
Bone Marrow Aspirate & Cytogenetic 
Response10
X
X
X
X
X
Molecular Response11
X
X
X
X
Additional Disease Assessments12
X
X
X
Exploratory Tests
Pharmacokinetics
PK Sampling13
X
X
X
X
X
X
Survival Follow-Up
Survival2
X
See footnotes on following pages.
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Definitions: AP = accelerated phase; BCR-ABL= Breakpoint Cluster Region-Abelson; BM = bone marrow; BP = blast phase; ECG = electrocardiogram; CHF = congestive heart 
failure; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; MI = myocardial infarction; Ph+ ALL = Philadelphia chromosome positive acute 
lymphoblastic leukemia; PK = pharmacokinetic; PT = prothrombin time; PTT = partial thromboplastin time; TIA = transient ischemic attack; WBC = white blood cell.
Footnotes for Schedule of Events Table 5 and Table 6.
1.
The End-of-Treatment (or early termination) Visit should be performed within 2 weeks (14 days) of the patient’s last dose of study drug.  The Follow-up 
Visit will be conducted 30 days (± 7 days) after the last dose of study drug.
2.
Survival data should be collected every 12 weeks ± 2 weeks starting after the last dose of study drug for up to 60 months from the initiation of therapy.
3.
Medical and surgical history and demographic information will be recorded.  Medical and surgical history includes diagnoses, therapies, medical and 
surgical treatments, and current medications, and must include any history of ischemic heart disease (including angina, myocardial infarction [MI], acute 
coronary syndrome, and/or coronary revascularization procedures), valvular heart disease, CHF, arrhythmias, myocarditis, peripheral arterial occlusive 
disease (including claudication, distal extremity amputation, angioplasty, and/or revascularization procedure), stroke (including TIA, cerebral 
atherosclerosis, and/or revascularization procedure), diabetes mellitus, hypertension, hypercholesterolemia, hyperlipidemia, deep venous thrombosis, 
pulmonary embolism, and other coagulopathy (eg, protein S or protein C deficiency or anticardiolipin antibody), physical inactivity, obesity, and 
smoking.  Family medical history will be collected and should include history of coronary artery disease and early death from MI or cerebrovascular 
accident in first-degree relatives.  Demographic information consists of the patient’s age, sex, and race (as allowed by local law and regulations).
4.
Both the initial leukemia diagnosis and the current screening diagnosis must be recorded.
5.
Height and weight only at screening.
6.
A complete physical examination must be performed at screening, on Cycle 1 Day1 prior to the first administration of study drug, and at the 
End-of-Treatment Visit. Physical examinations at other time points may be directed to relevant findings in the patient.  ECOG status must be assessed 
during all physical examinations. Comprehensive eye exams should be performed at baseline (or at the next visit if not done at baseline for ongoing 
patients) and as clinically indicated.
7.
Thyroid function test will measure the levels of TSH, free T3 and free T4. The test will be performed at screening and Day 1 of Cycle 3.
8.
If a patient is ineligible based on a non-fasting triglyceride level, the test may be repeated with a fasting level to determine eligibility. Fasting serum 
triglycerides, specifically LDL cholesterol levels should be collected at baseline (or at the next visit if not done at baseline for ongoing patients) and then 
as clinically indicated.
9.
An ECHO should be performed at the end of Cycle 3 only if clinically indicated and at the End-of-Treatment or Follow-up Visit only if abnormality 
develops during study.
10.
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.  A BM aspirate is required every 3 months for CP patients, and at the end of Cycle 1, Cycle 2, and then every 2 months for AP,
BP, and Ph+ ALL patients.  A BM aspirate is performed at the End-of-Treatment Visit if it has been ≥12 weeks for CP and ≥8 weeks for AP or BP or 
Ph+ ALL since the last BM aspirate.  Bone marrow aspirates and biopsies may be performed at other times when clinically indicated.
11.
Samples of peripheral blood (all patients) and BM (BP and Ph+ ALL patients only)
12.
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.
13.
PK blood sampling will be conducted as follows:
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●Blood samples for PK analysis will be collected during both Cycle 1 and Cycle 2, immediately prior to the first dose (time 0), and 0.5, 1, 2, 4, 6, 8, and 
24 hours after the first dose.  The 24-hour sample will be collected prior to dosing on Day 2 for both cycles.  Blood samples will also be collected 
prior to dosing on Cycle 1 Days 8, 15, and 22. An additional sample will be collected for AP, BP, and Ph+ ALL patients prior to dosing on Cycle 1 
Day 28.
●Regarding Phase II portion patients, PK samples will not be collected.
●PK sample collection for patients who will be given 15 mg ponatinib daily in order to investigate PK linearity in Japanese patients, sampling time will 
be 0 (just before administration), 0.5, 1, 2, 4, 6, 8, and 24 hours after intake on Day 1 and Day 8 in Cycle 1, respectively.
14.
Patients in phase I portion: informed consent should be obtained before the dosing on Day 1 of Cycle 2 
15.
Fasting glucose levels should be collected at baseline (or at the next visit if not done at baseline for ongoing patients) and then as clinically indicated.
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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 BM and pregnancy test, below).  Otherwise, samples or 
activities should occur within 3 days of the scheduled study day unless otherwise noted in the 
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.
Procedures for determining response criteria in CP, and AP, BP, and Ph+ ALL patients are 
summarized below. These procedures are also listed in following sections by study phase.
Chronic Phase:
●
Complete hematologic response (CHR): Hematologic response determination occurs for 
CP patients with each 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 months.  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 months, according to the same schedule as the BM 
aspirates.
Accelerated Phase, BP, and Ph+ ALL:
●
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 on Cycle 1 Day 28, Cycle 2 Day 28, and at the end of each even-numbered cycle 
thereafter.
●
Major cytogenetic response (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 months.  Conventional banding for cytogenetics is required.  More frequent 
assessments are allowed but are not required.
●
Major molecular response (MMR): Collection of peripheral blood for determination of 
molecular response occurs every 2 months, according to the same schedule as the BM 
aspirates. For BP and Ph+ ALL, a sample of marrow aspirate for molecular response is 
also collected.
7.1
Screening Period Procedures, Medical History, and Demographics
All screening tests must be performed within 21 days prior to the first dose of ponatinib with the 
exception of the screening BM aspirate (within 42 days) and screening pregnancy test (within 
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7 days).  Patients must continue to maintain laboratory values within eligibility parameters if any 
given procedure or laboratory test is repeated prior to the start of ponatinib on Cycle 1 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, and must include any history of ischemic heart 
disease (including angina, MI, acute coronary syndrome, and/or coronary 
revascularization procedures), valvular heart disease, CHF, arrhythmias, myocarditis, 
peripheral arterial occlusive disease (including claudication, distal extremity 
amputation, angioplasty, and/or revascularization procedure), stroke (including TIA, 
cerebrovascular atherosclerosis, and/or revascularization procedure), diabetes 
mellitus, hypertension, hypercholesterolemia, hyperlipidemia, deep venous 
thrombosis, pulmonary embolism, any other coagulopathy (eg, protein S or protein C 
deficiency or anticardiolipin antibody), physical inactivity, obesity, and smoking.  
Family medical history will be collected and should include history of coronary artery 
disease and early death from MI or cerebrovascular accident in first-degree relatives.  
o
Demographic information consists of the patient’s age, gender, and race.
●
Cancer diagnosis and prior cancer therapy
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 
of 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 including hepatosplenomegaly, comprehensive eye exam, and 
ECOG performance status.  If the comprehensive eye exam was not performed at 
baseline, it should be done at the next visit for ongoing patients.
●
CBC with differential
●
Serum chemistry, including amylase and lipase
●
Serum triglycerides
●
PT and PTT
●
Pregnancy test (if applicable)
●
12-lead ECG 
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●
ECHO
●
AEs and concomitant medications and/or concurrent treatment
●
BM aspirate and cytogenetic response
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
●
Molecular response
o
Samples of peripheral blood (all patients) and BM (BP and Ph+ ALL patients only)
●
Additional disease assessments (eg, evaluation of extramedullary disease sites in AP, BP, 
and Ph+ ALL)
●
●
7.1.1    Screen 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.
7.2
Treatment Period Procedures
An eCRF must be completed for any patient who receives study drug.
Patients will be instructed to take the prescribed number of tablets with water, with or without 
food, at approximately the same time each day.
Procedures to be performed during the study are listed in Table 5 for CP patients and Table 6 for 
AP, BP, and Ph+ ALL patients.  
The following should be noted with regard to the primary and secondary endpoints:
Chronic Phase
●
CHR determination occurs with each CBC and differential.  
●
For MCyR, BM aspirate for morphology and cytogenetics is required every 3 months.  
●
For MMR, peripheral blood collection is required every 3 months.  
Accelerated Phase, BP, and Ph+ ALL
●
MaHR determination occurs with each physical examination, CBC and differential, and 
BM aspirate.
●
For MCyR, BM aspirate for morphology and cytogenetics is required on Day 28 of 
Cycles 1, 2, and then every 2 months.  
●
For MMR, peripheral blood collection is required every 2 months.
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For all patients, an assessment of hepatosplenomegaly must be recorded at each physical 
examination.  
7.3
End of Treatment or Early Termination Procedures
The End-of-Treatment (or early termination) Visit should be performed within 2 weeks (14 days) 
of the patient’s last dose of study drug.  An End-of-Treatment reason must be recorded for any 
patient who receives study drug and/or is enrolled in the study.
The following tests and procedures are required at the End-of-Treatment (or early termination) 
Visit for all patients:
●
Vital signs
●
Complete physical examination, including hepatosplenomegaly and ECOG performance 
status
●
CBC with differential
●
Serum chemistry including amylase and lipase
●
Pregnancy test, if applicable
●
12-lead ECG
●
ECHO
●
AEs and concomitant medications and/or concurrent treatment
●
BM aspirate and cytogenetic response
●
Molecular response
o
Samples of peripheral blood (all patients) and BM (BP and Ph+ ALL patients only)
●
BCR-ABL Mutation detection
●
Molecular genetics
7.4
Follow-up
The Follow-up Visit will be conducted 30 days (± 7 days) after the last dose of study drug.
The following tests and procedures are required at the Follow-up Visit for all patients:
●
Vital signs
●
Complete physical examination, including hepatosplenomegaly and ECOG performance 
status
●
CBC with differential
●
Serum chemistry, including amylase and lipase
●
ECHO
●
AEs and concomitant medications and/or concurrent treatment
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7.5
Survival Follow-up
Survival data for all patients will be collected every 12 weeks ± 2 weeks starting after the last 
dose of study drug for up to 60 months from initiation of therapy.  These data do not need to be 
obtained during a visit, and phone contact is acceptable.
8
ADVERSE EVENT REPORTING
8.1
Adverse Events
8.1.1
Adverse Event Definition
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, and that 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 to the medicinal product.  Any worsening 
of a pre-existing condition that is temporally associated with the use of the study drug (eg, occurs 
after the first dose of study drug) is also an AE.
Adverse events include:
●
Abnormal test findings
●
Changes in physical exam findings
●
Other untoward medical events, regardless of their relationship to the study drug, such as 
injury, events that require surgery, accidents, or apparently unrelated illnesses
●
Hypersensitivity
Additionally, AEs may include signs or symptoms resulting from:
●
Drug overdose
●
Drug withdrawal
●
Drug abuse
●
Drug misuse
●
Drug interactions
●
Drug dependency
●
Exposure in utero
8.1.2
Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE are as follows:
●
Test result is associated with accompanying symptoms that are considered clinically 
significant in the opinion of the investigator.
●
Test result requires additional diagnostic testing (other than merely repeating an 
abnormal test) or medical/surgical intervention.
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●
Test result leads to a change in study drug dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy.
●
Test result is considered to be an AE by the investigator or sponsor.
8.1.3
Performing Adverse Event Assessments
All observed or volunteered AEs, regardless of treatment group or suspected causal relationship 
to the investigational product(s), will be reported as described in the following sections.
For all AEs, the investigator must pursue and obtain information adequate to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a serious AE 
(SAE; see Section 8.2) requiring immediate notification to 
).
8.1.4
Reporting Period
Serious AEs require immediate notification to 
beginning from the time the patient 
provides informed consent, which is obtained prior to the patient’s participation in the clinical 
study (ie, prior to undergoing any study-related procedure and/or receiving investigational 
product), through and including 30 days after the last administration of investigational product.  
Any SAE occurring any time after the reporting period must be promptly reported to ARIAD 
Pharmacovigilance and Risk Management or its designated representative (within 24 hours of the 
investigator’s awareness) if a causal relationship to the investigational product is suspected.
For all enrolled patients, AEs (serious and non-serious) should be recorded on the eCRF during 
the on-study period, which begins with signing the informed consent form and concludes 30 days 
following the last dose of study drug.
8.1.5
Adverse Event Severity
The severity of AEs will be assessed according to the CTCAE, v.4.0 (see Appendix D).  If the 
AE is not defined in the CTCAE, the investigator will determine the severity of the AE based on 
the following definitions:
●
Mild (Grade 1): The AE is noticeable to the patient but does not interfere with routine 
activity.  The AE does not require discontinuing administration or reducing the dose of 
the study drug.
●
Moderate (Grade 2): The AE interferes with routine activity but responds to symptomatic 
therapy or rest.  The AE may require reducing the dose, but not discontinuing 
administration of the study drug.
●
Severe (Grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy.  In addition, the AE leads to discontinuing 
administration or reducing the dose of the study drug.
●
Life-Threatening (Grade 4): The AE requires discontinuing administration of the study 
drug.  The patient is at immediate risk of death.
●
Death (Grade 5): The patient dies as a result of AE(s).
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8.1.6
Causality
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious).  An investigator’s causality assessment is the determination of whether there exists 
a reasonable possibility that the investigational product caused or contributed to the AE.
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and on the SAE form 
and report such an assessment in accordance with the SAE reporting requirements.
The investigator will use medical consideration and the following categories of causality to 
determine the relatedness of an AE with study drug, based on the following definitions.  Not all 
criteria in each category of relatedness must be present.  Also, if an AE related to study drug 
continues after the follow-up visit, the patient must be followed until the event returns to baseline 
(or becomes less than CTCAE grade 1), or the investigator judges that it becomes stable, chronic, 
or irreversible. 
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 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 or ambiguous
Possibly Related (drug related)
●
There is evidence of exposure to study drug
●
The temporal sequence of the AE onset relative to administration of 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 study drug is 
reasonable
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●
The AE is more likely explained by study drug than by another cause
Definitely Related (drug related)
●
There is evidence of exposure to study drug
●
The temporal sequence of the AE onset relative to administration of study drug is 
reasonable
●
Dechallenge is positive
●
Rechallenge (if feasible) is positive
●
The AE shows a pattern consistent with previous knowledge of the test drug or a test drug 
class
8.1.7
Expectedness
The expectedness of an SAE is assessed by the Sponsor in the overall classification of SAEs for 
regulatory reportability.  The current Investigator’s Brochure section, “Summary of Data and 
Guidance for the Investigator,” will be used as the reference for determination of expectedness
and risk assessment for ponatinib.
8.2
Serious Adverse Events and Adverse Events of Special Interest
8.2.1
Serious Adverse Event Definition
The investigator or the sponsor may determine the seriousness of an AE based on the following.  
An AE is considered an SAE if at least one of the following conditions applies:
●
Death: An AE that results in death is any patient death within 30 days of the last dose of 
study drug administration.  The cause of death or AE that resulted in a fatal outcome is 
the SAE.
●
Life-threatening AE: An AE that places the patient, in the view of the investigator or the 
sponsor, at immediate risk of death from the event as it occurred (ie, this does not include 
an event that, had it occurred in a more severe form might have caused death).
●
Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 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.
●
A congenital anomaly/birth defect: A fixed, permanent impairment established at or 
before birth
●
Cancer: Occurrence or diagnosis of a new cancer during the study is considered an SAE.
●
Any AE associated with an overdose of study drug.  An overdose of study drug is defined 
as an occurrence of administered dose exceeding that which is prescribed by the 
investigator per protocol.
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●
Important medical event: Medical and scientific judgment should be exercised in 
determining whether an event is an important medical event.  An important medical event 
may not result in death, be life-threatening, or require hospitalization.  However, if it is 
determined that the event may jeopardize the patient and/or may require intervention to 
prevent one of the other outcomes listed in the definition above, the important medical 
event should be reported as serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization; or the development of drug dependency 
or drug abuse.

Progression of the malignancy under study (including signs and symptoms of 
progression)
o
Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the eCRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as an AE.

Hospitalizations: Adverse events that are reported from clinical studies and require 
hospitalization or prolongation of hospitalization are considered serious.  Any initial 
admission (even if less than 24 hours) to a health care facility meets these criteria. 
Adverse events that require emergency room care that do not result in hospital admission 
are not SAEs unless assessed by the investigator to be an important medical event.  
Hospitalization does not include the following:

Hospice facilities

Respite care

Skilled nursing facilities

Nursing homes

Routine emergency room admissions

Same day surgeries (as outpatient/same day/ambulatory procedure)
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Hospitalization or prolongation of hospitalization in the absence of a precipitating AE 
is not in itself an SAE.  Examples include:

Social admission (eg, patient has no place to sleep)

Protocol-specified admission during a clinical study (eg, for a procedure required 
by the study protocol)

Optional admission not associated with a precipitating AE (eg, for elective 
cosmetic surgery that was planned prior to study enrollment [appropriate 
documentation is required for these cases])
Hospitalization or prolongation of hospitalization for scheduled therapy of the target 
malignancy of the study is not considered an SAE
8.2.2
Identification of Adverse Events of Special Interest
The following terms have been identified as adverse events of special interest (AESIs) for 
ponatinib.  These events generally meet one of the seriousness criteria and should therefore be 
handled as SAEs.  However, in the event that an AESI is not fatal or life-threatening, or does not 
require or prolong hospitalization, it should be classified as medically important and, therefore, 
serious.  All AESIs are to be classified as SAEs.

Myocardial infarction: the Third Universal Definition of Myocardial Infarction 
(Thygesen et al, 2012) is used to define MI. Acute MI is used in a clinical setting when 
there is evidence of myocardial necrosis consistent with myocardial ischemia.  Any one 
of the following constitutes MI:
o
A rise and/or fall of cardiac biomarker values (preferably cardiac troponin [cTn]) with 
at least 1 value above the 99th percentile upper reference limit (URL) and with at least 
1 of the following:

Symptoms of ischemia

New or presumed new significant ST-segment T-wave changes or new left 
branch bundle block (LBBB)

Development of pathological Q waves in the ECG

Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality

Identification by angiography or autopsy of an intracoronary thrombus
o
Cardiac death, with symptoms suggestive of myocardial ischemia and presumed new 
ischemic ECG changes or new LBBB; death occurred before cardiac biomarkers were 
obtained or would be increased
o
Percutaneous coronary intervention-related MI, arbitrarily defined by elevation of 
cTn values (greater than 5 x 99th percentile URL) in patients with normal baseline 
values (less than 99th percentile URL), or a rise of cTn values greater than 20% if 
baseline values are elevated and are stable or falling.  In addition, either (i) symptoms 
suggestive of myocardial ischemia, (ii) new ischemic changes, (iii) angiographic 
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findings consistent with a procedural complication, or (iv) imaging demonstration of 
new loss of viable myocardium or new regional wall motion abnormality are required.
o
Stent thrombosis associated with MI when detected by coronary angiography or 
autopsy in a setting of myocardial ischemia, and with a rise and/or fall of cardiac 
biomarker values, with at least 1 value above the 99th percentile URL
o
Coronary artery bypass grafting-related MI, arbitrarily defined by elevation of cardiac 
biomarker values (greater than 10 x 99th percentile URL) in patients with normal 
baseline cTN values (less than 99th percentile URL).  In addition, either (i) new 
pathological Q waves or new LBBB, (ii) angiographic-documented new graft or new 
native coronary artery occlusion, or (iii) imaging evidence of new loss of viable 
myocardium or new regional wall motion abnormality
!
Prior MI is defined by any one of the following criteria:
o
Pathological Q waves with or without symptoms in the absence of non-ischemic 
causes
o
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to 
contract, in the absence of a non-ischemic cause
o
Pathological findings of a prior MI
!
Angina: symptoms of myocardial ischemia without diagnostic evidence of an MI by 
cardiac biomarkers, ECG, imaging studies, or coronary angiography
!
Coronary artery disease: an event in which coronary athero- or arteriosclerosis is 
reported on angiogram (without evidence of thrombus), and no associated angina or 
evidence of an MI are reported (Thygesen et al, 2012)
!
Stroke: (ischemic or hemorrhagic) evidence of infarction or hemorrhage of CNS tissue, 
based either on neuroimaging (preferably including diffusion-weighted magnetic 
resonance imaging [MRI]) or clinical signs of permanent neurologic dysfunction (Easton 
et al, 2009)
!
Transient ischemic attack (TIA): transient episode of neurodysfunction caused by focal 
brain, spinal cord, or retinal ischemia, without evidence of acute infarction on 
neuroimaging (preferably including diffusion-weighted MRI) (Easton et al, 2009)
!
Peripheral arterial occlusive disease: evidence of athero- or arteriosclerosis (with or 
without thrombus) on angiography.
8.2.3
Reporting Serious Adverse Events and Adverse Events of Special Interest
The Investigator or designee must notify 
 the ICCC for the study, within 24 hours after 
becoming aware of an SAE or AESI.  Additional or follow-up information on an SAE or AESI 
must also be reported immediately.  This timeframe also applies to additional new information 
(follow-up) on previously forwarded SAEs or AESIs.  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.
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8.2.4
Information to be Provided by the Investigator for a Serious Adverse Event or 
Adverse Event of Special Interest
Information should be provided on the Serious Adverse Event 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 SAE/AESI
●
Relationship of the SAE/AESI to the study drug
●
Outcome of the SAE/AESI
8.2.5
Follow-up Information on a Serious Adverse Event or Adverse Event of Special 
Interest
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 investigator.  For all 
SAEs (including AESIs), the investigator is obligated to pursue and provide information to 
  In addition, an Investigator may be requested by 
to obtain specific information in 
an expedited manner.  This information may be more detailed than that captured on the AE form.  
In general, this will include a description of the SAE in sufficient detail to allow for a complete 
medical assessment of the case and independent determination of possible causality.  Information 
on other possible causes, such as concomitant medication and illnesses, must be provided.
Required Follow-up for Serious Adverse Events or Adverse Events of Special Interest
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/AESIs.  If an 
SAE/AESI continues after the follow-up visit, the patient must be followed until the event 
returns to baseline (or becomes less than CTCAE grade 1), or the investigator judges that it 
becomes stable, chronic, or irreversible. The medical monitor may specify a longer period of 
time if required to assure the safety of the patient.
Sponsor Responsibility for Expedited Safety Reports
ARIAD will notify investigators of all reportable SAEs/AESIs.  This notification will be in the 
form of an expedited safety report.  Upon receiving such notices, the investigator must review 
and retain the notice with other study-related documentation.
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The investigator and Institutional Review Board (IRB) will determine if the informed consent 
requires revision.  The investigator should also comply with IRB/EC procedures for reporting 
any other safety information.
Suspected serious adverse reactions and other significant safety issues reported from the
investigational product development program shall be reported to the relevant competent health 
authorities in all concerned countries according to local regulations (either as expedited safety 
reports and/or in aggregate reports), by the sponsor or its designated representative.
8.3
Other Safety Issues
8.3.1
Pregnancy
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.
Females and males 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 study drug, and again at treatment discontinuation.  A negative pregnancy test must be 
documented prior to administration of study drug.
Patients need to be in complete abstinence from sexual intercourse 4 weeks before the initial 
drug dosing or need to use at least one of the contraceptive methods suggested below. Other 
contraceptive options are to be discussed with the investigator, who should advise the patient 
how to use them properly.
- Hormonal contraception
- Intrauterine device
- Spermicide
- Barrier method of contraception
If a patient is confirmed pregnant during the study, study drug administration must be 
discontinued immediately.  The investigator must immediately notify the ARIAD medical 
monitor of this event and record the pregnancy on a Pregnancy Form.  Initial information 
regarding a pregnancy must be immediately forwarded to 
The investigator must immediately (within 24 hours of the investigator’s awareness) 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.
8.3.2
Overdose
In the event of an overdose, the sponsor should be contacted to discuss details of the overdose 
and formulate a clinical management plan.  No information regarding overdose of ponatinib in 
humans is available.  No specific antidotes exist for the treatment of ponatinib overdose.  In the 
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event of an accidental overdose, the patient should be monitored for possible signs of toxicity 
and general supportive care should be provided.
9
PLANNED STATISTICAL METHODS
9.1
General Considerations
Descriptive statistics and analyses will be provided for each dose level, and for patients 
combined across dose levels where applicable.
Data from patients in the phase II expansion phase will be summarized together with data from 
patients in the dose-escalation cohorts, as appropriate within disease group, with each disease 
type summarized separately (CP-CML, AP-CML, BP-CML, Ph+ALL), and with the advanced 
phases (AP-CML, BP-CML, and Ph+ALL) pooled.  Descriptive statistics (such as means, 
medians, standard deviations, ranges for continuous data, and percentages for categorical data) 
will be used to summarize patient characteristics, treatment administration/compliance, efficacy, 
safety, and PK parameters.  Data will also be displayed graphically, where appropriate.
A clinical study report will be written once primary endpoint data are available for all patients 
(approximately 6 months after the last patient is enrolled), which will be the basis of a regulatory 
submission. Further follow-up data will be summarized separately.
9.2
Analysis Populations
DLT Evaluable Population (phase I only): This population includes all patients who complete 
at least 75% of their planned doses during Cycle 1, unless missed doses are due to AEs.
Treated Population: This population includes all patients who have received at least 1 dose of 
study drug.
9.3
Study Endpoints
9.3.1
Primary Endpoints
Phase I
Safety of the recommended dose of oral ponatinib in Japanese patients with CML who are 
resistant or intolerant to dasatinib or nilotinib, or with Ph+ ALL who are resistant or intolerant to 
prior TKIs
Phase II
In the phase II component, the primary efficacy endpoints will be:
●
For CML patients in CP at study entry: MCyR, defined as CCyR or PCyR
o
CP patients in CCyR are not eligible for this study.
●
For CML patients in AP, BP, or Ph+ ALL at study entry: MaHR, defined as CHR or no 
evidence of leukemia (NEL)
o
AP, BP, and Ph+ ALL patients in MaHR are not eligible for this study.
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9.3.2
Secondary Endpoints
Secondary efficacy endpoints will be:
●
For CML patients in CP:
o
Hematologic responses: CHR
o
Cytogenetic responses: confirmed MCyR
o
Molecular responses: MMR
●
For CML patients in AP or BP or Ph+ ALL patients:
o
Cytogenetic responses: CCyR, PCyR, confirmed MCyR
o
Molecular responses: MMR
●
For all patients: time to response (TTR), duration of response, progression-free survival
(PFS), and OS
9.3.3
Exploratory Endpoints
Exploratory endpoints for all patients:
9.4
Determination of Sample Size
Six patients will be enrolled at each ponatinib dose level of 30 mg and 45 mg to allow for 
adequate assessment of tolerability and evidence of clinical activity.  The number of patients at 
each dose level is consistent with phase I dose-finding studies.
An additional 3 patients will be included at 15 mg for the purposes of PK sample collection 
during Cycle 1 in order to determine PK linearity in Japanese patients.  These patients will be 
allowed to dose-escalate to the recommended dose (at the discretion of the investigator) and will 
be assessed for efficacy and safety as phase II patients.
The patients who participated in phase I component will also be assessed for efficacy and safety 
together with patients enrolled in phase II component.
For phase II component, the needed patient number is calculated as follows: 
In preliminary data from the PACE phase II study of ponatinib in patients with CML or Ph+ 
ALL who were resistant or intolerant to nilotinib or dasatinib or who have a T315I mutation,  
MCyR rate was 47% (116/248) in CP-CML, MaHR rate was 67% (37/55) in AP-CML and 37% 
(33/89) in BP-CML and Ph+ALL, respectively. Based on this result, it is assumed 40% MCyR 
rate for CP-CML and 40% MaHR rate for AP-CML, BP-CML, and Ph+ALL.
Because effective therapy has not yet been established for these patients, it is anticipated that 
more than 10 % MCyR rate for CP-CML and more than 10% MaHR rate for AP-CML, BP-
CML, and Ph+ALL is considered clinically relevant.
It is assumed 40 % efficacy rate and 10% uninteresting rate for MCyR rate as well as MaHR rate 
for AP-CML, BP-CML, and Ph+ALL. Because the target population is very small, a 1-sided 5% 
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significance level is used for this sample-size calculation. Sixteen patients in each group (CP-
CML,AP-CML, BP-CML, and Ph＋ALL) are needed to retain 80% power for a testing using 
binomial distribution. Assuming 1 ineligible patient per group would be included, 17 patients per 
group (total 34 patients) are planned to be enrolled.
Because analysis of the primary endpoint is based on combined data from the phase I and phase 
II components, total patient enrollment in either phase should be sufficient to meet these target 
patient totals.
In addition, for these disease groups (and possibly other subgroups of interest) confidence 
intervals (CIs) will be calculated; in the event these contain estimates from the global pivotal 
phase II ponatinib PACE study (AP24534-10-201), a Bayesian analysis will be performed, using 
data from the PACE study as the prior distribution (more details to be provided in the Statistical 
Analysis Plan).  This will allow for more precise probabilistic statements about the combined 
study population in each disease group, and will also provide a method of inference if fewer than 
5 patients are enrolled in any of the groups.
9.5
Efficacy Analysis
All efficacy analyses will be performed separately by disease group: CP vs. AP vs. BP vs. 
Ph+ ALL, and will include all patients in the treated population.  Additionally, an analysis of the 
primary efficacy endpoint will be performed, pooling the AP, BP, and Ph+ALL populations.
The primary analysis will be performed after the last patient enrolled has completed six 28-day 
cycles of treatment, and will include all data collected at that time.
9.5.1
Definitions of Efficacy Endpoints
Primary efficacy endpoints for this study are defined as follows:
●
CP-CML: Major cytogenetic response, which is defined as CCyR or PCyR.  Patients 
entering the study already in PCyR must achieve a CCyR in order to be considered as 
achieving an MCyR.  The criteria for response are given in Appendix A.
●
AP-CML, BP-CML, Ph+ ALL: Major hematologic response, which is defined as CHR 
and NEL.  Major hematologic response will be confirmed by a peripheral blood complete 
blood count (CBC) and differential no earlier than 28 days after the response is observed.  
The criteria for response are given in Appendix A.
Secondary efficacy endpoints for this study 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 study in PCyR, confirmed MCyR will be defined as 
2 assessments of CCyR at least 28 days apart.
●
Major molecular response (as defined in Appendix 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 
Appendix A) are met, censored at the last date at which the criteria for response are met
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●
Progression-free survival, which is defined as the interval from the first dose of study 
treatment until the criteria for progression (as defined Appendix 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 study are defined as follows:
●
●
9.5.2
Primary Efficacy Endpoint Analysis
CP-CML Patients
The primary analysis of the primary efficacy endpoint of MCyR will be performed using a 
1-sided exact 95% CI for the MCyR rate and will be based on the total CP-CML patients 
enrolled in the dose-escalation phase (including an additional 3 patients dosed at 15 mg) and 
expansion phase.  Major cytogenetic response rate is defined as the proportion of patients who 
have achieved a CCyR or PCyR after initiation of study treatment.  Patients entering the study 
already in PCyR must achieve a CCyR in order to be considered a success for the MCyR rate.
AP-CML, BP-CML, Ph+ ALL Patients
Major hematologic response rate is defined as the proportion of patients who have achieved a 
confirmed CHR or NEL after initiation of study treatment.  The primary analysis of the primary 
efficacy endpoint of MaHR will be performed using a 1-sided exact 95% CI for MaHR rate and 
will be based on the total patients enrolled in the dose escalation phase (including an additional 3 
patients dosed at 15 mg) and expansion phase for combined data across these disease group (AP-
CML and BP-CML/Ph+ ALL).
9.5.2.1
Data Handling Rules for the Primary Analyses of the Primary Efficacy 
Endpoint
The key data handling rules for the primary efficacy analyses are as follows:
●
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 
Appendix A) are not available, the patient will be considered as not a success for that 
particular visit.
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9.5.2.2
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 study 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 1-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 a 1-sided exact 95% CI will be calculated.
●
Progression-free survival, OS, and TTR will be estimated using the Kaplan-Meier 
method.  The median duration of each endpoint and a 1-sided exact 95% CI will be 
calculated.
9.6
Safety Analysis
All patients receiving at least 1 dose of study drug will be considered evaluable for safety.  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 study.  Similar analyses will be 
performed on AESIs.  Listings of laboratory test results and any imaging studies (including 
ECGs) will also be generated, and descriptive statistics summarizing changes in these 
assessments over time will be presented.
9.7
Interim Analysis
No interim analysis is planned for this study.
9.8
Protocol Deviations/Violations
To be protocol-compliant, a patient must not have any major protocol deviations during the study 
period.  Protocol deviations will be identified prior to database lock and will be listed by 
treatment group in the clinical study report.
10
QUALITY CONTROL AND 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, Clinical Investigator's Brochure, eCRFs and instructions for their 
completion, procedure for obtaining informed consent, and 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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10.1
Investigators and Study Administrative Structure
A list of investigators and study administrative structure are shown in separate pamphlets.
10.2
Study Monitoring
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 eCRFs and the dispensing and inventory record 
(adequate time and space for these visits should be allocated by the investigator)
●
Compliance with regulations (verification will require comparison of source documents 
to the eCRFs)
11
ETHICAL CONDUCT OF THE STUDY
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 GCP guidelines and the applicable 
regulatory requirements.
11.1
Institutional Review Board 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 should also 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 contractual agreement has been signed by the 
sponsor and the clinical site.
11.2
Patient Information and 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 the site’s proposed informed consent document should be submitted to the sponsor for 
review and comment before submission to the site’s 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 the informed consent
specified in the regulations.  Some regulations may require the disclosure of additional 
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information to the patient and/or inclusion of additional information in an informed consent 
document.
Nothing in 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.
11.3
Patient Confidentiality
All unpublished information that the sponsor gives to the investigator shall be kept confidential 
and shall not be published or disclosed to a third party without the prior written consent of the 
sponsor. 
12
DATA HANDLING AND RECORD KEEPING
12.1
Case Report Forms and Study Records
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 study.  All 
pertinent data records are to be submitted to the sponsor during and/or at completion or 
termination of the study.
12.2
Access to Source Documentation
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 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.
12.3
Retention of Data
Trial documents must be retained according to JGCP Items 26 and 41.  

The sponsor must maintain trial documents until a longer period of the following 
dates: a day of approval for manufacture and sales, 3 years after trial discontinuation, 
or 3 years after the study completion.  The trial documents include protocol, 
contracts, clinical study reports, eCRFs, monitoring reports, audit reports, and trial 
data as well as study drug inventory records with information regarding 
manufacture date, manufacture procedures, manufactured amount, quality of safety, 
distribution to the site(s), return, and destruction of the study drug.  If re-inspection 
for the study drug is required after approval for manufacture and sales, the 
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documents that contain the information about efficacy and safety of the drug must 
be collected and maintained for a longer period of the following points: 5 years after 
approval or the completion date of the re-inspection.

The head of the site must maintain trial documents until a longer period of the 
following dates: a day of approval for manufacture and sales, 3 years after trial 
discontinuation, or 3 years after the study completion.  The trial documents include
protocol, contracts, clinical study reports, eCRFs, monitoring reports, audit reports, 
and trial data as well as study drug inventory records with the information regarding 
manufacture date, manufacture procedures, manufactured amount, quality of safety, 
distribution to the site(s), return, and destruction of the study drug. 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.
12.4
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.
13
PUBLICATION AND DISCLOSURE POLICY
The investigator must notify the IRB/EC of the conclusion of the clinical study.  This report 
should be made within 3 months of completion or termination of the study.  The final report sent 
to the IRB/EC is also to be sent to the sponsor and, along with the completed eCRFs, constitutes 
the final summary to the sponsor, thereby fulfilling the regulatory responsibility.
Section 801 of the FDA Amendments Act mandates registration with ClinicalTrials.gov of 
certain clinical trials of drugs (including biological products) and medical devices subject to 
FDA regulations for any disease or condition.  The International Committee of Medical Journal 
Editors (ICMJE) requires trial registration as a condition for publication of research results 
generated by a clinical trial (http://www.icmje.org).
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14
REFERENCES
Apperley JF, Cortes JE, Kim D-W, et al. Desatinib in the treatment of Chronic Myeloid 
Leukemia in Accelerated Phase After Imatinib Failure: The START Trial. Clin Oncol.
2009;27:3472-3479.
Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger 
M, Gratwohl A, Guilhot F, Hochhaus A, Horowitz M, Hughes T, Kantarjian H, Larson R, 
Radich J, Simonsson B, Silver RT, Goldman J, Hehlmann R; European LeukemiaNet. Chronic 
myeloid leukemia: an update of concepts and management recommendations of European 
LeukemiaNet. J Clin Oncol. 2009;27(35):6041-6051.
Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML 
treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the 
ATP phosphate-binding loop (P-loop) are associated with a poor prognosis [published online 
ahead of print March 6, 2003]. Blood. 2003;102(1):276-283. doi:10.1182/blood-2002-09-2896.
Cortes J, Hochhaus A, Hughes T, Kantarjian H. Front-line and salvage therapies with tyrosine 
kinase inhibitors and other treatments in chronic myeloid leukemia [published online ahead of 
print January 10, 2011]. J Clin Oncol. 2011;29(5):524-531. doi:10.1200/JCO.2010.31.3619.
Deininger MWN, Goldman J, Melo J. The Molecular Biology of Chronic Myeloid Leukemia. 
Blood. 2000;96:3343-3356.
Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack: a 
scientific statement for healthcare professionals from the American Heart Association/American 
Stroke Council. Stroke. 2009; 40:2276-2293.
Jabbour E, Kantarjian H, Jones D, et al. Frequency and clinical significance of BCR-ABL 
mutations in patients with chronic myeloid leukemia treated with imatinib mesylate [published 
online ahead of print July 20, 2006]. Leukemia. 2006;20(10):1767-1773. 
doi:10.1038/sj.leu.2404318.
Jones D, Kamel-Reid S, Bahler D, et al. Laboratory practice guidelines for detecting and 
reporting BCR-ABL drug resistance mutations in chronic myelogenous leukemia and acute 
lymphoblastic leukemia: a report of the Association for Molecular Pathology. J Mol Diagn. 
2009;11(1):4-11. doi:10.2353/jmoldx.2009.080095.
Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia 
chromosome-positive ALL. N Engl J Med. 2006;354:2542-2551.
Kantarjian H, O’Brien S, Talpaz M, et al. Outcome of patients with Philadelphia 
chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure. Cancer. 
2007;109:1556-1560.
Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed 
chronic-phase chronic myeloid leukemia. N Engl J Med. 2010; 362(24):2260-2270.
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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;348(11):994-1004.
O’Hare T, Eide CA, Deininger MWM. BCR-ABL kinase domain mutations, drug resistance and 
the road to ac of chronic myeloid leukemia. Blood. 2007;110:2242-2249.
O’Hare T, Deininger MWN, Eide CA, et al. Targeting the BCR-ABL signaling pathway in 
therapy-resistant Philadelphia chromosome-positive leukemia [published online ahead of print 
November 22, 2010]. Clin Cancer Res. 2011;17(2):212-221. 
doi:10.1158/1078-0432.CCR-09-3314.
Pinilla-Ibarz J, Bello C. Modern approaches to treating chronic myelogenous leukemia. Curr 
Oncol Rep. 2008;10(5):365-371.
Talpaz M, Shah N, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia 
chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2541.
Terasawa T, Dahabreh I, Trikalinos TA. BCR-ABL mutation testing to predict response to 
tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Version 2. PLoSCurr. 2010 
December 15 [revised 2011 January 28].
Thygesen K, Alpert JS, Jaffe AS. Third Universal Definition of Myocardial Infarction. 
Circulation. 2012;126:2020-2035.
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15
APPENDICES
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APPENDIX 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 7 (Table 5 and Table 6) 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)
vii.
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)
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viii.
No evidence of Leukemia (NEL)
a)
WBC ≤institutional upper limit of normal
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) clinical practice 
guidelines (accessed February 2007).
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 two 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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APPENDIX B
Prohibited Drugs Affecting the QT Interval
The list of drugs that can be associated with Torsades de Pointes or prolonged QT interval can be 
found online at 
www.azcert.org/medical-pros/drug-lists/bycategory.cfm.
This online site does not include all prohibited medications and should be used as a guideline.  
Refer to the prescribing information to determine if a particular medication can be associated 
with Torsades de Pointes or prolonged QT interval.
Three categories of drugs are listed on this website.  Concomitant use of drugs in the first 
category (Drugs with Risk of Torsades de Pointes) is prohibited.  Agents in the two categories of 
lesser risk (Drugs with Possible Risk of Torsades de Pointes; and Drugs with Conditional Risk of 
Torsades de Pointes) should be avoided.
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APPENDIX C
Medications that are Strong Inhibitors or Inducers of CYP3A4/5/7
The list of drugs that are strong inhibitors or inducers of CYP3A4/5/7, and thereby concomitant 
administration with ponatinib could result in clinically relevant drug-drug interactions, can be 
found online at 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm116617.htm
Drugs listed should be avoided if possible.  This online site should be used as a guideline; refer 
to the prescribing information to determine if a particular medication is a strong CYP3A4/5/7
inhibitor or inducer.
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APPENDIX D
National Cancer Institute Common Terminology Criteria for Adverse 
Events
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:
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
This version of the CTCAE is compatible at the AE term level where each CTCAE term is a 
Medical Dictionary for Regulatory Activities (MedDRA) terminology Lowest Level Term 
(LLT).  CTCAE version 4.0 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).
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SAP_001.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 Phase I/II Multi-center, Open-label Study of Ponatinib in Japanese Patients with 
Chronic Myeloid Leukemia (CML) who have failed Dasatinib or Nilotinib or Ph+ Acute 
Lymphoblastic Leukemia (ALL) who have failed Prior Tyrosine Kinase Inhibitors (TKIs)
NCT Number: NCT01667133
SAP Approve Date: 04 March 2015
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.


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Statistical Analysis Plan
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Statistical Analysis Plan
PROTOCOL TITLE: A Phase I/II Multi-center, Open-label Study of Ponatinib in Japanese 
Patients with Chronic Myeloid Leukemia (CML) who have failed Dasatinib or Nilotinib or 
Ph+ Acute Lymphoblastic Leukemia (ALL) who have failed Prior Tyrosine Kinase 
Inhibitors (TKIs)
PROTOCOL NUMBER:   AP24534-11-106
PROTOCOL DATE: 
SAP VERSION:
Version 1.0
DATE:
04 March 2015
SPONSOR:
  
ARIAD Pharmaceuticals, Inc.
26 Landsdowne Street
Cambridge, MA 02139-4234
Telephone: +1 (617) 494-0400
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Statistical Analysis Plan
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TABLE OF CONTENTS
1
INTRODUCTION.........................................................................................6
1.1
Statistical Analysis Plan....................................................................6
1.2
Study Objectives................................................................................6
1.2.1
Primary Objectives................................................................6
1.2.2
Secondary Objectives ............................................................6
1.3
Modifications from the Protocol ......................................................6
2
SOFTWARE AND DICTIONARIES..........................................................7
2.1
Statistical Analysis and Tabulation Software.................................7
2.2
Dictionaries ........................................................................................7
3
DEFINITION OF TERMS ...........................................................................7
3.1
Patient Groups...................................................................................7
3.2
Efficacy Assessment...........................................................................8
3.2.1
Primary Endpoints................................................................8
3.2.2
Secondary Endpoints.............................................................9
3.2.3
Exploratory Endpoints..........................................................9
3.3
Safety Assessment..............................................................................9
3.3.1
Adverse Events/Drug Related Adverse Events...................9
3.3.2
Laboratory Test Results and Vital Signs...........................10
3.3.3
Other Safety Assessment Endpoints..................................12
4
CASE AND DATA HANDLING ...............................................................13
4.1
Case and Data Handling .................................................................13
4.2
The Definition of Baseline...............................................................13
4.3
Handling of Missing Values............................................................13
4.3.1
For Evaluation of CHR/MaHR..........................................13
4.3.2
A Complete Blood Count (CBC) with WBC 
Differential:..........................................................................13
4.3.3
Data Handing for PK Data:................................................14
4.3.4
The Data Handling Rule for Evaluation of MCyR, 
MaHR, Confirmed MCyR, CHR and MMR:...................14
4.3.5
2.The Handling of Missing or Invalid Baseline Values
for MCyR: ............................................................................14
4.3.6
The Handling of Missing or Invalid Post-baseline 
Values for MCyR:................................................................15
4.3.7
The Handling Rule for Baseline MaHR Status: ...............15
4.3.8
The Data Handling Rule for MaHR:.................................15
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Statistical Analysis Plan
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4.4
Handling of Safety Data..................................................................16
4.4.1
Handling of Adverse Events ...............................................16
4.4.2
Handling of Other Safety Data...........................................19
4.5
Handling of Longitudinal Data ......................................................19
4.5.1
Calculation Method of Number of Days............................19
4.5.2
Time Windows .....................................................................19
5
STATISTICAL ANALYSIS.......................................................................20
5.1
Significance Level, Confidence Interval........................................20
5.2
Multiplicity.......................................................................................20
5.3
Analysis Methods.............................................................................20
5.3.1
Descriptive Statistics ...........................................................20
5.3.2
Incidence Rates of Treatment-Emergent Adverse 
Events/Drug Related Adverse Events................................20
5.4
Rounding Digits ...............................................................................20
5.4.1
Displaying of Descriptive Statistics....................................20
5.4.2
Rounding Digits for Percentages........................................20
6
SUBJECT DISPOSITION..........................................................................21
6.1
Flowchart of Subject Disposition ...................................................21
6.2
Subject Disposition..........................................................................22
7
STUDY POPULATIONS, DEMOGRAPHICS AND OTHER 
BASELINE CHARACTERISTICS, AND STUDY DRUG
ADMINISTRATION...................................................................................22
7.1
Demographics and Other Baseline Characteristics......................22
7.2
Drug Study Administration............................................................25
8
EFFICACY ASSESSMENT.......................................................................25
8.1
Primary Endpoints..........................................................................25
8.1.1
Primary Analysis of Primary Endpoints...........................25
8.1.2
Sensitivity Analysis of Primary Endpoints........................26
8.1.3
Additional Analysis of Primary Endpoints.......................26
8.1.4
Bayesian Analysis ................................................................27
8.2
Secondary Endpoints.......................................................................27
8.2.1
Confirmed MCyR (cCCyR or cPCyR)..............................27
8.2.2
Confirmed CHR...................................................................27
8.2.3
Major Molecular Response.................................................28
8.2.4
Progression-Free Survival ..................................................29
8.2.5
Overall Survival...................................................................31
8.2.6
Time to Response.................................................................31
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8.3
Covariate Adjustments ...................................................................32
8.4
Multicenter Study............................................................................32
8.5
8.5 Subgroup Analysis.....................................................................32
8.6
Stratified Analysis ...........................................................................33
8.7
Interim Analysis...............................................................................33
9
PK ASSESSMENT......................................................................................33
9.1
PK Analysis ......................................................................................33
9.1.1
Ponatinib Concentration at Each Time Point...................33
9.1.2
PK Parameters Estimated from PK Profile......................33
9.1.3
Dose-Linearity Among Dose Levels...................................34
9.1.4
Comparison Between this Study and Study 
Conducted in US(USA101). ................................................34
9.1.5
Box and whisker plots of the steady-state, dose-
normalized AUC(0-24h) and Cmax..........................................34
9.1.6
PK Listings...........................................................................34
10
SAFETY ASSESSMENT............................................................................35
10.1
Treatment-Emergent Adverse Events/ Drug Related Adverse 
Events................................................................................................35
10.1.1
Numbers and Incidence Rate of Patients with 
Treatment-emergent Adverse Events................................35
10.1.2
Numbers and Incidence Rate of Patients with 
Treatment-emergent Adverse Events by MedDRA 
Code ......................................................................................35
10.1.3
Numbers and Incidence Rate of Patients with 
Treatment-Emergent Adverse Events According to 
Severity by MedDRA Code.................................................35
10.2
Assessments of Laboratory Test Results, Vital Signs, Left 
Ventricular Ejection Fraction, and QTcF Interval......................36
10.2.1
Descriptive Statistics of Transition of Laboratory Test 
(Haematology) Results ........................................................36
10.2.2
Descriptive Statistics of Transition of Laboratory Test 
(Chemistry) Results.............................................................36
10.2.3
Descriptive Statistics of Vital Signs....................................36
10.2.4
Descriptive Statistics of Left Ventricular Ejection 
Fraction (LVEF) ..................................................................37
10.2.5
Descriptive Statistics of QTcF Interval .............................37
11
CHANGE HISTORY..................................................................................38
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TABLE OF TABLES
Table 1 
Software and Versions Used in this Study ...........................................7
Table 2
Dictionaries Used in this Study .............................................................7
Table 3
Definition of Patient Groups .................................................................8
Table 4
Definitions of AE and Causal Relationship to the Study Drug........10
Table 5
Laboratory Test Results and Vital Signs Evaluated in This Study.11
Table 6
Electrocardiogram ...............................................................................12
Table 7
Definitions of analysis populations .....................................................13
Table 8
Determination of Cytogenetic Response if Examined Metaphases 
are Fewer Than 20................................................................................15
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1
INTRODUCTION
1.1
Statistical Analysis Plan
This document is the Statistical Analysis Plan (SAP) containing definitions and descriptions 
of statistical analysis procedures for “A phase I/II multi-center, open-label study of ponatinib 
in Japanese patients with chronic myeloid leukemia (CML) who have failed dasatinib or 
nilotinib or Ph+ acute lymphoblastic leukemia (ALL) who have failed prior tyrosine kinase 
inhibitors (TKIs) (protocol number: AP24534-11-106)”.
1.2
Study Objectives
1.2.1
Primary Objectives

The primary objective of the phase I component is to examine the safety of the 
recommended dose of oral ponatinib in Japanese patients with CML, who are resistant 
or intolerant to dasatinib or nilotinib or Ph+ ALL, who are resistant or intolerant to prior 
TKIs. 

The primary objective of the phase II component is to confirm the anti-leukemic 
activity of ponatinib in Japanese patients with CML, who are resistant or intolerant to 
dasatinib or nilotinib or Ph+ ALL, who are resistant or intolerant to prior TKIs as 
evidenced by clinical responses, molecular responses, and clinical outcomes.
1.2.2
Secondary Objectives
The secondary objectives of this study are:

To examine the PK of ponatinib in Japanese patients with CML who are resistant or 
intolerant to dasatinib or nilotinib or Ph+ ALL, who are resistant or intolerant to prior 
TKIs.

To describe potential pharmacogenomic markers of ponatinib anti-leukemic activity and 
to characterize the molecular status of patients.
1.3
Modifications from the Protocol
N/A
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2
SOFTWARE AND DICTIONARIES
2.1
Statistical Analysis and Tabulation Software
Table 1
Software and Versions Used in this Study
Software and Versions
OS
Microsoft Windows XP
Statistical Analysis Software
SAS V.9.2
Tabulation Software
Microsoft Word and Excel 2010 
WinNonlin
WinNonlin Ver. 6.1 or later
2.2
Dictionaries
Table 2
Dictionaries Used in this Study
Category
Dictionary
Remarks
Adverse Events
MedDRA version 17 or the 
latest Version 
For adverse event summary tables, System 
Organ Class and preferred term will be applied, 
and the version of MedDRA will be provided. 
Unless otherwise specified, output tables will be 
sorted by descending number of subjects and 
alphabetical order for preferred terms. 
Name of Medication 
(Concomitant Drugs)
WHODDB3E Sept 2011
Use the PN codes.
Laboratory Data
NCI CTCAE Version 4.0
For some laboratory tests, grade will be ranked 
according to CTCAE.
3
DEFINITION OF TERMS
3.1
Patient Groups
For the Phase I portion, analysis for the phase II dose determination is basically performed by 
each initial dose level (30 mg and 45 mg).  For the Phase II portion, efficacy and safety 
analyses include all patients treated in this study using data collected in both portions. 
Analysis is basically performed for each disease group (CP-CML, AP-CML, BP-CML, and 
Ph+ ALL) and a pooled group of the advanced phases (AP-CML, BP-CML, and Ph+ ALL). 
The primary analysis of the primary endpoints and selected secondary endpoints is also 
performed for dose cohorts formed according to initial dose: 30 mg, 15/45 mg. The patient 
groups are defined in the Table 3. 
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Table 3
Definition of Patient Groups
Phase 
Definitions
Phase I Portion
- 30 mg cohort: Patients initially treated with 30 mg ponatinib 
- 45 mg cohort: Patients initially treated with 45 mg ponatinib 
Phase II Portion
By Disease 
- CP-CML: Treated patients with CP-CML (data in the phase 1 portion is included)
- AP-CML: Treated patients with AP-CML (data in the phase 1 portion is included)
- BP-CML: Treated patients with BP-CML (data in the phase 1 portion is included)
- Ph+ ALL: Treated patients with Ph+ ALL (data in the phase 1 portion is included)
- Pooled AP-CML, BP-CML, and Ph+ ALL group: Treated patients with AP-CML, BP-
CML or Ph+ ALL (data in the phase 1 portion is included)
- All treated patients (data in the phase 1 portion is included)
Phase II Portion
By Initial Dose 
- 30 mg: Patients initially treated with 30 mg ponatinib (data in the phase 1 portion is 
included)
- 15/45 mg: Patients initially treated with 15 mg or 45 mg ponatinib (data in the phase 1 
portion is included)
- All treated patients (data in the phase 1 portion is included)
3.2
Efficacy Assessment
3.2.1
Primary Endpoints
Phase I:  
Safety of the recommended dose of oral ponatinib in Japanese patients with CML who are 
resistant or intolerant to dasatinib or nilotinib or Ph+ ALL, who are resistant or intolerant to 
prior TKIs.
Phase II:  
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. Patients entering the trial already in PCyR must achieve 
a CCyR in order to be considered as achieving an MCyR. The criteria for response are 
provided in Appendix A of the protocol.
For CML patients in AP, BP, or Ph+ ALL at study entry: Major hematologic response 
(MaHR), defined as complete hematologic response (CHR) or no evidence of leukemia 
(NEL). AP, BP, and Ph+ ALL patients in MaHR are not eligible for this study. 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 
Appendix A of the protocol.
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3.2.2
Secondary Endpoints
For CML patients in CP:
!
Hematologic responses: Complete hematologic response (CHR). The criteria for CHR 
are provided in Appendix A of the protocol.
!
Cytogenetic responses: 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.
!
Molecular responses: Major molecular response (MMR). The criteria for MMR are 
provided in Appendix A of the protocol.
For CML patients in AP, BP, or Ph+ ALL patients:
!
Cytogenetic responses: CCyR, PCyR, confirmed MCyR. Confirmed MCyR is defined 
as 2 assessments of CCyR or PCyR at least 28 days apart. For patients entering the trial 
in PCyR, confirmed MCyR will be defined as 2 assessments of CCyR at least 28 days 
apart.
!
Molecular responses: MMR. The criteria for MMR are provided in Appendix A of the 
protocol.
For all patients: 
Time to response, duration of response, progression-free survival, and overall survival.
3.2.3
Exploratory Endpoints
!
!
3.3
Safety Assessment
3.3.1
Adverse Events/Drug Related Adverse Events
CCI
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Table 4
Definitions of AE and Causal Relationship to the Study Drug
Term
Definition
AE (Adverse Event)
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 to the medicinal product.  Any worsening of a 
preexisting condition, which is temporally associated with the use of the study 
drug (ie, occurs after the first dose of study drug), is also an AE.
Drug Related Adverse Event
The Investigator will use medical consideration and use the following 
categories of causality to determine the relatedness of an AE with the study 
drug based on the following definitions: 

Definitely Not Related (not drug related)

Probably Not Related (not drug related)

Possibly Related (drug related)

Probably Related (drug related)

Definitely Related (drug related)
“Possibly Related”, “Probably Related”, “Definitely Related” AEs are defined 
as Drug Related AEs. 
3.3.2
Laboratory Test Results and Vital Signs
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Table 5
Laboratory Test Results and Vital Signs Evaluated in This Study
Classification
Examination Component
Unit
Rounding Digit
Hematology
White Blood Cell count
x10^9/L
0.01
Lymphocyte 
%
0.1
Monocyte 
%
0.1
Eosinophil 
%
0.1
Basophil 
%
0.1
Neutrophil 
%
0.1
Neutrophil count
x10^9/L
0.1
Lymphocyte count
x10^9/L
0.1
Monocyte count
x10^9/L
0.1
Eosinophil count
x10^9/L
0.1
Basophil count
x10^9/L
0.1
Hemoglobin
g/L
1
Hematocrit
%
0.001
Platelet count
x10^9/L
1
Absolute neutrophil count (ANC)
x10^9/L
0.001
Metamyelocytes
%
0.1
Promyelocytes
%
1
Myelocytes
%
0.01
Blasts
% 
0.1
Bands
%
0.1
Atypical Lymphocytes
%
0.1
Metamyelocytes count
x10^9/L
0.1
Promyelocytes count 
x10^9/L
0.1
Myelocytes count
x10^9/L
0.1
Blasts count
x10^9/L
0.1
Bands count
x10^9/L
0.1
Atypical Lymphocytes count
x10^9/L
0.1
Chemistry
Sodium
mmol/L
1
Potassium
mmol/L
0.1
chloride
mmol/L
1
bicarbonate
mmol/L
1
BUN
mmol/L
0.1
Glucose
mmol/L
0.1
Albumin
g/L
0.1
Creatinine
umol/L
1
Total bilirubin (direct and indirect)
umol/L
1
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Classification
Examination Component
Unit
Rounding Digit
AST (SGOT)
U/L
1
ALT (SGPT)
U/L
1
Alkaline Phosphatase
U/L
1
Magnesium
mmol/L
0.01
Phosphorous
mmol/L
0.01
Calcium
mmol/L
0.01
Amylase
U/L
1
Lipase
U/L
1
Triglycerides
mmol/L
0.01
Prothrombin time (PT)
seconds
0.1
Partial Thromboplastin Time (PTT)
seconds
0.1
Thyroid Function Tests
Free T3
pmol/L
0.01
Free T4
pmol/L
0.1
Thyroid-stimulating Hormone (TSH)
mIU/L
0.001
Vital Signs
Temperature
degrees 
0.1
Pulse Rate
beats/min
1
Respiratory rate
breaths/min
1
Systolic Blood Pressure
mmHg
1
Diastolic Blood Pressure
mmHg
1
Height
cm
0.1
Weight
kg
0.1
3.3.3
Other Safety Assessment Endpoints
Table 6
Electrocardiogram
Classification
Unit
Rounding Digit
Heart Rate
bpm
1
PR
ms
1
QRS
ms
1
RR
ms
1
QTc
ms
1
QTcF
ms
1
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4
CASE AND DATA HANDLING
4.1
Case and Data Handling
The criteria listed below will be fulfilled for the handling of each case. 
Table 7
Definitions of analysis populations
Analysis Population
Definition
Consented Patients
All Patients who gave informed consent.
Treated Population
This population includes all patients who have received at least 1 dose of 
study drug. The primary analysis of the primary endpoints and all the 
secondary endpoints will be performed using the treated population.
Per-protocol (Cytogenetic) 
Population
This population includes all CP-CML patients in the treated population 
who have a baseline cytogenetic assessment with at least 20 metaphases 
examined excluding those with 0/20 Ph+ metaphases at baseline. If at 
least one treated CP-CML patient does not meet the criteria for per-
protocol (cytogenetic) population, a secondary analysis of the primary 
endpoint will be performed using the per-protocol (cytogenetic) 
population. 
Per-protocol (Hematologic) 
Population
This population includes all patients in the treated population in AP-
CML, BP-CML, and Ph+ ALL Patients who have a baseline BM 
assessment for which the percentage of BM blasts can be determined,
excluding those with MaHR at baseline. If at least one treated AP-CML, 
BP-CML, or Ph+ ALL patient does not meet the criteria for per-protocol 
(hematologic) population, a secondary analysis of MaHR will be 
performed using the per-protocol (hematologic) population. 
Dose-Limiting Toxicities (DLT) 
Evaluable Population (phase I 
only)
This population includes all patients who complete at least 75% of their 
planned doses during Cycle 1, unless missed doses are due to AEs. This 
population will be used for DLT assessment and the determination of the 
maximum tolerated dose.
PK Population
Patients who have at least one PK measurement.
4.2
The Definition of Baseline
The last non-missing valid value collected before and on the date of the first dose of study 
treatment will be defined as baseline.
4.3
Handling of Missing Values
4.3.1
For Evaluation of CHR/MaHR
For evaluation of CHR/MaHR, missing bone marrow blasts or promyelocytes will be 
imputed as zero if one of the two values is present.
4.3.2
A Complete Blood Count (CBC) with WBC Differential:
A CBC with WBC differential is required for the determination of MaHR in AP-CML, BP-
CML, and Ph+ ALL patients, and Complete Hematologic Response (CHR) in CP-CML 
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patients. To derive the response status, if the sum of the percentages of the reported cell 
types of the differential is at least 98%, all other cell types not reported in the differential will 
be assumed to be 0.
4.3.3
Data Handing for PK Data:

Concentrations below the limit of quantification, e.g., <0.500
o
Concentrations <0.500 will be imputed as 0 if occurring before Tmax.
o
Concentration <0.500 will be imputed as 0.25 if occurring right after Tmax.
o
Subsequent concentrations <0.500 after Tmax will be imputed as 0.

Missing data:
Any observations with missing or time values for PK data will be omitted from the 
analysis.

Data after dose adjustment:
o
If a patient had any dose adjustments, including dose interruption and/or reduction,
within 7 days of Cycle 2 Day 1 (during Cycle 1 Day 23 to Cycle 2 Day 1), this 
patient’s data will be omitted from the calculations for the dose cohort to which the 
patient was initially assigned.
o
If a patient in 45 mg cohort had a dose reduction to 30 mg within 7 days of Cycle 2 
Day 1 (during Cycle 1 Day 23 to Cycle 2 Day 1), this patient’s data will be used 
for the calculations for 30 mg cohort along with the data from patients in 30 mg 
cohort. Handling of Efficacy Data.
4.3.4
The Data Handling Rule for Evaluation of MCyR, MaHR, Confirmed MCyR, 
CHR and MMR:

For a given visit, if all of the data required to support an assessment of response (see 
Protocol Appendix A) are not available, the patient will be considered as not a success 
for that particular visit.
4.3.5
2.The Handling of Missing or Invalid Baseline Values for MCyR:

Patients with no Ph+ metaphase out of at least 20 metaphase cells at baseline (meeting 
the criteria for CCyR) will be conservatively analyzed as non-responders in the analysis 
of the treated population, regardless of whether they maintained response. They will be 
excluded from the per-protocol (cytogenetic) population.

Patients with fewer than 20 metaphases examined at baseline will be conservatively 
analyzed as non-responders in the analysis of the treated population, regardless of post-
baseline response. These patients will be excluded from the per-protocol (Cytogenetic) 
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population. Patients with missing baseline cytogenetic assessments will be analyzed as 
non-responders.
4.3.6
The Handling of Missing or Invalid Post-baseline Values for MCyR:
At any given cytogenetic assessment, if fewer than 20 metaphases are examined, the 
determination of PCyR will be based on the handling rules specified in Table 8.
Table 8
Determination of Cytogenetic Response if Examined Metaphases are 
Fewer Than 20
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.
4.3.7
The Handling Rule for Baseline MaHR Status:
Eligibility criteria require that AP-CML, BP-CML, and Ph+ ALL patients not enter the trial 
already in MaHR. Two of the three assessments required for the determination of MaHR, 
CBC with differential and a physical examination (including assessment of extra-medullary 
disease) are performed at screening and on Cycle 1 Day 1. The last valid assessment will be 
used as the baseline assessment.
4.3.8
The Data Handling Rule for MaHR:

Patients, who meet the criteria for MaHR at baseline, will be conservatively analyzed as 
non-responders for the analysis of the treated population and will be excluded from the 
per-protocol (hematologic) population.

Patients, for whom bone marrow blasts are not determined at baseline, will be 
conservatively analyzed as non-responders in the analysis of the treated population, 
regardless of post-baseline response. These patients will be excluded from the per-
protocol (hematologic) population.  

A bone marrow aspirate is required for a patient to be considered as meeting the criteria 
for MaHR. Missing bone marrow blasts or promyelocytes will be imputed as zero if 
one of the two values is present. (This rule is also described in “4.3 Handling of 
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missing values”.) MaHR will be confirmed by a peripheral blood CBC and differential 
no earlier than 28 days after the initial assessment of MaHR.

The assessments for bone marrow aspirate, CBC with differential, and physical 
examination need be performed within 14 days of one another to assess whether a 
patient meets the criteria for MaHR or not. 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 will be confirmed by a peripheral blood CBC and 
differential no earlier than 28 days later.
4.4
Handling of Safety Data
4.4.1
Handling of Adverse Events
Treatment-emergent AEs are the AEs that start on or after the first dose date and the AEs 
whose partially available start date cannot rule out the possibility of starting on or after the 
first dose date.
All AEs reported in the database during the on-study period will be included in the listing of 
AEs and each AE will be flagged as treatment-emergent or not.
Treatment-Emergent Adverse Event Flag

Sites may “split” AEs that are ongoing as of first dose date into two records: one that 
ends as of first dose date and one that begins on first dose date. Therefore in some 
cases, what may at first appear as an AE that begins on first dose date is really a 
continuation of an AE that began prior to first dose date. If all of the following criteria 
are met for any two AE records then the two records should be considered as one event 
for purposes of assessing a treatment-emergent adverse event, as they were present prior 
to treatment and did not worsen in severity or relatedness:
o
The preferred term of the first AE = the preferred term of the second AE.
o
The start date of the first AE is before the date of first dose.
o
The end date of the first AE is one day before the date of first dose or equal to the 
date of first dose.
o
The start date of the second AE = the date of first dose.
o
The severity of the second AE ≤ the severity of the first AE.
o
The relatedness of both the first and the second AEs is “Not Related”.

After determining which records should be treated as a single event, the treatment-
emergent flag can be determined as follows:
o
All AEs with an onset date on or after the first dose date and no later than 30 days 
after the last dose date.
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o
In the case of missing onset date, impute using the rules defined in the following 
Section 3 then determine if imputed date is on or after first dose date. 
Treatment-Related Adverse Event Flag

All AEs for which relationship to study treatment is classified as “Possibly Related”, 
“Probably Related”, or “Definitely Related”

If relationship to study treatment is missing, then the relationship will be imputed as 
treatment related.

Imputations are for the purposes of aggregated summaries of AEs. Listings of 
individual AEs should not display the imputed relationship.
Imputation Rules for Missing Onset and Resolution Date 
In general the imputation should be conservative, such that onset dates should be imputed to 
be as early as possible and resolution dates will be imputed to be as late as possible. Impute 
resolution date first and then impute onset date using imputed resolution date.
Resolution Date

If day is missing but month and year are non-missing (YYYY-MM-UU), impute as the 
earliest of:
o
Last day of the month (28, 29, 30, or 31, depending on in which month the adverse 
event resolved)
o
Last contact date for patients who did not start follow-up or discontinued follow-up 
due to a reason other than death
o
Data cut-off date
o
Death date

If day and month are missing (YYYY-UU-UU), impute as the earliest of:
o
December 31 (YYYY-12-31)
o
Last contact date for patients who did not start follow-up or discontinued follow-up 
due to a reason other than death
o
Data cut-off date
o
Death date

If date is completely missing (i.e. AE is ongoing):
o
For AEs meeting the criteria for seriousness or of special interest, impute as 
earliest of:
-
Data cut-off date 
-
Death date
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o
For the other AEs, impute as earliest of:
-
Data cut-off date
-
Last contact date for patients who did not start follow-up or discontinued 
follow-up due to a reason other than death
-
Treatment discontinuation date + 30 days
-
Death date
Onset Date
If day is missing but month and year are non-missing (YYYY-MM-UU), impute as follows:

If year and month are the same as year and month of first dose date:
o
If resolution date (or imputed resolution date) is on or after first dose date, impute 
as first dose date.
o
If resolution date (or imputed resolution date) is prior to first dose date, impute as 
latest of:
-
First day of month
-
Informed consent date

If year is the same as year of first dose date and month is after month of first dose date, 
impute as first date of month.

If year is the same as year of first dose date and month is before month of first dose 
date, impute as latest of:
o
First day of month
o
Informed consent date

If year is after year of first dose date, impute as first day of month.

If year is before year of first dose date, impute as latest of:
o
First day of month
o
Informed consent date
If day and month are missing and year is non-missing (UU-UUU-YYYY), impute as follows:

If year is the same as year of first dose date:
o
If resolution date (or imputed resolution date) is on or after first dose date, impute 
as first dose date.
o
If resolution date (or imputed resolution date) is prior to first dose date, impute as 
latest of:
-
First day of month
-
Informed consent date

If year is after year of first dose date, impute as January 1 (YYYY-01-01).
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Statistical Analysis Plan
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!
If year is before year of first dose date, impute as latest of:
o
January 1 (YYYY-01-01)
o
Informed consent date
If date is completely missing:
!
If resolution date (or imputed resolution date) is on or after first dose date, impute as 
first dose date.
!
If resolution date (or imputed resolution date) is prior to first dose date, impute as 
informed consent date.
Some preferred terms coding manifestations of similar medical conditions will be re-grouped 
based on the synonym infrastructure determined through sponsor medical review.
4.4.2
Handling of Other Safety Data
Data that meet any of the criteria below will be treated as missing, and excluded from all 
analyses. 
Treated as missing due to 
reference value
If measurements other than PK data are considered inappropriate because 
hemolysis, fibrin or other abnormalities are found in the sample, they are 
treated as missing values.
Additionally, if units and/or reference ranges for measurements are missing, the 
measurements are treated as missing values.
4.5
Handling of Longitudinal Data
4.5.1
Calculation Method of Number of Days 
Number of days is calculated by the following formula:
!
Number of Days (n) = Day of event  First Day of event + 1
Therefore, the first day of event will be Day 1, and the next day will be Day 2.
Duration is calculated using number of days as follows:
!
Year: number of days/365.25
!
Month: number of days/(365.25/12)
4.5.2
Time Windows
Calculation of summary statistics over time is done by each CRF visit and even if actual visit 
date is deviated from the planned data, all the data will be included in the analysis without 
considering time window, unless otherwise specified.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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4.5.2
4.5.


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Statistical Analysis Plan
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5
STATISTICAL ANALYSIS
5.1
Significance Level, Confidence Interval
No formal statistical hypothesis testing will be done for the primary endpoints. The primary 
analysis of the primary endpoints and secondary efficacy endpoints will be performed using 
an exact 1-sided 95% lower confidence limit. For the primary endpoints and secondary 
efficacy endpoints, the 2-sided 95% confidence interval (CI) will be provided as well. For all 
the other parameters to be estimated, the 2-sided 95% confidence interval will be provided.
5.2
Multiplicity
No adjustment will be made for multiplicity in this study.
5.3
Analysis Methods
5.3.1
Descriptive Statistics
Descriptive statistics defined in this SAP include the number of subjects (N), arithmetic 
mean, standard deviation, minimum, median, and maximum of the data, if not specified. 
5.3.2
Incidence Rates of Treatment-Emergent Adverse Events/Drug Related 
Adverse Events
The incidence rates of TEAEs or drug related AEs are calculated as a percentage of the 
number of subjects with AEs or drug related AEs in Treated Population:
5.4
Rounding Digits
5.4.1
Displaying of Descriptive Statistics
Arithmetic Mean, Standard Deviation, and Median

Rounded to one more significant digit than what was used to collect the variable. 
Minimum and Maximum

Rounded to the same number of significant digits used to collect the variable.
If multiple significant digits are measured among subjects, set an alternative significant digit.
5.4.2
Rounding Digits for Percentages 
Round to the nearest tenths (0.1).
100
Population
Treated
AEs
Related
TEAEs/Drug
with 
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
atient
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Statistical Analysis Plan
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6
SUBJECT DISPOSITION
6.1
Flowchart of Subject Disposition
Population:
Consented Patients 
Contents:
Calculate the number of following Patients:
Consented Subjects 
in the Dose Escalation 
Phase I Portion
Screen failures
Enrolled Patients in 
Phase I Portion
Consented Subject
in the Phase II Portion
Enrolled Patients in 
Phase II Portion
Screen failures
Enrolled Patients in Entire Study
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Consente
onse
in the 
in the
O
alalalal 
o
No
o
N


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Statistical Analysis Plan
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6.2
Subject Disposition
Population:
Treated Patients 
Contents:
Disposition tables by phase/dose and by diagnosis are created: 

Calculate the patient number in Treated Population.

Calculate the patient number and percentage of DLT Evaluable Population.

Calculate the number and percentage of patients who discontinued treatment and 
primary reason of treatment discontinuation.

Calculate the patient number and percentage of patients who discontinued study and the 
primary reason for study discontinuation.

Calculate the patient number and percentage of patients who died on study and by death 
reason.

Calculate the summary statistics of duration of follow-up.

These numbers of patients or percentages above are calculated for the patient groups 
defined in Table 3
Definition of Patient Groups.
7
STUDY POPULATIONS, DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS, AND STUDY DRUG ADMINISTRATION
7.1
Demographics and Other Baseline Characteristics
Population:
Treated Population
Contents:
Examine the distribution of demographics and other baseline characteristics.
For categorical data and ordinal data, calculate the number of subjects and percentages. 
For continuous data, calculate the descriptive statistics.
Summarize Demographics and Other Baseline Characteristics by the patient groups 
defined in Table 3
Definition of Patient Groups.
Definitions:
Age: Age at the time of informed consent.
BMI: BMI will be calculated by dividing weight (kg) by square of height (m).
Unknown and Missing values: If unknown or missing values are observed, add 
“Unknown” category and only calculate the number of subjects. Remove “Unknown” 
category from the denominator for incidence rates and from tests.
Classification [Unit]
Category/Statistics
Gender
Male, Female
Age [Year]
N, Mean, Standard Deviation, Minimum, Median, Maximum
Between 18 and 44 , Between 45 and 64, At least 65 (≥65)
< 50, 50 - 65, 65 < - <75,  ≥ 75
Race
Asian
Diagnosis
CP-CML, AP-CML, BP-CML, Ph+ ALL
Years since initial diagnosis of 
current phase
N, Mean, Standard Deviation, Minimum, Median, Maximum
<5, 5-<10, ≥10
Major Cytogenetic response  Status
CCyR, PCyR, Less than PCyR, Less than 20 metaphases examined, 
missing
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Classification [Unit]
Category/Statistics
Major Hematologic response  Status
Valid bone marrow blasts, not in MaHR
Valid bone marrow blasts, in MaHR
Bone marrow blasts not determined
Complete Hematologic response  
Status (CP-CML patients)
Not in CHR
CHR
Prior Exposure to Dasatinib and 
Nilotinib
Dasatinib, Nilotinib, Dasatinib and Nilotinib, Dasatinib or Nilotinib 
Reason for Stopping the Last 
Dasatinib
Resistant, Intolerant, Other
Reason for Stopping the Last 
Nilotinib
Resistant, Intolerant, Other
Prior exposure to TKI(s)
Imatinib
Dasatinib
Nilotinib
Bosutinib
Bafetinib (INNO-406)
KW-2449
Tozasertib (NK – 0457)
Danusertin (PHA-739358)
XL228
DCC-2036
Radotinib
Prior exposure to TKI(s)
(Number of TKIs)
N, Mean, Standard Deviation, Minimum, Median, Maximum
0, 1, 2, ≥3, Missing 
Prior exposure to Approved TKI(s)
1 Approved TKI
  IMATINIB only
  DASATINIB only
  NILOTINIB only
2 Approved TKIs
  IMATINIB + DASATINIB 
  IMATINIB + NILOTINIB 
  DASAT INIB+ NILOTINIB
3 Approved TKIs 
  IMATIB + DASATINIB + NILOTINIB
Number of prior regimens
1, 2, 3, 4, 5, 6, >6
CCI
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable 
or Nilotin
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Terms of Use
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Statistical Analysis Plan
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Classification [Unit]
Category/Statistics
Resistance/Intolerance 
Resistant to Dasatinib or Nilotinib
  Resistance to Dasatinib/Nilotinib Only
  Both resistant & Intolerant to Dasatinib/Nilotinib
  Intolerant to Dasatinib/Nilotinib Only
  Neither resistant nor Intolerant to Dasatinib/Nilotinib
Best response to most recent 
Dasatinib or Nilotinib
containing regimen
CMR
MMR
CCyR
PCyR
Less than PCyR
MaHR (AP-CML, BP-CML, Ph+ ALL)
CHR (CP-CML)
Stable
None/Progressive disease
Unknown
Best response to most recent anti-
leukemia regimen
CMR
MMR
CCyR
PCyR
Less than PCyR
MaHR (AP-CML, BP-CML, Ph+ ALL)
CHR (CP-CML)
Stable
None/Progressive disease
Unknown
BCR/ABL/ABL ratio (IS)
≤ 0.0032%
0.0032% - ≤ 0.01%
0.01% - ≤ 0.1%
0.1% - <- 1%
1% - ≤10%
>10%
E1a2 variant
Atypical Transcripts
Missing
Prior Stem Cell Transplant
Yes, No
Prior Exposure to 
Homoharringtonine
Yes, No
Prior Chemotherapy
Yes, No
Reason for Stopping the Last Cancer 
Therapy.
Resistant, Intolerant, Other
Extramedullary Involvement
(location)
Splenomegaly, hepatomegaly, Other, No extrameduallry involvement, 
Missing
ECOG Performance Status
Not Assessed, Grade 0, Grade 1, Grade 2, Grade 3, Grade 4, Grade 5
Weight [kg]
N, Mean, Standard Deviation, Minimum, Median, Maximum
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Classification [Unit]
Category/Statistics
Height [kg]
N, Mean, Standard Deviation, Minimum, Median, Maximum
BMI[kg/m2]
N, Mean, Standard Deviation, Minimum, Median, Maximum
7.2
Drug Study Administration
Population:
Treated Population
Contents:
Calculate descriptive statistics of the following variables:

Treatment period

Number of days dosed

Actual Total dose

Dose intensity

Relative Dose intensity
Calculate the following subject number and percentage: 

Subjects whose Dose was reduced

Subjects whose Dose was interrupted for at least 3 days
Patient groups are defined in Table 3
Definition of Patient Groups.
Definitions:
Planned Total dose (mg): treatment period for each dosage
Actual Total dose (mg): Sum of actual dosages taken (if dosage changed, actual total dose will 
be calculated by each dose)
Relative Dose Intensity (%): (Actual Total dose/Planned Total dose)*100(%)
Treatment period (days): Last day of study drug administration (or Date of withdrawal) -
First day of Test Drug administration+1
Dose Intensity (mg/day):(Actual Total dose/ Treatment period )
The last day of Cycle 1: defined as 28 days after the first dosing day (the day=the first 
administration day+27)
8
EFFICACY ASSESSMENT
8.1
Primary Endpoints 
8.1.1
Primary Analysis of Primary Endpoints
Population:
Treated Population
Contents:
<CP-CML Patients>
Primary Endpoint: MCyR
The primary analysis of the primary efficacy endpoint of MCyR is performed by calculating 
MCyR rate and its exact 1-sided 95% lower confidence limit using the all CP-CML patients 
treated in the phase I portion and phase II portion. 
Proportion of each category included in MCyR (CCyR, PCyR) will also be presented.
<AP-CML, BP-CML, Ph+ ALL Patients>
Primary Endpoint: MaHR
The primary analysis of the primary efficacy endpoint of MaHR will be performed by 
calculating MaHR and its exact 1-sided 95% lower confidence limit using the all AP-CML, 
BP-CML, and Ph+ ALL patients treated in the phase I portion and phase II portion for 
combined data across these disease groups.
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Additionally, same analysis is done by the following group:

AP-CML

BP-CML

Ph+ ALL
Proportion of each category included in MaHR (CHR, NEL) will also be presented.
Definitions:
<CP-CML Patients>
Primary Endpoint: MCyR
Major cytogenetic response rate: The proportion of patients who have achieved a CCyR (no 
Ph+ cells) or PCyR (1-35% Ph+ cells) by 12 months after the initiation of study treatment. 
Patients entering the study already in PCyR must achieve a CCyR by 12 months in order to be 
considered a success for the MCyR rate.
<AP-CML, BP-CML, Ph+ ALL Patients>
Primary Endpoint: MaHR
Major hematologic response rate: The proportion of patients who have achieved a 
confirmed CHR or NEL by 6 months after the initiation of study treatment.
The primary analysis of the primary endpoints and secondary endpoints will be performed 
after the last enrolled patient has completed the 12th 28-day cycles of treatment using all data 
collected at that time. 
8.1.2
Sensitivity Analysis of Primary Endpoints
Population:
Treated Population
Contents:
<CP-CML Patients>
The sensitivity analysis of MCyR for CP-CML patients will be performed by calculating 
MCyR rate at or by 3-month assessment, 6-month assessment, 9-month assessment, 12-month 
assessment, and during the entire on study treatment period after the initiation of study 
treatment using the treated population, i.e., CP-CML patients treated in the phase I portion and 
phase II portion. 
Proportions of patients who have achieved CCyR and PCyR will also be presented.
<AP-CML, BP-CML, Ph+ ALL Patients>
The sensitivity analysis of MaHR will be performed by calculating MaHR during the entire on 
study treatment period and its exact 1-sided 95% lower confidence limit using the treated 
population, i.e., total patients treated in the phase I portion and phase II portion for each 
individual disease group and the combined disease group (AP-CML, BP-CML, and Ph+ ALL).
Proportions of patients who have achieved CHR and NEL will also be presented.
8.1.3
Additional Analysis of Primary Endpoints
Additional analysis of the primary endpoints may be performed using the per-protocol 
populations if any treated patients do not meet the criteria for per-protocol populations.
Population:
Per-protocol Population
Contents:
<CP-CML Patients>
Additional analysis of MCyR for CP-CML patients may be performed by calculating MCyR 
rate by 12 months and its lower 1-sided exact 95% limit using the per-protocol (cytogenetic) 
population, i.e., CP-CML patients treated in the phase I portion and phase II portion and had a 
baseline cytogenetic assessment with at least 20 metaphases examined and no CCyR at 
baseline.
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Proportions of patients who have achieved CCyR and PCyR will also be presented.
<AP-CML, BP-CML, Ph+ ALL Patients>
Additional analysis of MaHR may be performed by calculating MaHR by 6 months and its
exact 1-sided 95% lower confidence limit for MaHR rate using the per-protocol (hematologic) 
population, i.e., total patients enrolled in the phase I portion and the phase II portion for each 
individual disease group and the combined disease group (AP-CML, BP-CML, and Ph+ ALL) 
excluding those with MaHR at baseline. 
Proportions of patients who have achieved CHR and NEL will also be presented.
8.1.4
Bayesian Analysis
Population:
Treated population in this trial and per-protocol Population in study AP24534-10-201 (PACE) 
Contents:
Bayesian inference of the response rates is carried out under the following assumptions: 1. The
number of patients who achieved the primary endpoint in the study populations of this study 
and PACE study follows a binomial distribution, binominal(p, n); 2. P has a prior distribution 
beta(a, b). The posterior distribution of p given that y patients achieve the primary endpoint is 
beta(n+a, n-y+b).  Bayesian analysis is implemented using PROC MCMC in SAS. The
estimated 1-sided 95% lower credible limit and 1-sided 95% lower highest posterior density 
limit of the observed response rates are presented. 
For CP-CML, MCyR rate by 12 months is analyzed.
For AP-CML, BP-CML, and Ph+ ALL Patients, Confirmed MaHR rate by 6 months is 
analyzed for each disease group and the combined disease group.  
Definitions:
MCyR: Same as the Definition of 8.1 Primary Analysis of Primary Endpoint.
MaHR: Same as the Definition of 8.1 Primary Analysis of Primary Endpoint.
8.2
Secondary Endpoints
8.2.1
Confirmed MCyR (cCCyR or cPCyR)
Population:
Treated Population
Contents:
The analysis will be performed by calculating confirmed MCyR rate and an exact 1-sided 95% 
lower confidence limit using the treated population. Proportions of patients who have achieved 
cCCyR and cPCyR will also be presented. Confirmed MCyR rate will be evaluated for the 
patient groups defined in Table 3.
Definitions
Confirmed MCyR: The proportion of patients who have achieved a confirmed CCyR or PCyR 
at least 28 days apart after the initiation of study treatment. Patients entering the study already 
in PCyR must achieve a confirmed CCyR at least 28 days apart in order to be considered as a 
success for the confirmed MCyR rate.
8.2.2
Confirmed CHR
Population:
Treated Population in CP-CML
Contents:
The analysis will be performed by calculating confirmed CHR rate and the exact 1-sided 95% 
lower confidence limit using the treated population in CP-CML patients.
Definitions:
Confirmed CHR: The proportion of patients who have achieved a confirmed CHR at least 28 
days apart after the initiation of study treatment. 
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8.2.3
Major Molecular Response 
Analysis of Molecular Response
Population:
Treated Population 
Contents:
The analysis will be performed by calculating Major molecular response (MMR) rate during 
the entire on study treatment time interval after the initiation of study treatment and the exact 1-
sided 95% lower confidence limit using the treated population.
Analysis will be done for patient groups defined in Table 3.
Definitions:
Additional Analysis of Molecular Response
Population:
Treated Population 
Contents:
The analysis will be performed by calculating the rates of MR4, MR4.5, MR5 at or by 3-month 
assessment, 6-month assessment, 9-month assessment, 12-month assessment, and during the 
entire on study treatment interval after the initiation of study treatment.
Analysis will be performed for the patient groups defined in Table 3.
Definitions:
Duration of Response 
Population:
Treated Population 
Contents:
Duration of response is estimated using the Kaplan-Meier method. 
The following number of patients and statistics will be presented:
!
Number of Patients evaluated
!
Number of Patients with Events and its percentage
!
Number of Patients censored and its percentage
!
Minimum duration
!
25th Percentile Duration
!
Median Duration
!
The exact 1-sided 95% lower confidence limit of Median Duration
!
The 2-sided 95% CI of Median Duration
!
75th Percentile Duration
!
Maximum Duration
!
Probability of not losing the response after 6 months
!
The 2-sided 95% CI of Probability of not losing the response after 6 months
!
Probability of not losing the response after 12 months
!
The 2-sided 95% CI of Probability of not losing the response after 12 months
For CP-CML, MCyR, CHR and MMR will be evaluated.
For AP-CML, BP-CML and Ph+ ALL, confirmed MaHR, MCyR, MMR will be evaluated.
CCI
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Property of Takeda: For Non-Commercial Us
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Population:
Treated Population 
Definitions
Duration of response: the interval between the first assessment at which the criteria for 
response are met until the criteria for loss of response are met, censored at the last valid 
response assessment date. If a patient has had one response assessment at which the response 
criteria are met and no further evaluable response assessments, the duration of response will be 
1 day. Duration of response is defined for patients who have achieved the primary endpoints, 
i.e., CP-CML patients who achieved MCyR by 12 month and AP-CML/BP-CML/Ph+ ALL 
patients who achieved MaHR by 6 month. Duration of CHR or MMR is defined for patients 
who have achieved response during the entire on study treatment period. 
Loss of MCyR: meeting any of the following criteria:
Patients entering the trial in PCyR: 2 consecutive cytogenetic assessments ≥ 28 days apart 
with Ph+ > 0% after achieving a CCyR. Patients with a single or multiple cytogenetic 
assessment with Ph+ > 0% followed by no additional cytogenetic assessments will be also 
considered as meeting the criteria for loss of MCyR.
Patients entering the trial not in PCyR: 2 consecutive cytogenetic assessments 28 days apart 
with Ph+ > 35% after achieving a PCyR or CCyR. Patients with a single or multiple 
cytogenetic assessments with Ph+ > 35% followed by no additional cytogenetic assessments 
will also be considered as meeting the criteria for loss of MCyR.
Loss of MaHR: 2 consecutive hematologic assessments ≥ 28 days apart at which the criteria 
for MaHR are not met. Patients with a single or multiple hematologic assessments at which the 
criteria for MaHR are not met followed by no additional hematologic assessments will also be 
considered as meeting the criteria for loss of MaHR.
Loss of CHR: 2 consecutive hematologic assessments ≥ 28 days apart at which the criteria for 
CHR are not met. Patients with a single or multiple hematologic assessments at which the 
criteria for CHR are not met followed by no additional hematologic assessments will also be 
considered as meeting the criteria for loss of CHR.
Loss of MMR: 2 consecutive molecular assessments ≥ 28 days apart at which the criteria for 
MMR are not met. Patients with a single or multiple molecular assessments at which the 
criteria for MMR are not met followed by no additional molecular assessments will be also 
considered as meeting the criteria for loss of MMR.
8.2.4
Progression-Free Survival 
Population:
Treated Population 
Contents:
Progression-free survival is estimated using the Kaplan-Meier method.
The following number of patients and statistics will be presented:

Number of Patients evaluated

Number of Patients with Events and its percentage

Number of Patients censored and its percentage

Minimum PFS

25th Percentile PFS

Median PFS

The exact 1-sided 95% lower confidence limit of Median PFS

The 2-sided 95% CI of Median PFS

75th Percentile PFS

Maximum PFS

Probability of Progression-free after 6 months

The 2-sided 95% CI of Probability of Progression-free after 6 months

Probability of Progression-free after 12 months

The 2-sided 95% CI of Probability of Progression-free after 12 months
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Population:
Treated Population 
Evaluated by the following groups:

CP-CML

Pooled group (AP-CML, BP-CML and Ph+ ALL)  
Definitions:
Progression-free survival: the interval from the first dose of study treatment until the criteria 
for progression are met or death, censored at the last response assessment.
The criteria for progression and date of disease progression are specified as follows,
In CP-CML patients, disease progression date is defined as the earliest of the following dates:

Death date 

Last dose date of patients who discontinued study treatment due to disease progression.

Initial date of the loss of MMR which is subsequently confirmed or the date of single loss 
followed by no additional assessment.

Initial date of the loss of MCyR, which is subsequently confirmed or the date of single loss 
followed by no additional assessment.

Initial date of the loss of CHR after the confirmation of CHR if patients have not achieved 
MCyR. Loss of CHR should be subsequently confirmed or followed by no additional 
assessment. 

Initial date of developing AP/BP (as defined in Table 1 in the protocol) based on the 
evaluation of peripheral blood and bone marrow at least 28 days after the first dose date, 
and after the dates of CHR confirmation, first MCyR and first MMR if patients have 
achieved any response(s).

Initial date of doubling of WBC to greater than 20,000 x109/L on 2 occasions at least 4 
weeks apart, at least 28 days after the first dose date, and after the dates of CHR 
confirmation, first MCyR and first MMR if patients have achieved any response(s).
In AP-CML patients, disease progression date is defined as the earliest of the following dates:

Death date 

Last dose date of patients who discontinued study treatment due to disease progression.

Initial date of the loss of MaHR after the confirmation of MaHR if patients have two 
instances of loss of MaHR at least 14 days apart

Initial date of increased peripheral blast or bone marrow blast to at least 30%, at least 28 
days after the first dose date, and after the dates of MaHR confirmation, first MCyR and 
first MMR if patients have achieved any response(s).

Initial date of the same as or worsening blast count from baseline at least 28 days after the 
first dose date, and after the dates of MaHR confirmation, first MCyR and first MMR if 
patients have achieved any response(s), in the following situations: post-baseline peripheral 
blasts are equal to or greater than baseline peripheral blasts when baseline peripheral blasts 
are non-missing; post-baseline peripheral blasts greater than 0 when baseline peripheral 
blasts are missing; post-baseline bone marrow blasts are greater than 5% and are equal to 
or greater than baseline bone marrow blasts when baseline bone marrow blasts are non-
missing;  post-baseline bone marrow blasts are greater than 5% when baseline bone 
marrow blasts are missing.
In BP-CML and PH+ ALL patients, disease progression date is defined as the earliest of the 
following dates:

Death date 

Last dose date of patients who discontinued study treatment due to disease progression.

Initial date of the loss of MaHR after the confirmation of CHR if patients have two 
instances of loss of MaHR at least 14 days apart

Initial date of the same or worsening blast from baseline at least 28 days after the first dose 
date, and after the dates of CHR confirmation, first MCyR and first MMR if patients have 
achieved any response(s), in the following situations: post-baseline peripheral blasts are 
greater than baseline peripheral blasts when baseline peripheral blasts are non-missing; 
post-baseline peripheral blasts are greater than 0 when baseline peripheral blasts are 
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Population:
Treated Population 
missing; post-baseline bone marrow blasts are greater than 5% and are greater than 
baseline bone marrow blasts when baseline bone marrow blasts are non-missing; post-
baseline bone marrow blasts are greater than 5% when baseline bone marrow blasts are 
missing.
8.2.5
Overall Survival 
Population:
Treated Population 
Contents:
Overall survival is estimated using the Kaplan-Meier method.
The following number of patients and statistics will be presented:

Number of Patients evaluated

Number of Patients with Events and its percentage

Number of Patients censored and its percentage

Minimum OS

25th Percentile OS

Median OS

The exact 1-sided 95% lower confidence limit of Median OS

The 2-sided 95% CI of Median OS

75th Percentile OS

Maximum OS

Probability of Survival after 6 months

The 2-sided 95% CI of Probability of Survival after 6 months

Probability of Survival after 12 months

The 2-sided 95% CI of Probability of Survival after 12 months
Evaluated by the following groups:

CP-CML

Pooled group (AP-CML, BP-CML and Ph+ ALL) 
Definitions
Overall Survival: 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.
8.2.6
Time to Response 
Population:
Treated Population 
Contents:
Time to response is estimated using the Kaplan-Meier method. Time to response will also be 
summarized with descriptive statistics for responders only.
The following number of patients and statistics will be presented:

Number of Patients evaluated

Number of Patients with Events and its percentage

Number of Patients censored and its percentage

Minimum time to response

25th Percentile time to response

Median time to response

The exact 1-sided 95% lower confidence limit of Median time to response

The 2-sided 95% CI of Median time to response

75th Percentile time to response

Maximum time to response
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Population:
Treated Population 

Probability of observing the response until 6 months

The 2-sided 95% CI of Probability of observing the response until 6 months

Probability of observing the response until 12 months

The 2-sided 95% CI of Probability of observing the response until 12 months
For CP-CML, MCyR, time to CHR and MMR will be evaluated.
For AP-CML, BP-CML and Ph+ ALL, time to MaHR, MCyR, and MMR will be evaluated.
Definitions
Time to response is defined as the interval from the first dose of study treatment until the 
criteria for response are first met, censored at the last response assessment.
8.3
Covariate Adjustments
N/A
8.4
Multicenter Study
Evaluation by each site is not done.
8.5
8.5 Subgroup Analysis
Subgroup analysis of the primary endpoint and selected secondary endpoints will be 
performed in patients formed according to time since initial diagnosis of current phase, 
mutation at baseline, and prior approved TKI therapies.

Patient groups based on time since initial diagnosis of current phase
o
0 - ≤ first tertile 
o
first tertile - ≤ second tertile
o
second tertile

Patient groups based on mutation at baseline
o
T315I
-
T315I only
-
T315I + 1 additional mutation
o
Other
-
One mutation other than T315I
-
No mutation
-
No sequencing data

Patient groups based on prior approved TKI(s)
o
1 approved TKI
-
Any
-
Dasatinib
-
Nilotinib
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o
2 approved TKIs
-
Any
-
Imatinib + Dasatinib
-
Imatinib + Nilotinib
-
Dasatinib + Nilotinib
o
3 approved TKIs
-
Imatinib + Dasatinib + Nilotinib
8.6
Stratified Analysis
N/A
8.7
Interim Analysis 
No formal interim analyses are planned for efficacy in this study. 
9
PK ASSESSMENT
9.1
PK Analysis
9.1.1
Ponatinib Concentration at Each Time Point
Population:
PK Population
Contents:
Calculate descriptive statistics (Arithmetic mean, SD, Minimum, Median, Maximum, 95% 
confidence intervals, Geometric mean and CV% (coefficient of variation)) of ponatinib 
concentration in each time point by each dose level (15 mg, 30 mg and 45 mg)  
Mean of concentration at each time point will be plot with an error bars (SD).
9.1.2
PK Parameters Estimated from PK Profile
Population:
PK Population
Contents:
Calculate the descriptive statistics (Arithmetic mean, SD, Minimum, Median, Maximum, 95% 
confidence intervals, Geometric mean and CV% (coefficient of variation)) for the following 
PK parameters by Dose level (15 mg, 30 mg and 45 mg ) and at each time point:

Cmax [ng/mL]

AUC(0-24h) [hr*ng/mL]

Tmax [hr]

Elimination half-life (t1/2)[hr]

CLss/F

Vd/F

RA(AUC)
Definitions:
Cmax [ng/mL] :Observed maximum concentration 
AUC (0-24h)[hr*ng/mL] :Area under the observed concentration- time curve from AUC(0-24h)
calculated using linear trapezoidal method.
Tmax [hr] :Time point of Cmax
Elimination half-life (t1/2) [hr] :Calculated as –In(2)/(Elimination rate constant for terminal 
phase). Elimination rate constant for terminal phase is derived from the log-linear regression 
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Population:
PK Population
on the terminal phase with several measurements. 
CLss/F: the apparent clearance at steady-state, unadjusted for bioavailability that is calculated 
as Dose/AUC (0-24h).
Vd/F: the apparent volume of distribution, unadjusted for bioavailability that is calculated as
CLss/F * (Elimination rate constant for terminal phase).
RA(AUC): AUC 0-24h Cycle 2 Day 1/ AUC 0-24h Cycle 1 Day 1
(For 15 mg, AUC 0-24h Cycle 1 Day 8/ AUC 0-24h Cycle 1 Day 1)
9.1.3
Dose-Linearity Among Dose Levels
Population:
PK Population
Contents:
Evaluate Dose-linearity among dose levels (15 mg, 30 mg and 45 mg ) using power model in 
terms of Cmax and AUC(0-24h) at Cycle 1 Day 1 and Cycle 2 Day 1(For 15 mg, Cycle 1 Day 1 
and Cycle 1 Day 8).
9.1.4
Comparison Between this Study and Study Conducted in US(USA101).
Population:
PK Population
Contents:
Comparison is based on dose-normalized mean of logarithmically-transformed Cmax and 
AUC(0-24h).  No formal hypothesis testing is planned. At each dose level (30 mg and 45 mg) and
for pooled group (30 mg and 45 mg), the PK parameters and the descriptive statistics for both 
studies will be displayed side-by-side.
9.1.5
Box and whisker plots of the steady-state, dose-normalized AUC(0-24h) and 
Cmax
Population:
PK Population
Contents:
Box and whisker plots of the steady-state, dose-normalized AUC(0-24h) and Cmax will be created 
for data of this trial and US trial (AP24534-07-101).
Dose-normalized AUC(0-24h) and Cmax will be plotted by each dose (30 mg and 45 mg) 
9.1.6
PK Listings
Listing of Ponatinib Concentration 
Listing of Pharmacokinetic parameters 
CCI
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Statistical Analysis Plan
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10
SAFETY ASSESSMENT
10.1
Treatment-Emergent Adverse Events/ Drug Related Adverse Events
10.1.1
Numbers and Incidence Rate of Patients with Treatment-emergent Adverse 
Events 
Population:
Treated Population
Contents:
Calculate the subject number for the followings:

Number of Patients

Number of Patients with TEAE

Number of Patients with Grade 3/4/5 TEAE

Number of Patients with Serious TEAE

Number of Patients with TRAE

Number of Patients with Grade 3/4/5 TEAE

Number of Patients with Serious TRAE

Number of Patients with TEAE Leading to Treatment Discontinuation, Reduction, 
Interruption, or Study Discontinuation
Calculate the number of subjects by the following groups:

30 mg

15/45 mg 

Total
10.1.2
Numbers and Incidence Rate of Patients with Treatment-emergent Adverse 
Events by MedDRA Code
Population:
Treated Population
Contents:
Calculate the number of subjects with TEAEs, incidence rates and percentages, by System 
Organ Class (SOC) and Preferred Term (PT) for the patient groups defined in Table 1.

Denominator to calculate the percentage: The number of subjects from the population 
in each group.

Each subject with more than one AE will be counted once ( a subject with one or 
more AEs will only be counted once).
Conduct the same analysis for Drug Related AEs, Serious AEs and Serious drug related 
AEs. 
10.1.3
Numbers and Incidence Rate of Patients with Treatment-Emergent Adverse 
Events According to Severity by MedDRA Code
Population:
Treated Population
Contents:
Calculate the number of subjects with AEs, incidence rates and percentages, by SOC and PT 
and CTCAE grade for the following patient groups initially treated at 30 mg, 15/45 mg, and 
any dosage:

CP-CML

Pooled group for advanced phases (AP-CML, BP-CML, and Ph+ ALL)  
Denominator to calculate the percentage: The number of subjects from the population in each 
group.
Each subject with more than one AE will be counted once at the greatest CTCAE grade ( a 
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Population:
Treated Population
subject with one or more AEs will only be counted once).
Conduct the same analysis for d related AEs, Serious AEs and Serious related AEs.
10.2
Assessments of Laboratory Test Results, Vital Signs, Left Ventricular 
Ejection Fraction, and QTcF Interval
10.2.1
Descriptive Statistics of Transition of Laboratory Test (Haematology) Results
Population:
Treated Population
Contents:
Calculate summary statistics for the baseline, the lowest post-baseline level and the highest 
post-baseline level. 
Calculate the patient numbers and percentages by shift in CTCAE grade from the baseline to 
the worst on-study result as follows:

No change from baseline,

Any worsening from baseline

Worsening to grade 3 or grade 4

<Grade 3 to grade 3

<Grade 3 to grade 4

Worsening to <grade 3

Improved from baseline

Unable to evaluate (note: missing at baseline or post-baseline)
Definitions:
ANC: White Blood Cell Counts* Neutrophil percentage (%) 
10.2.2
Descriptive Statistics of Transition of Laboratory Test (Chemistry) Results
Population:
Treated Population
Contents:
Calculate summary statistics for the baseline, the lowest post-baseline level and the highest 
post-baseline level. 
Calculate the patient numbers and percentages by shift in CTCAE grade from the baseline to 
the worst on-study result as follows:

No change from baseline,

Any worsening from baseline

Worsening to grade 3 or grade 4

<Grade 3 to grade 3

<Grade 3 to grade 4

Worsening to <grade 3

Improved from baseline

Unable to evaluate (note: missing at baseline or post-baseline)
10.2.3
Descriptive Statistics of Vital Signs
Population:
Treated Population
Contents:
Calculate the descriptive statistics for the baseline and the maximum post-baseline blood 
pressure.
Categorize patients according to the systolic and diastolic blood pressure and calculate the 
numbers of patients (and percentages) by shift from the baseline category to the worst post-
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Population:
Treated Population
baseline category.
Systolic blood pressure (mmHg)
<120
120 – 139
140 – 159
≥160
Diastolic blood pressure (mmHg)
<80
80 – 89
90 – 99
≥100 
10.2.4
Descriptive Statistics of Left Ventricular Ejection Fraction (LVEF)
Population:
Treated Population
Contents:
Calculate the descriptive statistics for the baseline and the minimum post-baseline ejection 
fraction.
Calculate the patient numbers and percentages by shift in CTCAE grade from the baseline to 
the worst on-study result.
10.2.5
Descriptive Statistics of QTcF Interval
Population:
Treated Population
Contents:
Calculate the descriptive statistics for the baseline and the maximum post-baseline QTcF 
interval.
Categorize patients according to the baseline and the maximum post-baseline QTcF interval 
(<450ms, 450 - <480ms, 480 – <500ms, and ≥500ms). Calculate the numbers of patients (and 
percentages) by shift from the baseline category to the worst post-baseline category.
Calculate the descriptive statistics for the change from the baseline and the maximum post-
baseline QTcF interval.
Categorize patients according to the change from the baseline to the maximum post-baseline 
level (<30 msec increase, 30-<60 msec increase, ≥60 msec increase, no change, decrease from 
baseline) and calculate the numbers of patients (and percentages) for each category.
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11
CHANGE HISTORY
Version
Data
Author
Comments
1.0
2015/03/04
Ariad Pharmaceuticals Inc.
Newly Created
PPD
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