A Randomized, Open-label, Phase 2 Trial of Ponatinib in Patients With Resistant Chronic Phase Chronic Myeloid Leukemia to Characterize the Efficacy and Safety of a Range of Doses
Phase: PHASE2
Conditions: Myeloid Leukemia, Chronic, Chronic Phase
Sponsor: Takeda

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CLINICAL STUDY PROTOCOL
Study Title:
A Randomized, Open-label, Phase 2 Trial of Ponatinib in 
Patients with Resistant Chronic Phase Chronic Myeloid 
Leukemia to Characterize the Efficacy and Safety of a Range of 
Doses
Protocol Number:
AP24534-14-203
Study Phase:
2
Product Name:
Ponatinib 
IND Reference Number:
78,375
EudraCT Number:
2014-001617-12
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421
USA
617-349-0200
Note: Takeda Development Center Americas, Inc, a wholly 
owned subsidiary of Takeda Pharmaceutical Company Limited, 
may be referred to in this protocol as “sponsor,” or “Takeda.”
Protocol Issue Date:
07 April 2021
Version Number:
Version 8.0
PROTOCOL REVISION HISTORY:
Amendment Number
Protocol Version Number
Date
Original Protocol
Version 1.0
02 February 2015
Amendment 1
Version 2.0
17 December 2015
Amendment 1.1
Version 2.1 (Norway)
18 December 2015
Amendment 1.2
Version 2.2 (Germany)
16 February 2016
Amendment 2
Version 3.0
30 March 2016
Amendment 2.1
Version 3.1 (Norway)
06 June 2016
Amendment 3
Version 4.0
30 May 2017
Amendment 4
Version 5.0
01 March 2018
Amendment 5
Version 6.0
18 April 2019
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Amendment Number
Protocol Version Number
Date
Amendment 6
Version 7.0
05 October 2020
Amendment 7
Version 8.0
07 April 2021
1
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda except to the extent necessary to obtain 
informed consent from those persons to whom the drug may be administered. Furthermore, the 
information is only meant for review and compliance by the recipient, his or her staff, and 
applicable institutional review committee and regulatory agencies to enable conduct of the study.
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2.2
Investigator Signature
I have read the protocol and agree that it contains all necessary details for carrying out the study 
as described.  I will conduct this protocol as outlined therein, including all statements regarding 
confidentiality.  I will make a reasonable effort to complete the study within the time designated.  
I will provide copies of the protocol and access to all information furnished by the sponsor to 
study personnel under my supervision.  I will discuss this material with them to ensure they are 
fully informed about the study drug and the study.  I understand that the study may be terminated 
or enrollment suspended at any time by the sponsor, with or without cause, or by me if it 
becomes necessary to protect the best interests of the study patients.
I agree to conduct this study in full accordance with all applicable regulations.
Investigator’s Signature 
Date (dd-mmm-yyyy)
Investigator’s Name (print)
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2.3
Sponsor Representative Signature
Takeda has approved of this protocol and assures that this study will be conducted according to 
all stipulations of the protocol, including all statements regarding confidentiality. 
Sponsor Representative’s Signature 
Date (dd-mmm-yyyy)
Sponsor Representative’s Name and Title (print)
Clinical Research & Development
Takeda Development Center Americas, Inc. (a wholly-owned subsidiary of Takeda 
Pharmaceutical Ltd. Co.)
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3
CONTACT INFORMATION
Sponsor
Takeda Development Center Americas, Inc.
(a wholly-owned subsidiary of Takeda Pharmaceutical 
Company Limited)
95 Hayden Avenue
Lexington, MA 02421
USA
617-349-0200
Sponsor Medical Monitor:
, MD
, Clinical Science
Takeda Oncology
300 Massachusetts Avenue
Cambridge, MA 02139
USA
Office Telephone: 
E-mail:
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4
PROTOCOL SYNOPSIS
Sponsor
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421
USA
Study Treatment
Ponatinib
Study Title
A Randomized, Open-label, Phase 2 Trial of Ponatinib in Patients with Resistant 
Chronic Phase Chronic Myeloid Leukemia to Characterize the Efficacy and Safety 
of a Range of Doses
Phase
Phase 2
Eligible Population
Patients with chronic phase chronic myeloid leukemia (CP-CML) who have received 
at least two prior tyrosine kinase inhibitor (TKI) therapies and have demonstrated 
resistance to treatment or have the T315I mutation
Summary and Study 
Rationale
Ponatinib is a novel, synthetic, orally active TKI specifically designed to optimally 
inhibit native BCR-ABL.  It is also active against mutated forms of the protein that 
can arise during treatment with other TKIs and cause resistance, including the T315I 
gatekeeper mutant.  The latter confers uniform resistance to all other available BCR-
ABL inhibitors (e.g., imatinib, nilotinib, dasatinib, and bosutinib).  Ponatinib 
(ICLUSIG®) is approved in the United States (US) for the treatment of adult 
patients with chronic phase, accelerated phase, or blast phase chronic myeloid 
leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia 
(Ph+ ALL) for whom no other TKI therapy is indicated and for treatment of adult 
patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) 
or T315I-positive Ph+ ALL.  In the European Union (EU), ponatinib is approved for 
the treatment of adult patients with CML (chronic phase, accelerated phase, or blast 
phase) and Ph+ ALL who are resistant to dasatinib (or nilotinib for CML), who are 
intolerant to dasatinib (or nilotinib for CML), and for whom subsequent treatment 
with imatinib is not clinically appropriate, or who have the T315I mutation.
The phase 2 clinical trial of ponatinib in patients with CML or Ph+ ALL who have 
had prior TKI therapy (AP24534-10-201, PACE), which supported the drug’s 
approvals, tested a starting dose of 45 mg daily. The 5-year data from this study 
confirmed that treatment with ponatinib continued to provide clinically meaningful 
responses.  In patients with CP-CML, the primary endpoint was met in more than 
double that of the most recent dasatinib or nilotinib therapy (55.4% vs. 25.8%) and 
85.7% remained in the primary endpoint for ≥550 days at 30 mg. The median 
duration of follow-up was 37.3 months. Continuing analyses of the phase 2 trial have 
demonstrated a higher cumulative incidence of arterial occlusive events (including 
cardiovascular, cerebrovascular, and peripheral vascular events) observed with a 
longer follow-up, than reported at the time of the initial approval.  Arterial occlusive 
events (AOEs)—including fatal myocardial infarction (MI), stroke, severe peripheral 
vascular disease, and the need for urgent revascularization procedures—have been 
reported in ponatinib-treated patients.
Current data suggest that a dose-effect relationship exists with efficacy and with the 
occurrence of AOEs, and that a lower daily dose may reduce the incidence of AOEs.  
This clinical study will assess the relationships of exposure with efficacy and safety: 
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patients will receive a range of initial doses, and at defined time points, patients in 
response will undergo a dose reduction.  The goal of the study will thus be to 
understand induction of responses, maintenance of responses, safety, and exposure-
response as consequences of these dosing strategies.
The primary endpoint of this study will be the achievement of ≤1% BCR-ABL1IS at 
12 months. This incorporates standard CML approaches to patient care and uses 
patient monitoring. Increasingly, patient monitoring is being performed by 
quantitation of BCR-ABL1 transcripts from a standard established by the 
international scale (IS) (Marin, 2014; NCCN, 2014; Baccarani et al, 2013; Marin et 
al, 2012; Lauseker et al, 2012; Saglio et al, 2012).  
This trial is being conducted in fulfillment of a Food and Drug Administration 
(FDA) post-marketing requirement (PMR2113-6).
Study Design
This is a multi-center, randomized phase 2 trial to characterize the safety and 
efficacy of ponatinib over a range of 3 starting doses.  Eligible patients must have 
CP-CML; have received at least 2 prior TKI therapies and have demonstrated 
resistance to treatment or have the T315I mutation.  
Patients will be randomized to receive once-daily oral administration of 1 of 3 
starting doses of ponatinib: 45 mg (Cohort A), 30 mg (Cohort B), or 15 mg (Cohort 
C).  Patients starting at 45 mg or 30 mg will have their daily dose reduced to 15 mg 
upon achievement of ≤1% BCR-ABL1IS, as defined in Section 14.1.3.
The study will consist of an initial 24-cycle Main Treatment Period; additionally, the 
study includes an optional Treatment Continuation Period.  All randomized patients 
will enter the Main Treatment Period and will remain on treatment in the Main 
Treatment Period until the occurrence of at least one of the following: absence of 
complete hematologic response (CHR) by 3 months, absence of major cytogenetic 
response (MCyR) at 12 months, absence of ≤1% BCR-ABL1IS at 12 months, loss of 
≤1% BCR-ABL1IS as defined in Section 16.5.1.1, development of intolerance, or 
completion of all 24 cycles of treatment (whichever occurs first). Patients who 
achieve ≤1% BCR-ABL1IS at any time point undergo dose reduction, and then lose 
≤1% BCR-ABL1IS are candidates for dose re-escalation to their starting dose, as 
described in Section 14.1.4.
Following completion of the 24-month Main Treatment Period or following early 
withdrawal from the Main Treatment Period before completing all 24 cycles of the 
Main Treatment Period, patients who are both tolerating ponatinib treatment and 
receiving clinical benefit from treatment may enter into an optional Treatment 
Continuation Period upon discussion and agreement between the investigator and 
medical monitor.  Examples of clinical benefit that could allow a patient to enter the 
Treatment Continuation Period include (but are not limited to) a reduction from 
baseline in BCR-ABLIS levels (but without meeting the protocol-defined response 
criterion of ≤1% BCR-ABL1IS at 12 months), an improvement in hematologic 
parameters (but without meeting the protocol-defined response criterion of CHR by 
3 months), or a BCR-ABLIS level indicative of clinical benefit (but that is > 1%, 
after loss of ≤1% BCR-ABL1IS at an earlier time point).  Each patient may remain 
on study treatment during the Treatment Continuation Period until the patient stops 
receiving clinical benefit or experiences unacceptable toxicity, or until the study is 
terminated by the sponsor (whichever occurs first).  Section 12 describes follow-up 
and data collection for such continuation patients.  Section 10.4 provides more detail 
about the study design including descriptions of the Main Treatment and Treatment 
Continuation Periods.
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The trial will assess hematologic response, cytogenetic response, and molecular 
response—as well as characteristics of efficacy, including time to and duration of 
responses—both by starting dose and after dose reduction.  AE rates and the rates of 
AOEs and venous thrombotic/embolic events (VTEs), in particular, will be 
measured.  Progression-free survival (PFS) and overall survival (OS) data will also 
be collected and analyzed.  Assessments will be performed according to standard 
international criteria.  The duration of patient participation will vary by patient 
depending on clinical benefit and toxicity.  Each dose cohort will be analyzed 
separately for efficacy, safety, and pharmacokinetics (PK).
Study Objectives
Primary Objective:
To characterize the efficacy of ponatinib administered in 3 starting doses (45 mg, 
30 mg, and 15 mg daily) in patients with CP-CML who are resistant to prior TKI 
therapy or have T315I mutation, as measured by ≤1% BCR-ABL1IS at 12 months.
Secondary Objectives:

To characterize the rate of major molecular response (MMR) at 12 and 24 
months and rate of major cytogenetic response (MCyR) by 12 months

To evaluate duration of MMR

To characterize the rates of AOEs, VTEs, AEs, and serious AEs (SAEs)

To evaluate safety differences among the 3 starting dose cohorts, particularly 
for AOEs and VTEs

To collect sparse PK samples to contribute to population PK and exposure-
response analyses of safety and efficacy.
Other Secondary Objectives:

To characterize the rates of cytogenetic responses and molecular responses; 
durability will be assessed by evaluating ≤1% BCR-ABL1IS response and 
major molecular response (MMR) at and by 6, 12, 18, and 24 months

To characterize the rate of discontinuation, dose reductions, and interruptions

To characterize the rates of hematologic responses

To evaluate time to response, duration of response, and survival outcomes
Exploratory Objectives:

Correlation of tumor cell and plasma biomarkers with ponatinib efficacy and 
safety 

Quality of life (QoL) and health outcomes 
Study Endpoints
Primary Endpoint:
≤1% BCR-ABL1IS at 12 months for each starting dose cohort. 
Secondary Endpoints:

Molecular response rates: MMR at 12 and 24 months

Cytogenetic response rates: MCyR by 12 months

Duration of MMR

Safety
a.
Rate of AOEs and VTEs in each dose cohort
b.
Rate of AEs in each dose cohort
c.
Rate of SAEs in each dose cohort
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Other Secondary Endpoints:

Cytogenetic response rates: CCyR at 12 months

Molecular response rates: MR4, and MR4.5 by and at 3-month intervals and 
MR1 (≤10% BCR-ABL1IS) at 3 months

Hematologic response rate: Complete hematologic response (CHR) at 3 
months

Tolerability:
a.
Rate of discontinuation due to AEs in each dose cohort
b.
Dose reductions due to AE in each dose cohort
c.
Dose interruptions in each dose cohort 

Duration of response:
a.
Rate of ≤1% BCR-ABL1IS by 12 months and at and by 6, 18, and 24 
months 
b.
MMR at and by 6 and 18 months; and by 12 and 24 months

Duration of response in responders

Time to response

Rate of progression to accelerated phase (AP-) or blast phase (BP-) CML

PFS

OS
Exploratory Endpoints:

Correlation of tumor cell and plasma biomarkers with ponatinib efficacy and 
safety 

QoL and health outcomes as measured by EuroQol (EQ)-5D-5L and 
Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu)
Diagnosis and Main 
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for the study:
1.
Have CP-CML and have received at least two prior TKI therapies and have 
demonstrated resistance to treatment 
OR 
Have documented history of presence of T315I mutation after receiving any 
number of prior TKI. 
a.
The diagnosis of CML will be made using standard hematopathologic 
and cytogenetic criteria; CP-CML will be defined by all of the 
following:
i
< 15% blasts in bone marrow
ii
< 30% blasts plus promyelocytes in bone marrow
iii
< 20% basophils in peripheral blood
iv
≥ 100 × 109/L platelets (≥ 100,000/mm3)
v
No evidence of extramedullary disease except 
hepatosplenomegaly
vi
No prior diagnosis of AP- or BP-CML
b.
Cytogenetic assessment at screening must demonstrate the BCR-ABL1 
fusion by presence of the t(9;22) Philadelphia chromosome
i
Variant translocations are only allowed provided they meet 
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inclusion criterion 1d.
c.
Resistance to prior TKI therapy is defined as follows (patients must 
meet at least 1 criterion): 
i
Three months after the initiation of prior TKI therapy: No 
cytogenetic response (> 95% Ph+) or failure to achieve CHR or 
new mutation
ii
Six months after the initiation of prior TKI therapy: BCR-
ABL1IS >10% and/or Ph+ >65% or new mutation
iii
Twelve months after the initiation of prior TKI therapy: 
BCR-ABL1IS >10% and/or Ph+ >35% or new mutation.
iv
At any time after the initiation of prior TKI therapy, the 
development of a new BCR-ABL1 kinase domain mutation(s).
v
At any time after the initiation of prior TKI therapy, the 
development of new clonal evolution 
vi
At any time after the initiation of prior TKI therapy, the loss of 
CHR, or CCyR, or the confirmed loss of MMR in 2 consecutive 
tests, one of which has a BCR-ABL1IS transcript level of ≥1% or 
new mutation
d.
> 1% of BCR-ABL1IS as shown by real-time polymerase chain reaction
[NOTE: The above criteria were adapted from Baccarani et al, 2013.]
2.
Age ≥18 years old.
3.
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 
0, 1, or 2.
4.
Have adequate renal function as defined by the following criterion:
a.
Serum creatinine ≤1.5 × upper limit of normal (ULN) for institution
b.
Estimated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula) 
5.
Have adequate hepatic function as defined by the following criteria:
a.
Total serum bilirubin ≤1.5 × ULN, unless due to Gilbert’s syndrome
b.
Alanine aminotransferase (ALT) ≤2.5 × ULN, or ≤5 × ULN if 
leukemic infiltration of the liver is present
c.
Aspartate aminotransferase (AST) ≤2.5 × ULN, or ≤5 × ULN if 
leukemic infiltration of the liver is present 
6.
Have normal pancreatic status as defined by the following criterion:
a.
Serum lipase and amylase ≤1.5 × ULN
7.
Have normal QT interval corrected (Frederica) (QTcF) interval on screening 
electrocardiogram (ECG) evaluation, defined as QTcF of ≤ 450 ms in males or 
≤ 470 ms in females.
8.
Have a negative pregnancy test documented prior to enrollment (for females 
of childbearing potential).
9.
Agree to use a highly effective form of contraception with sexual partners 
from randomization through at least 4 months after the end of treatment (for 
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female and male patients who are fertile).
10.
Provide written informed consent.
11.
Be willing and able to comply with scheduled visits and study procedures.
12.
Have recovered from toxicities related to prior anticancer therapy to 
NCI CTCAE v 4.0 grade ≤1.
Main Exclusion Criteria
Patients are not eligible for participation in the study if they meet any of the 
following exclusion criteria:
1.
Have used any approved TKIs or investigational agents within 2 weeks or 
6 half-lives of the agent, whichever is longer, prior to receiving study drug. 
2.
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, or have not recovered 
(> grade 1 by the National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE], v4.0) from AEs (except alopecia) due to 
agents previously administered.
3.
Have undergone autologous or allogeneic stem cell transplant (SCT) < 60 
days prior to receiving the first dose of ponatinib; have any evidence of 
ongoing graft versus-host disease (GVHD) or GVHD requiring 
immunosuppressive therapy.
4.
Are being considered for hematopoietic SCT (HSCT) within 6-12 months of 
enrollment (note: ponatinib is not to be used as a bridge to HSCT in this trial).
5.
Are taking medications with a known risk of Torsades de Pointes 
(Appendix A).
6.
Have previously been treated with ponatinib.
7.
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.
8.
Have clinically significant, uncontrolled, or active cardiovascular disease, 
specifically including, but not restricted to:
a.
Any history of myocardial infarction (MI), unstable angina, cerebrovascular 
accident, or transient ischemic attack (TIA)
b.
Any history of peripheral vascular infarction, including visceral infarction
c.
Any revascularization procedure, including the placement of a stent 
d.
Congestive heart failure (CHF) (New York Heart Association [NYHA] 
class III or IV) within 6 months prior to enrollment, or left ventricular 
ejection fraction (LVEF) less than lower limit of normal, per local 
institutional standards, within 6 months prior to enrollment
e.
History of clinically significant (as determined by the treating physician) 
atrial arrhythmia or any history of ventricular arrhythmia
f.
Venous thromboembolism, including deep venous thrombosis or pulmonary 
embolism, within 6 months prior to enrollment
9.
Have uncontrolled hypertension (i.e., >150 and >90 for SBP and DBP, 
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respectively). Patients with hypertension should be under treatment at study 
entry to ensure blood pressure control. Those requiring 3 or more 
antihypertensive medications should be discussed with the medical monitor.
10.
Have poorly controlled diabetes defined as HbA1c values of > 7.5%. Patients 
with preexisting, well-controlled, diabetes are not excluded.
11.
Have a significant bleeding disorder unrelated to CML.
12.
Have a history of alcohol abuse.
13.
Have a history of either acute pancreatitis within 1 year of study enrollment or 
of chronic pancreatitis.
14.
Have malabsorption syndrome or other gastrointestinal illness that could 
affect oral absorption of study drug.
15.
Have a history of another malignancy, other than cervical cancer in situ or 
basal cell or squamous cell carcinoma of the skin; the exception is if patients 
have been disease-free for at least 5 years and are deemed by the investigator 
to be at low risk for recurrence of that malignancy.
16.
Are pregnant or lactating.
17.
Have undergone major surgery (with the exception of minor surgical 
procedures, such as catheter placement or BM biopsy) within 14 days prior to 
the first dose of ponatinib.
18.
Have an active infection which requires intravenous antibiotics.
19.
Have a known history of human immunodeficiency virus infection; testing is 
not required in the absence of prior documentation or known history.
20.
Have any condition or illness that, in the opinion of the investigator, would 
compromise patient safety or interfere with the evaluation of the drug.
21.
Have hypersensitivity to the ponatinib active substance or to any of its 
inactive ingredients listed in Section 14.7.1.
Approximate Number of 
Patients
The total enrollment will be 276 patients, with 92 (1:1:1) patients in each cohort. 
Approximate Duration of 
Patient Participation
The duration of patient participation will be approximately 24 months for all patients 
in the Main Treatment Period, with an option for patients completing or 
discontinuing from the Main Treatment Period who are still receiving clinical benefit 
from treatment to enter a Treatment Continuation Period after discussion and 
agreement between the investigator and medical monitor.  Each patient will undergo 
a period of up to 3 weeks for screening prior to treatment. The duration of therapy 
will be determined by each patient’s response and toxicity profile, and patients may 
remain on ponatinib in the study if the benefit-risk profile remains favorable.  
Patients will be followed for 30 days after last dose of study drug.
Approximate Duration of 
Study
The estimated duration of the trial is at least 96 months, including 36 months for 
enrollment and a treatment period of approximately 5 years.  The total duration of 
therapy, and therefore of the study, will be determined by each patient’s response 
and toxicity profile; the study will continue until all patients have been discontinued 
from the study or the study is terminated by the sponsor (whichever occurs first).
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Approximate Number of 
Study Centers
Approximately 150 centers; multi-national. 
Dosage and 
Administration
Patients will be randomized to receive once-daily oral administration of 1 of 3 
starting doses of ponatinib: 45 mg (Cohort A), 30 mg (Cohort B), or 15 mg (Cohort 
C).  Patients starting at 45 mg or 30 mg will have their daily dose reduced to 15 mg 
upon achievement of ≤1% BCR-ABL1IS (as defined within the protocol). 
Mandatory dose reduction on response details are described in Section 14.1.3. 
Dose interruptions or reductions should be implemented for patients who experience 
treatment-related AEs (TRAEs) upon clinical judgment of the investigator.  
Guidelines for management of TRAEs are described in Section 14.2.2. 
Concomitant Treatment
Medical or surgical treatment necessary for the patient’s well-being is permitted.  
Where appropriate, patients may be treated with hematopoietic growth factors for 
limited times.
Antidiabetic Treatment
Patients with diabetes are at increased risk of experiencing arterial occlusive events 
while being treated with ponatinib. Therefore, as a part of the assessment and 
management of the patient’s cardiovascular risk factors, initiation of or 
modifications to diabetic care should be considered in patients being treated with 
ponatinib who have elevated glucose levels.  The American Diabetes Association 
guidelines should be followed, and antidiabetic treatment and lifestyle intervention 
(including but not limited to weight loss, decreased fat intake, calorie restriction, 
increased physical activity, and smoking cessation) should be started in any patient 
with fasting glucose > 130 mg/dL (7.2 mmol/L) and/or HbA1c ≥7% (Diabetes 
Prevention Program Research Group, 2002; American Diabetes Association, 
Position Statement 2003).
Hypertension Treatment
Hypertension (HTN) may contribute to risk of arterial occlusive events.  Patients 
who have HTN should be managed appropriately before initiating treatment.  During 
ponatinib treatment, blood pressure elevations should be monitored and managed.  
Hypertension should be treated to achieve a goal of < 150/90 mmHg.  Initial 
antihypertensive treatment should generally include a thiazide-type diuretic, calcium 
channel blocker, angiotensin-converting enzyme inhibitor, or angiotensin receptor 
blocker (James et al, 2014).  Ponatinib treatment should be temporarily interrupted if 
HTN is not medically controlled.  Patients may require urgent clinical intervention 
for HTN associated with confusion, headache, chest pain, or shortness of breath.  
Prohibited Treatments
The following concurrent medications and treatments are prohibited:

Other anticancer therapies

Other investigational drugs or devices

Medications with a known risk of Torsades de Pointes (see Appendix A)

Herbal preparations or related over-the-counter preparations containing herbal 
ingredients

Elective surgery requiring inpatient care
Medications that are potent inhibitors or inducers of CYP3A4 (see Appendix B) 
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should be avoided, but are not prohibited (see Section 14.6).
Medications that prolong the QT interval (QT), but are without a known risk of 
Torsades de Pointes, should be avoided but are not prohibited.  If such medications 
are necessary and are used while a patient is on study, additional ECG monitoring 
should be performed as clinically indicated.
Efficacy Evaluation
Hematologic response rate, cytogenetic response rate, molecular response rate, and 
disease progression will be assessed according to standard criteria, as follows:

Bone marrow aspirates for assessment of cytogenetic response

BCR-ABL1IS assessment to determine molecular response

Complete blood count (CBC) for assessment of hematologic response

Survival follow-up
Patients will be followed for response, progression, and survival, for 24 months 
following treatment assignment in the Main Treatment Period. Patients who continue 
to receive treatment in the Treatment Continuation Period will continue to be 
followed to ensure continued clinical benefit and compliance with study treatment.  
Section 12 describes follow-up for all patients in the study.
Safety Evaluation
Safety assessments will include physical and laboratory examinations.  AEs will be 
graded according to the NCI CTCAE, v4.0.
All patients receiving at least 1 dose of ponatinib will be considered evaluable for 
safety.  The AE, AOE and VTE incidence rates, as well as the frequency of 
occurrence of overall toxicity—categorized by toxicity grades (severity)—will be 
described for each cohort.  Listings of laboratory test results will also be generated, 
and descriptive statistics summarizing the changes in laboratory tests over time will 
be presented. 
Pharmacokinetic 
Evaluation
Blood samples will be collected at specified time points to characterize the 
pharmacokinetics of ponatinib. Upon implementation of Amendment 6, no further 
PK sample collection will be performed as all ongoing patients have completed at 
least 12 cycles of treatment.
Plasma ponatinib concentration-time data will be obtained to contribute to 
population PK and exposure-response analyses of safety and efficacy. The analysis 
plan for the population PK and exposure-response analyses will be defined 
separately and the results of these analyses will be reported separately. 
Exploratory Biomarker 
Evaluation
The mutation status of BCR-ABL1 and other genes implicated in tumor biology 
and/or drug metabolism will be determined through analyses of tumor cells collected 
at study entry, on-study, and/or at end of treatment.  Blood plasma samples collected 
at screening, on study, and/or at end of treatment will be used to evaluate circulating 
biomarkers associated with ponatinib efficacy and safety. 
Quality of Life and 
Health Outcomes 
Evaluation
Patients will complete the EQ-5D-5L and FACT-Leu questionnaires at various times 
throughout the study. 
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Statistical Analysis
Overview of Trial Design:
This is a phase 2, randomized trial in patients with CP-CML.  The study will be 
stratified by age at baseline (≥60 vs. < 60 years) and history of hypertension, 
diabetes, and/or hyperlipidemia (yes/no). 
Cohorts A, B, and C will consist of CP-CML patients (resistant to previous TKI 
therapy or who have T315I mutation) being administered a daily starting dose of 45 
mg, 30 mg, or 15 mg ponatinib, respectively.  Patients starting at 45 mg or 30 mg 
will have their daily dose reduced to 15 mg upon achievement of ≤1% BCR-ABL1IS
(as defined below and in the protocol).  Each cohort of patients will be analyzed 
separately for efficacy and safety.
The primary endpoint for this trial will be ≤1% BCR-ABL1IS rate at 12 months. The 
primary analysis is planned after all patients have at least 12 months of follow-up; 
however, preliminary analyses may be performed at earlier time points. A final 
analysis is planned to be performed after all patients have at least 5 years of follow-
up.
Statistical inference will be made for each of the 3 cohorts separately, with the 
primary endpoint of ≤1% BCR-ABL1IS tested at 2-sided 0.05/3=0.0167 significant 
level using the Bonferroni method for multiplicity adjustment.  The primary analysis 
of the primary endpoint of ≤1% BCR-ABL1IS will be performed using a 2-sided 
exact 98.3% confidence interval (CI) for ≤1% BCR-ABL1IS rate based on the 
intention-to-treat (ITT) population.  Any other comparisons will be descriptive.
Sample Size Determination: 
The primary endpoint for this trial will be the ≤1% BCR-ABL1IS rate at 12 months.  
Consistent with the phase 2 PACE trial, the null or uninteresting ≤1% BCR-ABL1IS
rate is set at 20%.  The alternative ≤1% BCR-ABL1IS rate is set at 35%.  Using the 
Bonferroni method, the overall 2-sided significant level for statistical testing in each 
cohort will be set at 0.0167.  The primary analysis of the primary endpoint of ≤1% 
BCR-ABL1IS will be performed using a 2-sided exact 98.3% CI for ≤1% BCR-
ABL1IS rate based on the ITT population.
A total sample size of 276 patients or 92 patients in each cohort (1:1:1) will 
distinguish a favorable ≤1% BCR-ABL1IS rate of 35% from a null or an 
uninteresting ≤1% BCR-ABL1IS rate of 20%, with a nominal 80% power and a 1-
sided type I error rate of 0.0083 (equivalent to a 2-sided 0.0167) using an exact 
binomial test. Using the 20% boundary for ≤1% BCR-ABL1IS, 29 or more ≤1% 
BCR-ABL1IS responders will be needed for a lower limit of the 2-sided exact 98.3% 
CI for the ≤1% BCR-ABL1IS rate to exceed 20%. 
Rationale for Number of 
Patients
The total number of patients planned to be enrolled in this study is based on the sum 
of the individual cohorts described in the statistical considerations (276 patients). 
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5
TABLE OF CONTENTS
1
CONFIDENTIAL PROPERTY OF TAKEDA........................................................2
2
SIGNATURE PAGES...............................................................................................3
2.1
Signatory*......................................................................................................3
2.2
Investigator Signature...................................................................................4
2.3
Sponsor Representative Signature................................................................5
3
CONTACT INFORMATION ..................................................................................6
4
PROTOCOL SYNOPSIS..........................................................................................7
5
TABLE OF CONTENTS........................................................................................17
6
LIST OF ABBREVIATIONS.................................................................................22
7
DEFINITIONS OF TERMS...................................................................................25
8
INTRODUCTION...................................................................................................27
8.1
Ponatinib Preclinical Summary ..................................................................28
8.2
Ponatinib Clinical Efficacy..........................................................................28
8.2.1
Phase 1 Clinical Trial of Ponatinib (AP24534-07-101)...................28
8.2.2
Phase 2 Clinical Trial of Ponatinib (AP24534-10-201, PACE).......29
8.3
Dose-Response Analyses..............................................................................30
8.3.1
Dose Intensity and Efficacy .............................................................30
8.3.2
Dose Intensity and Safety ................................................................32
8.4
Rationale for Dose Reduction after Response ............................................33
8.5
Rationale behind Measures to Reduce Risk ...............................................34
8.6
Rationale for the Ponatinib Phase 2 Dose-Ranging Clinical Trial ............35
9
STUDY OBJECTIVES...........................................................................................36
9.1
Primary Objective .......................................................................................36
9.2
Secondary Objectives ..................................................................................36
9.3
Other Secondary Objectives .......................................................................37
9.4
Exploratory Objectives ...............................................................................37
10
INVESTIGATIONAL PLAN .................................................................................37
10.1
Overall Study Design and Plan ...................................................................37
10.1.1
Primary Endpoint............................................................................38
10.1.2
Secondary Endpoints.......................................................................38
10.1.3
Other Secondary Endpoints ............................................................38
10.1.4
Exploratory Endpoints ....................................................................39
10.2
Description of Treatment ............................................................................39
10.3
Randomization.............................................................................................39
10.4
Treatment Periods.......................................................................................40
10.4.1
Main Treatment Period ...................................................................40
10.4.2
Optional Treatment Continuation Period.......................................40
11
SELECTION OF STUDY POPULATION............................................................41
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11.1
Inclusion Criteria ........................................................................................41
11.2
Exclusion Criteria........................................................................................43
12
STUDY PROCEDURES.........................................................................................44
12.1
Schedule of Events.......................................................................................44
12.1.1
Changes to Study Procedures Due to COVID-19 Pandemic..........52
12.2
Patient Registration and Identification ......................................................57
12.2.1
Screen Failures.................................................................................57
12.2.2
Early Discontinuation from Study Drug Administration or 
Assessments......................................................................................57
12.3
Study Duration ............................................................................................57
12.4
Withdrawal Criteria....................................................................................58
12.4.1
Main Treatment Period ...................................................................58
12.4.1.1
Failure to Meet or Maintain Protocol-Defined Response 
Criteria in the Main Treatment Period..................................59
12.4.2
Treatment Continuation Period ......................................................59
12.5
Study or Site Termination...........................................................................60
12.6
Sample Collection, Storage, and Shipping..................................................60
13
EFFICACY AND SAFETY ASSESSMENTS .......................................................60
13.1
Efficacy Assessments...................................................................................60
13.2
Safety Assessments ......................................................................................61
13.2.1
Adverse Events.................................................................................61
13.3
PK Evaluations............................................................................................61
13.4
Exploratory Biomarker Evaluations in Tissue and Plasma.......................61
13.5
QoL Assessments.........................................................................................61
13.5.1
EQ-5D-5L.........................................................................................61
13.5.2
FACT-Leu ........................................................................................62
14
STUDY TREATMENT...........................................................................................62
14.1
Study Treatment..........................................................................................62
14.1.1
Starting Dose Assignment................................................................62
14.1.2
Treatment Administration...............................................................62
14.1.3
Mandatory Dose Reduction for Response Scheme .........................62
14.1.4
Loss of Response after Dose Reduction for ≤1% BCR-ABL1IS ....63
14.1.5
Treatment during the Treatment Continuation Period .................64
14.2
Supportive Care...........................................................................................64
14.2.1
Management of Selected AEs ..........................................................65
14.2.1.1
Arterial Occlusive and Venous Thrombotic/Embolic 
Events....................................................................................65
14.2.1.2
Neuropathy............................................................................66
14.2.1.3
Hepatotoxicity........................................................................67
14.2.1.4
CHF and Left Ventricular Dysfunction.................................67
14.2.1.5
Hypertension .........................................................................67
14.2.1.6
Ocular Toxicity......................................................................67
14.2.1.7
Pancreatitis and Lipase or Amylase Elevations.....................67
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14.2.1.8
Hemorrhage ..........................................................................68
14.2.1.9
Fluid Retention and Edema...................................................68
14.2.1.10 Cardiac Arrhythmias.............................................................68
14.2.1.11 Myelosuppression..................................................................68
14.2.1.12 Tumor Lysis Syndrome (TLS) ...............................................68
14.2.1.13 Rash and/or Pruritus.............................................................69
14.2.1.14 Diarrhea, Nausea, and Vomiting...........................................69
14.2.1.15 Constitutional Symptoms/Joint Pain .....................................69
14.2.1.16 Compromised Wound Healing and Gastrointestinal 
Perforation ............................................................................70
14.2.1.17 Posterior Reversible Encephalopathy Syndrome (PRES)......70
14.2.2
Dose Modifications for Adverse Drug Reactions............................70
14.2.2.1
Dose Reduction Guidelines....................................................70
14.2.2.2
Dose Modifications for AOEs and VTEs...............................76
14.2.2.3
Dose Re-Escalation after Resolution of Adverse Drug 
Reactions ...............................................................................79
14.3
Prior and Concomitant Treatment(s)/Therapy..........................................80
14.4
Permitted Treatment...................................................................................80
14.5
Prohibited Treatment(s)/Therapy...............................................................80
14.6
Potential Drug Interactions.........................................................................81
14.7
Treatment Supply........................................................................................81
14.7.1
Formulation, Packaging, and Labeling...........................................81
14.7.2
Treatment Storage, Dispensing, and Accountability......................82
14.7.2.1
Disposition of Used Supplies .................................................82
14.7.2.2
Inventory of Unused Supplies................................................82
15
ADVERSE EVENT REPORTING ........................................................................83
15.1
AEs...............................................................................................................83
15.1.1
AE Definition ...................................................................................83
15.1.2
Abnormal Test Findings..................................................................83
15.1.3
Performing AE Assessments............................................................84
15.1.4
Reporting Period..............................................................................84
15.1.5
AE Severity ......................................................................................84
15.1.6
Causality...........................................................................................85
15.1.7
Expectedness ....................................................................................86
15.2
Serious Adverse Events (SAEs) and Adverse Events of Special 
Interests (AESIs) .........................................................................................86
15.2.1
Serious Adverse Events Definition ..................................................86
15.2.1.1
Progression of the malignancy under study (including 
signs and symptoms of progression)......................................87
15.2.1.2
Hospitalizations.....................................................................87
15.2.2
AESIs................................................................................................88
15.2.3
Reporting SAEs................................................................................89
15.2.4
Information to be Provided by the Investigator for an SAE..........90
15.2.5
Follow-up Information on a SAE ....................................................90
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15.3
Other Safety Issues......................................................................................91
15.3.1
Contraception and Pregnancy.........................................................91
15.3.2
Overdose...........................................................................................92
16
PLANNED STATISTICAL METHODS ...............................................................92
16.1
General Considerations...............................................................................92
16.2
Analysis Populations ...................................................................................93
16.3
Study Endpoints ..........................................................................................93
16.4
Determination of Sample Size.....................................................................94
16.5
Efficacy Analysis .........................................................................................94
16.5.1
Definitions of Efficacy Endpoints....................................................94
16.5.1.1
Molecular Response Definitions............................................94
16.5.1.2
Cytogenetic Response Definitions .........................................95
16.5.1.3
Hematologic Response Definitions........................................96
16.5.1.4
Event-Related Definitions......................................................96
16.5.2
Primary Endpoint Analysis .............................................................97
16.5.2.1
Data Handling Rules for the Primary Analyses of the 
Primary Endpoint..................................................................97
16.5.3
Secondary Efficacy Endpoint Analyses...........................................98
16.5.3.1
Secondary Efficacy Endpoints...............................................98
16.5.3.2
Data Handling Rules for Secondary Efficacy Endpoint 
Analyses.................................................................................98
16.5.4
Subgroup Analyses of the Primary Endpoint and Secondary 
Efficacy Endpoints...........................................................................99
16.5.5
Exploratory Analysis on Treatment Continuation Period .............99
16.6
Safety Analysis.............................................................................................99
16.6.1
Analysis of AOEs and VTEs............................................................99
16.6.2
Analysis of Categories of AEs........................................................100
16.6.3
Other Safety Analyses....................................................................100
16.6.4
Analyses of Treatment Discontinuation Rate due to AEs, Dose 
Reductions, and Dose Interruptions..............................................101
16.7
Exposure-Response Analysis.....................................................................101
16.8
QoL/Health Outcomes Analysis................................................................101
16.9
Exploratory Biomarker Analyses .............................................................101
16.10
Protocol Deviations/Violations..................................................................101
17
QUALITY CONTROL AND QUALITY ASSURANCE ....................................101
17.1
Investigators and Study Administrative Structure ..................................102
17.2
Study Monitoring ......................................................................................102
18
ETHICAL CONDUCT OF THE STUDY............................................................103
18.1
Institutional Review Board or Ethics Committee Approval....................103
18.2
Patient Information and Consent .............................................................103
18.3
Patient Confidentiality ..............................................................................103
18.4
Study Committees......................................................................................104
18.4.1
Data Monitoring Committee (DMC).............................................104
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8
INTRODUCTION
This protocol describes a phase 2 open-label study of 3 different starting dosages of ponatinib for 
treatment of patients with refractory chronic myeloid leukemia (CML) in chronic phase (CP).  
Ponatinib was designed to inhibit the BCR-ABL1 protein, the pathogenetic driver of CML, with 
high potency and pan-inhibitory capability.  Pan-inhibition refers to ponatinib’s ability, in 
preclinical experiments, to inhibit or prevent the emergence of all single mutations that arise in 
the course of therapy with imatinib, dasatinib, nilotinib, and bosutinib, and which have been 
observed to engender resistance of CML to treatment with these currently available tyrosine 
kinase inhibitors (TKIs).  Data from the phase 1 and phase 2 clinical trials of ponatinib have 
supported the preclinical findings and demonstrated that ponatinib has substantial activity in 
CML that has become resistant to prior therapy.
Ponatinib (ICLUSIG®) is approved in the United States (US) for the treatment of adult patients 
with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or 
Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other 
TKI therapy is indicated and for treatment of adult patients with T315I-positive CML (chronic 
phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL. In the European Union 
(EU), ponatinib is approved for the treatment of adult patients with CML (chronic phase, 
accelerated phase, or blast phase) and Ph+ ALL who are resistant to dasatinib (or nilotinib for 
CML) and intolerant to dasatinib (or nilotinib for CML) and for whom subsequent treatment with 
imatinib is not clinically appropriate, or who have the T315I mutation.
The phase 2 clinical trial of ponatinib in patients with CML or Ph+ ALL who have had prior TKI 
therapy (AP24534-10-201, PACE), which supported the drug’s approvals, tested a starting dose 
of 45 mg daily. The 5-year data from this study confirmed that treatment with ponatinib 
continued to provide clinically meaningful responses.  In patients with CP-CML, the primary 
endpoint was met in more than double that of the most recent dasatinib or nilotinib therapy 
(55.4% vs. 25.8%) and 85.7% remained in the primary endpoint for ≥550 days at 30 mg.  The 
median duration of follow-up was 37.3 months. Continuing analyses of the phase 2 trial have 
demonstrated a higher cumulative incidence of arterial occlusive events (including 
cardiovascular, cerebrovascular, and peripheral vascular events) observed with a longer follow-
up, than reported at the time of the initial approval.  Arterial and venous thrombosis and 
occlusions—including fatal myocardial infarction (MI), stroke, severe peripheral vascular 
disease, and the need for urgent revascularization procedures—have been reported in ponatinib-
treated patients.
Current data suggest that a dose-effect relationship exists with efficacy and with the occurrence 
of arterial occlusive events (AOEs), and that a lower daily dose may reduce the incidence of 
AOEs.  This clinical study will assess the relationships of exposure with efficacy and safety: 
patients will receive a range of initial doses, and at defined time points, patients in response will 
undergo a dose reduction.  The goal of the study will thus be to understand induction of 
responses, maintenance of responses, safety, and exposure-response as consequences of these 
dosing strategies.
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The primary endpoint of this study will be the achievement of ≤1% BCR-ABL1IS at 12 months. 
This incorporates standard CML approaches to patient care and uses patient monitoring. 
Increasingly, patient monitoring is being performed by quantitation of BCR-ABL1 transcripts 
from a standard established by the international scale (IS) (Marin, 2014; NCCN, 2014; Baccarani 
et al, 2013; Marin et al, 2012; Lauseker et al, 2012; Saglio et al, 2012).  
This trial is being conducted in fulfillment of an FDA post-marketing requirement (PMR2113-6).
8.1
Ponatinib Preclinical Summary
In vitro assays demonstrated that ponatinib potently inhibits the kinase enzymatic activity of 
native ABL1 and mutant versions of the protein, including T315I, with IC50 concentrations 
between 0.4 and 2.0 nM.  Ponatinib inhibited the in vitro kinase activity of additional kinases 
with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, 
FGFR, and EPH receptors and the SRC families of kinases, as well as KIT, RET, TIE2, and 
FLT3.  In a cell line expressing native BCR-ABL1, ponatinib inhibited viability with an IC50
< 1 nM.  Ponatinib also potently inhibited viability (with IC50s < 40 nM) of cell lines expressing 
14 major clinically-observed BCR-ABL1 mutants that are resistant to the other approved TKIs.  
The ability of ponatinib to suppress the emergence of resistant mutants was also assessed.  Using 
an in vitro mutagenesis screen approach, which has successfully predicted mutations that confer 
clinical resistance to the approved TKIs (Bradeen et al, 2006), 40 nM concentration of ponatinib 
was found to suppress the emergence of any resistant BCR-ABL1 mutation (O’Hare et al, 2009).  
Based on these data, the hypothesis that ponatinib will treat BCR-ABL1-driven leukemia with 
high potency and effectiveness was tested in phase 1, 2, and 3 trials.
8.2
Ponatinib Clinical Efficacy
8.2.1
Phase 1 Clinical Trial of Ponatinib (AP24534-07-101)
The phase 1 trial of ponatinib enrolled 81 patients with hematologic malignancies who had no 
other effective treatment options.  Doses from 2 mg to 60 mg were investigated, and 45 mg was 
chosen as the recommended phase 2 dose (RP2D).  The trial has completed, with all 81 patients 
discontinued from the study.  As of 18 October 2016, the MCyR rate for CP-CML patients 
(N=31/43) was 72% (CCyR rate of 65.1%) and 83.3% in patients with T315I; the MMR rate for 
these patients was 55.8%; and the MR4.5 (≤0.0032% BCR-ABL1IS) rate was 32.6%.  Duration 
of MCyR ranged from 8 to 345 weeks (median not yet reached), and the Kaplan-Meier method 
estimated that 72% of responders will remain in MCyR at 4years.  At the time of analysis, of the 
43 CP-CML patients, 22 who achieved MCyR remained on study—20 of whom were in 
continuous MCyR.
Steady-state peak plasma concentrations of ponatinib at dose levels of 45 mg, 30 mg, and 15 mg 
exceeded the concentration (40 nM) required to suppress the emergence of any resistant 
BCR-ABL1 mutations.  Efficacy was demonstrated at each of these dose levels, and responses 
were maintained for patients who started at 45 mg and reduced to 15 mg (all 3 of the ongoing 
CP-CML patients in the 15-mg dose cohort had achieved and maintained MCyR at the time of 
filing).
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As of 18 October 2016, the most common treatment-emergent AEs (TEAEs) (≥30%) were rash 
(49.4 %), nausea (45.7%), fatigue (45.7%),  headache (43.2%), arthralgia (39.5%), constipation 
(39.5%), vomiting (39.5%), hypertension (37.0%), pyrexia (37.0%), edema peripheral (35.8%), 
platelet count decreased (35.8%), abdominal pain (34.6%), diarrhea (32.1%) and rash 
erythematous (30.9%).  
Overall, 81.5% of patients experienced a treatment-emergent SAE.  Pancreatitis, the 
dose-limiting toxicity (DLT) in the phase 1 study, was the most common treatment-related SAE, 
occurring in 12.3% of patients.  The SAEs with the highest incidence (> 5% of patients), 
regardless of relationship to study treatment, were febrile neutropenia (14.8%), pneumonia 
(13.6%), pancreatitis (12.3%), pyrexia (11.1%), neoplasm progression (8.6%), abdominal pain 
(7.4%), atrial fibrillation (7.4%), and dyspnea (6.2%).  Serious AOEs and VTEs occurred in 
24 patients (30%): 13 (16%) had cardiovascular SAEs, 5 (6%) had cerebrovascular SAEs, 7 (9%) 
had peripheral vascular SAEs, and 4 (5%) had venous SAEs.  A more detailed presentation of 
AEs is provided in the Clinical Investigator’s Brochure for ponatinib.
8.2.2
Phase 2 Clinical Trial of Ponatinib (AP24534-10-201, PACE)
The phase 2 trial enrolled 449 patients with refractory CML (all phases) or Ph+ ALL that was 
either resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation.  Patients 
received 45 mg ponatinib orally once daily (QD).  The 5-year study report was completed, with 
10 patients still ongoing at 1 site in Korea as of the data cutoff date of 06 February 2017.  
Median duration of follow-up for the overall population was 37.3 months (range: 0.07-73.13).  
As of 06 February 2017, the overall MCyR rate for CP-CML patients (N=148) was 55.4% and 
overall CCyR rate was 46.1% (N=123).  The MCyR and CCyR rate for CP-CML R/I patients 
were 50.7% and 39.9% respectively, and for CP-CML patients with the T315I mutation 
confirmed at baseline, the MCyR and CCyR rates were 70.3% and 65.6% respectively.  The 
overall MMR rate was 40.4% (57.8% in T315I patients) (Table 1).  
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Table 1
Best Response to Therapy (Treated Population) in CP-CML Patients 
(AP24534-10-201)
CP-CML Patients
Total
N=267
Cohort A 
CP/R/I
N=203
Cohort B
CP/T315I
N=64
Hematologic, n (%)a
N=267
N=203
N=64
CHRa
251 (94.0)
192 (94.6)
59 (92.2)
Cytogenetic, n (%)b
N=267
N=203
N=64
MCyR
148 (55.4)
103 (50.7)
45 (70.3)
CCyR 
123 (46.1)
81 (39.9)
42 (65.6)
PCyR
25 (9.4)
22 (10.8)
3 (4.7)
Molecular, n (%)c
N=267
N=203
N=64
MMR
108 (40.4)
71 (35.0)
37 (57.8)
Data extraction date: 06 February 2017
a  Hematologic response is defined as CHR for Cohorts A and B.
b  Patients entering the study in PCyR must have achieved a CCyR to be considered as having met MCyR criteria.
c  Patients for whom a valid baseline MMR assessment was missing or who met the criteria for MMR at baseline were analyzed 
as nonresponders.  
Abbreviations: CP-CML=chronic phase chronic myeloid leukemia; CHR=complete hematologic response; MCyR=major 
cytogenetic response; CCyR=complete cytogenetic response; PCyR=partial cytogenetic response; MMR=major molecular 
response; R/I=resistant/intolerant
As of 06 February 2017, the most commonly reported TEAEs (i.e., incidence of ≥20% of 449 
patients overall, in decreasing order of frequency) were platelet count decreased, abdominal pain, 
rash, constipation, headache, dry skin, hypertension, fatigue, pyrexia, arthralgia, nausea, 
neutrophil count decreased, anemia, diarrhea, lipase increased, vomiting, myalgia, and pain in 
extremity.
SAEs considered to be treatment-related were reported in 172/449 patients (38.3%). The most 
common SAEs considered by the Investigator to be treatment-related were pancreatitis 
(25/449 patients; 5.6%) and peripheral arterial occlusive disease (14/449 patients; 3.1%). All 
other treatment-related SAEs were reported in <3% of the overall population. In general, 
treatment-related SAEs were reported in a higher proportion of CP-CML patients (who had the 
longest treatment duration) compared with AP-CML and dBP-CML/Ph+ ALL patients.
8.3
Dose-Response Analyses
This clinical trial will test 2 modulations of dose: both a range of starting doses utilized in the 
phase 1 and 2 clinical trials (as described in Section 8.2.1 and Section 8.2.2), and dose reduction 
at defined time points for patients in response.  The data that support these approaches derive 
from univariate and multivariate analyses of the relationship of dose, efficacy, and safety and 
analyses of the effects of dose reductions on response and safety.
8.3.1
Dose Intensity and Efficacy
The impact of dose on MCyR in patients with CP-CML has been evaluated using 
2 methodologies: a multivariate analysis adjusting for covariates, and an analysis of dose 
response in patients with at least 3 months of follow-up that separates them into tertiles of dose 
intensity (the latter analysis also includes CCyR and MMR).  Both analyses show that increasing 
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dose intensity is associated with higher response rates, and that factors affecting MCyR rate 
include dose intensity, patient age, prior TKI exposure, and baseline platelet counts (Table 2).
Table 2
Multivariate Logistic Regression Analyses of MCyR by 12 Months in 
CP-CML Patients (AP24534-10-201)
Reduced Multivariate Model1
Unit for OR
Covariate
OR
p-value
Dose intensity to time of first event
3.222
< 0.0001
15 mg/day
Time Since Diagnosis (years)
NS
10 years
Prior Regimens (up to 6)
0.734
0.0028
1
Baseline T315I Mutation
NS
1
log10 Baseline Neutrophils
NS
1
log10 Baseline Platelets
2.236
0.1207
1
Age (years)
0.808
0.0415
10 years
Number TKIs
NS
1
Medical Hx of Diabetes
NS
1
Medical Hx of Ischemia
NS
1
1Data extraction date: 03 September 2013
Abbreviations: Hx=history, NS=not significant, OR=odds ratio.
As further evidence, an analysis of CP-CML patients from the phase 2 PACE trial who had 
received at least 3 months of follow-up showed a decline in MCyR and MMR from the highest 
dose-intensity tertile to the lowest dose-intensity tertile (Table 3).  Response rates are 
nevertheless high in the lowest tertile and higher in the higher tertiles.
Table 3
Response Rate by Dose Tertile in CP-CML Patients (AP24534-10-201)
Dose Intensity (mg/day)
Response (%)
MCyR
CCyR
MMR
> 40 (n=80)
76%
70%
56%
> 26 to ≤40 (n=79)
68%
54%
48%
≤26 (n=79)
42%
30%
22%
Data extraction date: 03 September 2013. 
N restricted to the subset of patients with at least 3 months of follow-up (to exclude the impact of patients who dropped out with 
insufficient exposure to see a response).
Abbreviations: CCyR=complete cytogenetic response, MCyR=major cytogenetic response, MMR=major molecular response.
In a population with refractory disease and few viable treatment options, achieving an initial 
response is among the most important goals of TKI treatment.  The starting dose of 45 mg once 
daily used in the phase 2 trial of ponatinib has been shown to yield responses in a high 
proportion of patients.  The exposure-response analyses to date also support the conclusions from 
univariate and multivariate analyses: that patients who receive a higher starting dose (and 
therefore, a higher exposure, on average) achieve a response more quickly.  However, response 
rates are sufficiently high to reasonably attempt identification—both prospectively and with 
greater resolution—of the effect of lower starting doses.  Thus, this clinical study will test 
starting doses across the range of doses (45, 30, and 15 mg) utilized in the phase 2 and phase 3 
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programs, with an aim to identify with specificity the response rates obtainable with lower initial 
doses of ponatinib.
8.3.2
Dose Intensity and Safety 
Multivariate analyses on data from the phase 2 PACE trial were also performed to elucidate the 
relationship between dose intensity (as measured by the daily dose given) and safety.  In general, 
increasing dose intensity correlated with an increased probability of experiencing AEs.  The 
factors associated with a lower probability of AEs were younger age, less time since diagnosis, 
and fewer prior TKIs.  Patients with a T315I mutation (who were generally younger, with a 
shorter time since diagnosis and fewer prior TKI therapies) did, in fact, experience less 
thrombocytopenia and neutropenia. 
With longer follow-up and the accumulation of AOEs and VTEs, the relationship between dose 
intensity and the events was examined, using multivariate analysis with an expanded set of 
covariates with a minimum of 24 months of follow-up.  All modeling showed that dose intensity 
(up to the time of the events) was statistically-significantly associated with an increase in event 
rate in univariate models, and became more significant when adjusting for covariates in 
multivariate models.  
The specific relationships among dose, AOEs and VTEs, and clinical covariates were also 
examined.  Data are shown below in Table 4.  The analysis demonstrates that the strongest 
associations with the occurrence of vascular events were observed with age (odds ratio 1.82; 
p < 0.0001), a medical history of diabetes (odds ratio 3.69; p=0.0003), dose intensity (odds ratio 
1.99/15-mg dose; p=0.0009), a medical history of ischemia (odds ratio 2.46; p=0.0087), and time 
since diagnosis (odds ratio 2.03; p=0.0228).  Other contributing factors were baseline neutrophil 
(p=0.0276) and platelet counts (p=0.0466), the number of prior regimens (p=0.0755), and the 
presence of the T315I mutation (p=0.1328). 
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Table 4
Multivariate Logistic Regression Analysis of Arterial Occlusive Events 
(AP24534-10-201)
Reduced Multivariate Model
Covariate
Odds Ratio1
p-value
Dose intensity to time of first event (mg/day)
1.99
0.0009
Time Since Diagnosis (years)
2.03
0.0228
Prior Regimens (up to 6)
0.81
0.0755
Baseline T315I Mutation
1.69
0.1328
log10 Baseline Neutrophils
2.00
0.0276
log10 Baseline Platelets
2.16
0.0466
Age (years)
1.82
< 0.0001
Medical History of Diabetes
3.69
0.0003
Medical History of Ischemia
2.46
0.0087
Data extraction date: 03 September 2013
Includes all phase 2 PACE study patients with baseline data available (N=441).
1Odds ratio values below 1 indicate a negative correlation, while values above 1 indicate a positive correlation.
These data suggest that the risk of AOEs can be influenced by dose, as well as by clinical and 
historical factors pertaining to the patient population.  The data, in conjunction with the 
dose-response data discussed above, provide the rationale for testing lower starting doses in 
CP-CML patients.  They also suggest that other measures to lower exposure, such as dose 
reduction, may be protective.
8.4
Rationale for Dose Reduction after Response 
Dose intensity appears to be related to the risk of arterial occlusive events, and preliminary 
analyses in patients with AEs suggest that patients can maintain response on doses lower than 
45 mg.  The multivariate analysis demonstrates that several covariates contribute significantly to 
the risk of vascular events.  
Data demonstrate that despite reductions in dose intensity (as a result of AEs), patients are able 
to maintain responses.  Data from the patients in the phase 2 PACE trial who underwent dose 
reduction are shown in Table 5.
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Table 5
Summary of Patients who Dose Reduced in AP24534-10-201 by 
Time Period
Achieved Response at 45 mg 
(N=87, 82 maintained response)
Achieved Response at 30 mg 
(N=46, 41 maintained response)
Dose Reduction Period
Number of 
Patients
Maintained 
Response
Number of 
Patients
Maintained 
Response
Any Dose Reduction
59
59 (100%) 
29
28 (97%)
≥ 60 Day Reduction
48
48 (100%)
20
20 (100%)
≥ 90 Day Reduction
32
32 (100%)
14
14 (100%)
≥ 120 Day Reduction
30
30 (100%)
13
13 (100%)
≥ 180 Day Reduction
27
27 (100%)
12
12 (100%)
≥ 360 Day Reduction 
19
19 (100%)
9
9 (100%)
Data extraction date: 06 January 2014
These findings illustrate that patients who achieved response, either at 45 mg or 30 mg, 
maintained responses after dose reduction (because of AEs) to 30 mg or 15 mg.  The 
maintenance of response appears to be independent of the length of dose reduction.  Thus, there 
is a rationale for testing a standard approach to dose reduction in patients who have achieved 
response in this study. 
Taken together, these data support the use of a 45-mg dose or a 30-mg dose to achieve a 
response in patients with no effective treatment options, and to then reduce the dose to maintain 
response while lowering the risk of long-term AEs.
8.5
Rationale behind Measures to Reduce Risk
Therapy with ponatinib should be initiated by a physician experienced in the diagnosis and 
treatment of patients with leukemia.  As discussed and as demonstrated in the multivariate 
analyses, several aspects of patient history contribute to the risk of developing vascular 
complications of therapy; while patients both with and without risk factors experience such 
complications, the presence of certain risks is strongly associated with AEs. Table 6
demonstrates the univariate relationship between a variety of historical risk factors and the 
occurrence of vascular complications in the phase 2 PACE trial.
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Table 6
Summary of Results of Univariate Logistic Regression Analysis of 
Arterial SAE Rates in AP24534-10-201
Risk Factor
Arterial SAE Rate 
in PACE Patients 
with Risk Factor1
Arterial SAE Rate 
in PACE Patients 
Excluding Patients 
with Risk Factor2
Relative Risk
None
-
11.8%
History of MI (n=18)
44.4%
10.4%
4.3
History of CAD (n=33)
42.4%
9.4%
4.5
History of coronary revascularization (n=14)
42.9%
10.8%
4.0
History of ischemic cardiac disease (n=57)
29.8%
9.2%
3.2
History of nonischemic cardiac disease (n=192)
13.5%
10.5%
1.3
History of ischemic disease (n=100)
27.0%
7.4%
3.6
Venous thromboembolism (n=8)
10.5%
11.9%
0.9
Diabetes (n=72)
23.6%
9.5%
2.5
Hypertension (n=239)
18.4%
4.3%
4.3
Hypercholesterolemia (n=246)
15.0%
7.9%
1.9
Obesity (n=109)
12.8%
11.5%
1.1
Age ≥ 65 years (n=155)
16.1%
9.5%
1.7
Any risk factor or disease history (n=376)
13.6%
2.7%
5.0
1 or more risk factors (n=344)
14.0%
4.8%
2.9
2 or more risk factors (n=214)
18.2%
6.0%
3.0
3 or more risk factors (n=88)
21.6%
9.4%
2.3
4 risk factors (n=20)
30.0%
11.0%
2.7
Data extraction date: 03 September 2013
1Patients with risk factor who had arterial SAEs/total patients with risk factor in phase 2 PACE study.
2Patients without risk factor who had arterial SAEs/total patients without risk factor in phase 2 PACE study.
Abbreviations: CAD=coronary artery disease; MI=myocardial infarction
It is clear that certain risks, such as prior MI or coronary disease, can be discretely identified in 
patient medical history and are associated with increased risk.  Thus, based on these 
observations, patients with MI, unstable angina, or CHF within 3 months prior to the first dose of 
ponatinib are excluded from the study.  Similarly, patients with a history of clinically significant 
atrial arrhythmia or any ventricular arrhythmia are also excluded.  
Other identified baseline risk factors for serious AOEs and VTEs include diabetes mellitus, 
hypertension, and hypercholesterolemia.  These conditions can be managed in the course of 
therapy; consequently, their appropriate medical treatment and control are mandatory in this 
clinical trial.
8.6
Rationale for the Ponatinib Phase 2 Dose-Ranging Clinical Trial
Ponatinib is approved for the treatment of CP-CML patients, based on response rate observations 
in refractory patients in a phase 2 clinical trial (AP24534-10-201, PACE).  Responses were 
achieved in heavily pretreated patients and in patients who had resistance mutations, but also in 
patients who did not.  Responses were durable, with 39.6% of CP-CML patients continuing to 
receive clinical benefit and remaining on ponatinib for > 4 years.  Continuing analyses of the 
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phase 2 trial have demonstrated a higher cumulative incidence of arterial occlusive events 
(including cardiovascular, cerebrovascular, and peripheral vascular events) observed with a 
longer follow-up, than reported at the time of the initial approvals in the US and EU.  Thus, there 
exists a need to examine strategies to lessen vascular complications of long-term therapy in these 
patients who have a substantial, unmet therapeutic need and stand to benefit from ponatinib 
therapy.
Analyses from the phase 1 and phase 2 trials suggest that a dose-effect relationship exists with 
the occurrence of responses.  The conclusions of the multivariate analyses support the 
proposition that higher dose intensities in refractory patients yield higher response rates across
the dose ranges tested.  This provides the basis for retaining a starting dose of 45 mg daily, which 
will maximize the possibility of each patient achieving a rapid response and maintaining it—both 
key requirements of successful therapy in patients with this unmet medical need.  Based on the 
preclinical findings and additional clinical observations, supporting evidence points to lower 
dose intensities having the capability to induce and maintain cytogenetic responses in patients 
with CP-CML.  Steady-state peak plasma concentrations of ponatinib at dose levels of 45 mg, 
30 mg, and 15 mg exceeded the concentration (40 nM) required to suppress the emergence of 
any resistant BCR-ABL1 mutations.  Efficacy was demonstrated at each of these dose levels, and 
responses were maintained for patients who started at 45 mg and reduced to 15 mg.  Thus, the 
initial doses in this study will be 45 mg, 30 mg, and 15 mg daily.
The accumulation of vascular complications is also related to dose.  Although patients without 
pre-existing risk factors experience vascular AEs, several risks have been identified that can aid 
in selecting appropriate patients for therapy; additionally, the management of concurrent medical 
conditions may further mitigate risk.
In summary, this randomized phase 2 clinical trial will examine a range of ponatinib doses—
both initially and as part of a dose reduction strategy—in CP-CML patients, and will generate 
data on efficacy and safety in relation to dose, supported by pharmacokinetic data.  The goal of 
this study is to test the hypothesis that each of the 3 starting doses will demonstrate the continued 
efficacy of ponatinib, and that the dose reduction strategy will lessen vascular occlusive 
complications in the resistant CP-CML patient population—including patients with or without 
the T315I mutation who have no alternative therapies available.
9
STUDY OBJECTIVES
9.1
Primary Objective

To characterize the efficacy of ponatinib administered in 3 starting doses (45 mg, 30 mg, 
and 15 mg daily) in patients with CP-CML who are resistant to prior TKI therapy or have 
T315I mutation, as measured by ≤1% BCR-ABL1IS at 12 months.
9.2
Secondary Objectives

To characterize the rate of major molecular response (MMR) at 12 and 24 months and rate 
of major cytogenetic response (MCyR) by 12 months

To evaluate duration of MMR
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
To characterize the rates of AOEs, VTEs, AEs, and SAEs  

To evaluate safety differences among the 3 starting dose cohorts, particularly for AOEs and 
VTEs

To collect sparse PK samples to contribute to population PK and exposure-response 
analyses of safety and efficacy 
9.3
Other Secondary Objectives

To characterize the rates of cytogenetic responses and molecular responses; durability will 
be assessed by evaluating ≤1% BCR-ABL1IS and MMR at and by 6, 12, 18, and 24 months

To characterize the rates of discontinuation, dose reductions, and dose interruptions

To characterize the rates of hematologic responses

To evaluate time to response, duration of response, and survival outcomes
9.4
Exploratory Objectives

Correlation of tumor cell and plasma biomarkers with ponatinib efficacy and safety 

Quality of Life (QoL) and health outcomes
10
INVESTIGATIONAL PLAN
10.1
Overall Study Design and Plan
This is a multi-center, randomized phase 2 trial to characterize the efficacy of ponatinib over a 
range of 3 starting doses.  Eligible patients must have CP-CML; have received at least 2 prior 
TKI therapies and have demonstrated resistance to treatment or have the T315I mutation, as 
defined in Section 11.  The trial will also assess the short- and long-term safety of the 3 starting 
doses investigated.
Patients will be randomized to receive once-daily oral administration of 1 of 3 starting doses of 
ponatinib: 45 mg (Cohort A), 30 mg (Cohort B), or 15 mg (Cohort C).  Patients starting at 45 mg 
or 30 mg will have their daily dose reduced to 15 mg upon achievement of ≤1% BCR-ABL1IS, 
as described in Section 14.1.3.  In the event of loss of ≤1% BCR-ABL1IS after dose reduction 
for response, and in the absence of AEs necessitating continued dose reduction, escalation back 
to the starting dose will be allowed, upon review and agreement with the medical monitor. 
All randomized patients will enter the Main Treatment Period.  Patients will remain on treatment 
in the Main Treatment Period for 24 months.  Following completion of or withdrawal from the 
Main Treatment Period (as described in Section 12.4.1), patients who are both tolerating 
treatment and receiving clinical benefit from treatment may enter into the optional Treatment 
Continuation Period upon discussion and agreement between the investigator and medical 
monitor.  Examples of clinical benefit that could allow a patient to enter the Treatment 
Continuation Period include (but are not limited to) a reduction from baseline in BCR-ABLIS
levels (but without meeting the protocol-defined response criterion of ≤1% BCR-ABL1IS at 
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12 months), an improvement in hematologic parameters (but without meeting the 
protocol-defined response criterion of complete hematologic response [CHR] by 3 months), or a 
BCR-ABLIS level indicative of clinical benefit (but that is > 1%, after loss of ≤ 1% BCR-ABL1IS
at an earlier time point; see Section 12.4.1.1).  Each patient may remain on study treatment 
during the Treatment Continuation Period until the patient either stops receiving clinical benefit 
or experiences unacceptable toxicity, or until the study is terminated by the sponsor (whichever 
occurs first).  Section 12 describes follow-up and data collection for patients in each of the Main 
Treatment and Treatment Continuation Periods.
The trial will assess hematologic response, cytogenetic response, and molecular response, as well 
as characteristics of efficacy including time and duration of responses, both by starting dose and 
after dose reduction.  AE rates—and the rates, in particular, of arterial occlusive events—will be 
summarized.  PFS and OS data will also be collected and analyzed.  Assessments will be 
performed according to standard international criteria.  Each dose cohort will be analyzed 
separately for efficacy, safety, and PK parameters.
10.1.1
Primary Endpoint

≤1% BCR-ABL1IS at 12 months for each dose cohort  
10.1.2
Secondary Endpoints

Molecular response rates: MMR at 12 and 24 months

Cytogenetic response rates: MCyR by 12 months

Duration of MMR

Safety
a.
Rate of AOEs and VTEs in each dose cohort
b.
Rate of AEs in each dose cohort
c.
Rate of SAEs in each dose cohort
10.1.3
Other Secondary Endpoints

Cytogenetic response rates: CCyR at 12 months

Molecular response rates: MR4, and MR4.5 by and at 3-month intervals and MR1 (≤10% 
BCR-ABL1IS) at 3 months  

Hematologic response rate: CHR at 3 months

Tolerability:
a.
Rate of discontinuation due to AEs in each dose cohort
b.
Dose reductions due to AE in each dose cohort
c.
Dose interruptions in each dose cohort 
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
Duration of response:
a.
Rates of ≤1% BCR-ABL1IS by 12 months and at and by 6, 18, and 24 months
b.
MMR at and by 6 and 18 months; and by 12 and 24 months 

Duration of response in responders

Time to response

Rate of progression to AP- or BP-CML

PFS

OS
10.1.4
Exploratory Endpoints

Correlation of tumor cell and plasma biomarkers with ponatinib efficacy and safety 

QoL and health outcomes as measured by EQ-5D-5L and FACT-Leu
10.2
Description of Treatment
Patients will be randomized to receive once-daily oral administration of 1 of 3 starting doses of 
ponatinib: 45 mg (Cohort A), 30 mg (Cohort B), or 15 mg (Cohort C). 
Mandatory dose reduction: Patients will undergo assessments for achievement of ≤1% 
BCR-ABL1IS and for consideration of mandatory dose reduction at 3, 6, 9, and 12 months (or if 
an unscheduled response assessment is performed).  The schedule for dose reduction is described 
in Section 14.1.3. 
Escalation for loss of response following dose reduction: Patients who undergo dose reduction 
upon achievement of ≤1% BCR-ABL1IS and who, with continued monitoring, lose the ≤1% 
BCR-ABL1IS may undergo dose escalation back to the starting dose at the discretion of the 
physician and upon review with the medical monitor.  The dose re-escalation schema is 
described in Section 14.1.4.
Dosing during the Treatment Continuation Period: Patients in the Treatment Continuation 
Period will be treated with study drug in accordance with Section 14.1.5. 
10.3
Randomization
Patients will be randomized in a 1:1:1 ratio to receive ponatinib in one of three different starting 
dose cohorts:

Cohort A: 45 mg QD with reduction to 15 mg at 3, 6, 9, or 12 months upon achievement of 
≤1% BCR-ABL1IS 

Cohort B: 30 mg QD with reduction to 15 mg at 3, 6, 9, or 12 months upon achievement of 
≤1% BCR-ABL1IS 

Cohort C: 15 mg QD with no change upon achievement of ≤1% BCR-ABL1IS 
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A cycle of therapy will comprise 28 days of treatment, regardless of dose.
The randomization will be stratified based on the patient’s baseline age (≥60 vs < 60 years) and 
history of hypertension, diabetes, and/or hyperlipidemia (yes/no).  Specific instructions for 
randomization will be supplied in the Study Reference Manual.  Randomization procedures 
should be performed following complete eligibility assessments and prior to the initiation of 
assigned treatment.  This study is open-label; patients, investigators, and the sponsor will know 
the identity of each patient’s study treatment.  
10.4
Treatment Periods
For each patient, treatment will start with the Main Treatment Period.  Following completion of 
the 24-month Main Treatment Period or following early withdrawal from the Main Treatment 
Period before completing all 24 cycles of the Main Treatment Period (as described in 
Section 12.4.1), patients who are both tolerating ponatinib treatment and receiving clinical 
benefit from treatment may enter into an optional Treatment Continuation Period upon 
discussion and agreement between the investigator and medical monitor.
10.4.1
Main Treatment Period
Patients will be treated with their randomized dose of study drug, with mandatory dose reduction 
and the option for dose re-escalation for loss of response, as described in Section 10.2.  Patients 
will remain in the Main Treatment Period until meeting any of the criteria for withdrawal (see 
Section 12.4.1), or until completing the full 24 cycles of the Main Treatment Period.
10.4.2
Optional Treatment Continuation Period
Patients who either complete the 24-cycle Main Treatment Period or who discontinue before 
completing 24 cycles because of failure to achieve or maintain protocol-defined responses (see 
Section 12.4.1.1) may enter the Treatment Continuation Period on a case-by-case basis if they 
are both tolerating treatment and receiving clinical benefit from ponatinib administration as 
determined by agreement between the investigator and medical monitor.  Written permission 
from the medical monitor must be obtained in advance of each patient entering the Treatment 
Continuation Period. Patients who enter the Treatment Continuation Period will be evaluated as 
per the SOE shown in Table 8.  For patients in the Treatment Continuation Period, the follow-up 
schedule will be arranged so that contact between the patient and the site occurs at least once 
every 3 months and a study visit occurs at least once every 6 months. After signing informed 
consent for protocol amendment 7, patients who have completed at least 24 cycles of treatment 
after randomization will be scheduled to attend study visits once every 6 months (see Table 8).  
Objective evidence supporting such continuation treatment will include overall tolerance, 
hematologic evidence for disease control relative to baseline, and lack of events requiring study 
discontinuation (Section 12.4.2).
With continued agreement between the investigator and medical monitor, each patient in the 
Treatment Continuation Period may remain on ponatinib until the patient stops receiving clinical 
benefit or experiences unacceptable toxicity, or until the study is terminated by the sponsor 
(whichever occurs first).  The clinical benefit to the patient must be assessed by the investigator, 
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with key evidence supporting clinical benefit recorded in the source documents, and with study-
specific clinical data recorded both in the source documents and in the electronic case report 
form (eCRF).
11
SELECTION OF STUDY POPULATION
11.1
Inclusion Criteria
All patients must take part in the informed consent process.  This process is described in 
Section 12.1.  Screening tests and procedures used to establish eligibility are outlined in 
Section 12.1, Table 7.  Documentation from the screening period is required for each inclusion 
and exclusion criterion.
All patients must meet all of the following inclusion criteria for study entry:
1.
Have CP-CML and have received at least two prior TKI therapies and have 
demonstrated resistance to treatment
OR
Have documented history of presence of T315I mutation after receiving any number 
of prior TKI. 
a.
The diagnosis of CML will be made using standard hematopathologic and 
cytogenetic criteria; CP-CML will be defined by all of the following:
i
< 15% blasts in bone marrow
ii
< 30% blasts plus promyelocytes in bone marrow
iii < 20% basophils in peripheral blood
iv ≥100 × 109/L platelets (≥100,000/mm3)
v
No evidence of extramedullary disease except hepatosplenomegaly
vi No prior diagnosis of AP- or BP-CML
b.
Cytogenetic assessment at screening must demonstrate the BCR-ABL1 fusion 
by presence of the t(9;22) Philadelphia chromosome.
i
Variant translocations are only allowed provided they meet inclusion 
criterion 1d.
c.
Resistance to prior TKI therapy is defined as follows (patients must meet at least 
1 criterion):
i
Three months after the initiation of prior TKI therapy: No cytogenetic 
response (> 95% Ph+) or failure to achieve a CHR or new mutation
ii
Six months after the initiation of prior TKI therapy: BCR-ABL1IS >10% 
and/or Ph+ >65% or new mutation
iii
Twelve months after the initiation of prior TKI therapy: BCR-ABL1IS
>10% and/or Ph+ >35% or new mutation
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iv
At any time after the initiation of prior TKI therapy, the development of a 
new BCR-ABL1 kinase domain mutation(s) 
v
At any time after the initiation of prior TKI therapy, the development of 
new clonal evolution 
vi
At any time after the initiation of prior TKI therapy, the loss of CHR, or 
CCyR, or the confirmed loss of MMR in 2 consecutive tests, one of which 
has a BCR-ABL1IS transcript level of ≥1% or new mutation
d.
>1% BCR-ABL1IS as shown by real-time polymerase chain reaction
[NOTE: The above criteria were adapted from Baccarani et al, 2013.]
2.
Age  ≥18 years old.
3.
Have an ECOG performance status of 0, 1, or 2.
4.
Have adequate renal function as defined by the following criterion:
a.
Serum creatinine ≤1.5 × ULN for institution
b.
Estimated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula) 
5.
Have adequate hepatic function as defined by the following criteria:
a.
Total serum bilirubin ≤1.5 × ULN, unless due to Gilbert’s syndrome
b.
ALT ≤2.5 × ULN, or ≤5 × ULN if leukemic infiltration of the liver is present
c.
AST ≤2.5 × ULN, or ≤5 × ULN if leukemic infiltration of the liver is present
6.
Have normal pancreatic status as defined by the following criterion:
a.
Serum lipase and amylase ≤1.5 × ULN
7.
Have normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in 
males or ≤ 470 ms in females.
8.
Have a negative pregnancy test documented prior to enrollment (for females of childbearing 
potential).
9.
Agree to use a highly effective form of contraception with sexual partners from 
randomization through at least 4 months after the end of treatment (for female and male 
patients who are fertile).
10.
Provide written informed consent. 
11.
Be willing and able to comply with scheduled visits and study procedures.
12.
Have recovered from toxicities related to prior anticancer therapy to NCI CTCAE v 4.0 
grade ≤1. 
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11.2
Exclusion Criteria
Patients are not eligible for participation in the study if they meet any of the following exclusion 
criteria:
1.
Have used any approved TKIs or investigational agents within 2 weeks or 6 half-lives of 
the agent, whichever is longer, prior to receiving study drug. 
2.
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, or have not recovered (> grade 1 by NCI CTCAE, v4.0) from AEs 
(except alopecia), due to agents previously administered.
3.
Have undergone autologous or allogeneic SCT < 60 days prior to receiving the first dose of 
ponatinib; have any evidence of ongoing GVHD or GVHD requiring immunosuppressive 
therapy.
4.
Are being considered for HSCT within 6-12 months of enrollment (note: ponatinib is not to 
be used as a bridge to HSCT in this trial).
5.
Are taking medications with a known risk of Torsades de Pointes (Appendix A).
6.
Have previously been treated with ponatinib.
7.
Have active 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.
8.
Have clinically significant, uncontrolled, or active cardiovascular disease, specifically 
including, but not restricted to:
a.
Any history of MI, unstable angina, cerebrovascular accident, or TIA
b.
Any history of peripheral vascular infarction, including visceral infarction
c.
Any revascularization procedure, including the placement of a stent 
d.
Congestive heart failure (CHF) (New York Heart Association [NYHA] class III or IV) 
within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less 
than lower limit of normal, per local institutional standards, within 6 months prior to 
enrollment
e.
History of clinically significant (as determined by the treating physician) atrial 
arrhythmia or any history of ventricular arrhythmia
f.
Venous thromboembolism, including deep venous thrombosis or pulmonary 
embolism, within 6 months prior to enrollment
9.
Have uncontrolled hypertension (i.e., >150 and >90 for SBP and DBP, respectively). 
Patients with hypertension should be under treatment at study entry to ensure blood 
pressure control. Those requiring 3 or more antihypertensive medications should be 
discussed with the medical monitor. 
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10.
Have poorly controlled diabetes defined as HbA1c values of > 7.5%. Patients with 
preexisting, well-controlled, diabetes are not excluded.
11.
Have a significant bleeding disorder unrelated to CML.
12.
Have a history of alcohol abuse.
13.
Have a history of either acute pancreatitis within 1 year of study enrollment or of chronic 
pancreatitis.
14.
Have malabsorption syndrome or other gastrointestinal illness that could affect oral 
absorption of study drug.
15.
Have a history of another malignancy, other than cervical cancer in situ or basal cell or 
squamous cell carcinoma of the skin; the exception is if patients have been disease-free for 
at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that 
malignancy.
16.
Are pregnant or lactating.
17.
Have undergone major surgery (with the exception of minor surgical procedures, such as 
catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.
18.
Have an active infection which requires intravenous antibiotics.
19.
Have a known history of human immunodeficiency virus infection; testing is not required 
in the absence of prior documentation or known history.
20.
Have any condition or illness that, in the opinion of the investigator, would compromise 
patient safety or interfere with the evaluation of the drug.
21.
Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients 
listed in Section 14.7.1.
12
STUDY PROCEDURES
12.1
Schedule of Events
Table 7 lists the screening and study procedures to be performed through Cycle 12. Table 8 lists 
the procedures to be performed after Cycle 12 through the end of the study.  Unless otherwise 
specified, the timing in which Cycle 1 tests are performed should be repeated in later cycles.  
Cycle visit samples or activities should occur within 3 days of the scheduled study day unless 
otherwise noted in the Schedule of Events.
Please maintain a special awareness of the assessments of the primary and secondary endpoints.
The following describes the procedures/tests required for this study:
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1
Screening Period Procedures
Screening tests and procedures are used to establish eligibility of the patient for the trial.  
Patients must continue to maintain laboratory values within eligibility parameters if any 
given procedure or laboratory test is repeated prior to randomization.
All screening tests must be performed within 21 days prior to randomization, with the 
exception of the screening bone marrow (BM) aspirate (to be performed within 42 days) 
and screening pregnancy test (to be performed within 7 days of first dose of study drug).
2
Informed Consent
All patients must take part in the informed consent process.  During the consent process, 
the person obtaining consent must inform the patient of all elements of informed consent.  
Adequate time must be allowed for questions and for the patient to make a voluntary 
decision.  No protocol-specific procedures are to be performed until the patient has signed 
and dated an Institutional Review Board (IRB)/Ethics Committee (EC)-approved informed 
consent form.  Each patient's participation in the trial begins with the signing and dating of 
the informed consent form.
3
Randomization
Specific instructions for randomization will be supplied in the Study Reference Manual.  
Randomization procedures should be performed within the 21-day screening period, 
following complete eligibility assessments and just prior to the initiation of assigned dose 
cohort.
4
Medical/Surgical History and Demographics
Medical and surgical history and demographic information will be recorded.  Medical and 
surgical history include diagnoses, therapies, and medical and surgical treatments.  
Special attention should be paid to documenting risk factors for cardiovascular, 
cerebrovascular, peripheral vascular, and venous thromboembolic disease.  The history 
must also include any history of ischemic heart disease (such as angina, myocardial 
infarction, acute coronary syndrome, coronary revascularization procedures, etc.); valvular 
heart disease; congestive heart failure; arrhythmias; myocarditis; peripheral arterial 
occlusive disease (including claudication, distal extremity amputation, angioplasty, or 
revascularization procedure); stroke (including TIAs, cerebral atherosclerosis, or 
revascularization procedures);  diabetes mellitus; hypertension; hypercholesterolemia; 
hyperlipidemia; deep venous thrombosis; pulmonary embolism; any other coagulopathy 
(for example, protein S or protein C deficiency or anticardiolipin antibody); physical 
inactivity; obesity; or smoking.  Family medical history will be collected, and should 
include any history of coronary artery disease, early death from myocardial infarction or 
cerebrovascular accident, sudden death, or bleeding or clotting diatheses in first-degree 
relatives.  Demographic information consists of the patient’s age, gender, race, and 
ethnicity (as allowed by local law and regulations).
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5
Leukemia Diagnosis and Prior Cancer Therapy 
Both the initial leukemia diagnosis and the current screening diagnosis must be recorded. 
Note: Only patients currently in CP-CML and those with no prior history of AP-CML or 
BP-CML are eligible.  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, as well 
as the reason for failure of or intolerance to each regimen.  Stem cell transplant or 
experimental therapy history is also recorded.
6
BCR-ABL1 Mutation History
At the time of screening, prior and current history of any known BCR-ABL1 mutations 
must be recorded.
7
Vital Signs
Vital signs are temperature, pulse, respiratory rate, and blood pressure (when the patient is   
seated).
8
Physical Examination and ECOG Performance Status
A complete physical examination, including measurement of weight, must be performed at 
screening; at Cycle 1, Day 1 prior to the first administration of study drug; and at the 
End-of-Treatment Visit.  All physical examinations should address the presence or absence 
of hepatomegaly and splenomegaly, which must be recorded.  The extent of the physical 
examination should be consistent with the medical history and the patient’s underlying 
disease.  ECOG performance status should be evaluated during each physical examination.  
Following the physical examination for Cycle 1, Day 1—with the exception of the 
End-of-Treatment Visit—all subsequent physical examinations (to be performed on 
Days 15 and 28 of Cycle 1 and Day 28 of Cycles 2, 3, 6, 9, 12, 18, and 24, and on Day 28 
of every sixth cycle thereafter for patients continuing on to the Treatment Continuation 
Period, as indicated in Table 7 and Table 8) may be directed to relevant findings in the 
patient, but should always include an assessment of hepatomegaly and splenomegaly.  
Height measurement is required at screening only.
9
Eye Exam
A detailed eye history and exam must be performed at screening. The eye exam should test 
visual acuity, refraction, pupillary function, ocular motility, and intraocular pressure. 
Perform a retinal examination, particularly noting the appearance of the retinal vasculature. 
Describe any signs of serious vascular occlusion (both venous and arterial) in the retina. 
Also, clinically evaluate for photophobia, conjunctival disease, uveitis, and cataracts. 
10
Complete Blood Count (CBC) with Differential
CBC with differential is defined as peripheral blood total white blood cell (WBC) count, 
hemoglobin, hematocrit, platelet count, absolute neutrophil count (ANC), and WBC 
differential, reported individually for each cell type. Cell types required for diagnosis and 
response assessment—including basophils, myelocytes, metamyelocytes, promyelocytes, 
and blasts, when present—must be quantified.  Hematologic assessments must be obtained 
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at screening and at every subsequent assessment, as specified in the Schedule of Events 
(Table 7 and Table 8), or more frequently as clinically indicated (e.g., to confirm the loss of 
hematologic response as defined in Section 16.5.1.3). 
11
Serum Analysis
a.
Chemistry
Serum chemistry consists of a peripheral blood draw with the following assessments: 
sodium, potassium, chloride, bicarbonate (or total carbon dioxide [CO2]), blood urea 
nitrogen (BUN, or urea), fasting glucose, albumin, creatinine, total bilirubin (direct 
and indirect), AST, ALT, alkaline phosphatase, magnesium, phosphorous, calcium, 
amylase, and lipase.
The full chemistry panel must be obtained at screening and at every subsequent 
assessment – with the exception of assessments on Day 15 during Cycle 2 and 
Cycle 3 which are lipase only – as specified in the Schedule of Events (Table 7 and 
Table 8), or more frequently as clinically indicated.
b.
Cholesterol/Lipid Assessment
Fasting serum lipid panel (total, high-density lipoprotein [HDL], and low-density 
lipoprotein [LDL])—including triglycerides—must be collected during screening 
and at subsequent time points as specified in the Schedule of Events (Table 7 and 
Table 8), or more frequently as clinically indicated.
c.
HbA1c, CRP, Troponin, and NT-proBNP or BNP
Hemoglobin A1c (HbA1c), C-reactive protein (CRP), cardiac troponin (cTn) (either T 
or I is acceptable, but whichever is used must be used consistently for a given 
patient), and N-terminal pro-brain natriuretic peptide (NT-proBNP) assessments must 
be performed at screening. If the investigational site is unable to perform NT-proBNP 
testing, a BNP test can be performed instead.  Additionally, HbA1c, CRP, cTn, and 
NT-proBNP (or BNP) assessments must be performed at the times specified in the 
Schedule of Events (Table 7 and Table 8), or more frequently as clinically indicated.
d.
Hepatitis B Serology
At the time of screening, blood serum must be tested for Hepatitis B serology 
(Hepatitis B surface Antigen, Hepatitis B core Antibody, and Hepatitis B surface 
Antibody) at minimum. Patients who are chronic carriers of Hepatitis B virus (HBV) 
and receive a BCR-ABL TKI therapy may have a reactivation of Hepatitis B. For 
patients with evidence of prior or current HBV infection, please refer to the IB 
version 8, Section 8.1.2.9.
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12
Pregnancy Test
The pregnancy test must be a beta-human chorionic gonadotropin (β-HCG) test, using 
either urine or serum.  Women who are not of childbearing potential (status post-
hysterectomy, status post-bilateral oophorectomy, or postmenopausal [defined as 
amenorrhea for at least 12 months]) do not need to have the test performed.  If the test is 
deemed necessary, it must be performed within 7 days of first dose of study drug and 
known to be negative prior to randomization.  Women of childbearing potential at study 
start must also complete the pregnancy test at the End-of-Treatment Visit.
13
Electrocardiogram (ECG)
All ECGs must be 12-lead ECGs.  The screening ECG must be performed within the 
21-day screening window prior to randomization.  Additionally, 12-lead ECGs must be 
performed at Cycles 3, 6, 12, 18, 24, and at the end of every sixth cycle thereafter for 
patients continuing on to the Treatment Continuation Period; and at End-of-Treatment, as 
specified in the Schedule of Events (Table 7 and Table 8)—or more frequently if clinically 
indicated.  Patients who have signed the informed consent form for protocol amendment 7 
and completed at least 24 cycles of treatment after randomization are to have 12-lead ECG 
assessments performed at least every 12 months (or more frequently if clinically indicated).  
If medications known to prolong the QTcF interval are used while a patient is on study, 
then additional ECG monitoring should be performed as clinically indicated.
14
Echocardiogram (ECHO)
An ECHO for assessment of LVEF must be performed within the 21-day screening 
window and at Cycles 12, 24, and at the end of every 12th cycle thereafter for patients 
continuing on to the Treatment Continuation Period; as well as at End-of-Treatment, as 
specified in the Schedule of Events (Table 7 and Table 8).  Additional ECHOs need only be 
performed if clinically indicated.
15
Adverse Events and Concomitant Medications
AEs and concomitant medications are to be recorded continuously throughout the treatment 
period—starting on the date of signed informed consent—and at the 30-day follow-up visit, 
as indicated in the Schedule of Events (Table 7 and Table 8).  It is expected that new and 
updated AEs and concomitant medications reported within the treatment period; ongoing 
AEs thought to be at least possibly study-drug related; and all ongoing SAEs should be 
followed at least every 4 weeks until they resolve to baseline (or to NCI CTCAE, v4.0 
grade ≤1), stabilize, or are considered to be chronic/irreversible.
16
Bone Marrow Aspirate/Cytogenetics
The bone marrow (BM) aspirate results should include the components required for 
assessing response of the patient.  All BM aspirates should quantify cell types required for 
diagnosis and response assessment, including promyelocytes and blasts.  Examination 
should include cytogenetic assessment by conventional banding.  Interphase fluorescence 
in situ hybridization (FISH) is not allowed.
The BM aspirate with or without an optional biopsy must occur within 42 days prior to 
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randomization and ± 7 days of the subsequent scheduled assessment at Cycle 12.  A BM 
aspirate with cytogenetic assessment is required in all patients on study after the first 
12 cycles. 
Patients with variant BCR-ABL1 translocations must be assessed for cytogenetic response, 
utilizing conventional BM cytogenetic techniques, as needed in accordance with local 
standard of care.
During Cycle 12, all patients must undergo a BM aspirate and cytogenetic assessment. 
A BM aspirate and cytogenetic assessment must be performed at the End-of-Treatment 
Visit if there have been no on-treatment BM assessments, or if the patient has greater than a 
1-log (i.e., 10-fold) increase in transcript level; the exception is if the level remains ≤1% 
BCR-ABL1IS.  Bone marrow aspirates and cytogenetic assessments may be performed at 
other times when clinically indicated (e.g., to confirm loss of cytogenetic response as 
defined in Section 16.5.1.2).  Results of any BM aspirate or cytogenetic assessment, 
whether scheduled or unscheduled, must be recorded in the patient’s electronic case report 
form (eCRF).
17
Blood Samples for BCR-ABL1IS Molecular Response Assessment
Testing of peripheral blood in all patients by quantitative, real-time polymerase chain 
reaction (PCR) of the BCR-ABL1 transcript must be done at screening; at the end of 
Cycles 3, 6, 9, 12, 15, 18, 21, and 24; at the end of every 3 cycles thereafter for patients in 
the Treatment Continuation Period who have completed < 24 total cycles of treatment in 
the study; at the end of every 6 cycles thereafter (at a minimum) for patients in the 
Treatment Continuation Period who have completed ≥24 total cycles of treatment in the 
study; and at the End-of-Treatment Visit. Specific instructions will be supplied in the Study 
Reference Manual.
This test will be performed by a central molecular diagnostics laboratory, and the results 
will be reported to the participating investigator.  However, in cases where a patient’s visit 
to the site is not feasible due to extenuating circumstances, such as the COVID-19 
pandemic, evaluation via local laboratories will be permitted.  The ratio of BCR-ABL1 to 
ABL1 transcripts will be reported on the International Scale.  For patients with variants of 
BCR-ABL1 for which there is no International Scale, only the absolute ratio of BCR-ABL1 
to ABL1 transcripts will be reported.  A portion of the sample collected for BCR-ABL1 
molecular response assessment may also be used for exploratory biomarker assessment.
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18
Blood Samples for Exploratory Biomarker Assessment
Peripheral blood for exploratory biomarker testing is to be collected at screening; at the end 
of Cycles 3, 6, 9, 12, 18, and 24; and at the End-of-Treatment Visit.  Specific instructions 
will be provided in the Study Reference Manual.  This sample will be used for analysis of 
molecular determinants in tumor cells of response or resistance to ponatinib, or those that 
are either present at the initiation of study treatment or develop during study treatment.  
This testing will include, but may not be limited to, analysis of BCR-ABL1 mutation status 
at select time points, the results of which will be reported to the participating investigator. 
19
Plasma Samples for Exploratory Biomarker Assessment
Plasma samples for exploratory biomarker testing are to be collected at screening; at the 
end of Cycles 1, 3, 6, and 12; and at the End-of-Treatment Visit.  Specific instructions will 
be provided in the Study Reference Manual.  These samples will be used to evaluate 
circulating biomarkers associated with ponatinib efficacy and toxicity.
20
EQ-5D-5L and FACT-Leu Assessments
Both the EQ-5D-5L instrument from the EuroQoL group and the FACT-Leu instrument 
will be used to collect patient-assessed QoL and health outcomes measures.  The 
instruments will be implemented at screening; at the end of Cycles 1, 3, 6, 12, 18, and 24; 
at the end of every 6 cycles thereafter for patients continuing on to the Treatment 
Continuation Period; and at the End-of-Treatment Visit.  All instruments will be 
administered to patients when they arrive for their scheduled visits, prior to any clinical 
measurements, assessments, evaluations, or procedures.  Patients are required to complete 
the instruments if there is a validated translation available in a language in which they are 
fluent.
21
Pharmacokinetic (PK) Samples 
A pre-dose blood sample will be collected within 1 hour prior to dosing on Day 28 of 
Cycles 1, 3, 6, 9 and 12.  Samples will also be collected at 1 (± 15 minutes), 
4 (± 30 minutes), and 6 (± 30 minutes) hours post-dose on Day 28 in Cycle 1. 
Additionally, an unscheduled trough assessment (to be collected within 1 hour prior to 
dosing) will be performed at the first scheduled visit following a dose reduction of at least 
7 days’ duration prior to the visit. 
Patients must be instructed not to take the day’s dose of ponatinib until after the pre-dose 
sample is collected.  The pre-dose sample should be collected as close as possible to 
24 hours after the prior dose; the administration time of the prior dose must be recorded, 
along with the time of the pre-dose PK sample.  A portion of the plasma sample collected 
for PK may also be used for exploratory biomarker assessments.
Upon implementation of Amendment 6, no further PK sample collection will be performed 
as all ongoing patients have completed at least 12 cycles of treatment.
22
Review of Patient Daily Dosing Diary
The patient dosing diary card will be completed by the patient on a daily basis and 
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reviewed by site staff at each visit. 
23
Treatment Continuation Procedures
Continuation patients (including both those who enter the Treatment Continuation Period 
before completing all 24 cycles of the Main Treatment Period and those who enter the 
Treatment Continuation Period after completing all 24 cycles of the Main Treatment 
Period) will generally be evaluated every 3 months according to the schedule of events for 
the Treatment Continuation Period as shown in Table 8.  Upon agreement between the 
investigator and the medical monitor, patients who have completed ≥24 cycles of 
treatment may be evaluated using an alternating schedule of telephone contact and patient 
visits (for visits that would otherwise occur at the end of odd- and even-numbered cycles, 
respectively, as shown in Table 8).  In all cases, the schedule will be arranged so that 
contact between the patient and the site occurs at least once every 3 months and a study 
visit occurs at least once every 6 months Table 8.
After signing informed consent for protocol amendment 7, all patients who have completed 
at least 24 cycles of treatment after randomization will be evaluated every 6 months 
according to the schedule of events for the Treatment Continuation Period as shown in 
Table 8.
Key evidence supporting clinical benefit must be recorded by the investigator in the source 
documents, with study-specific clinical data recorded both in the source documents and in 
the eCRF as instructed in the eCRF Completion Guidelines.  Patients must be withdrawn 
from the Treatment Continuation Period if they are no longer receiving clinical benefit in 
the opinion of the investigator or if they meet any of the criteria shown in Section 12.4.2.  
The investigator may contact the medical monitor if needed to discuss a patient’s continued 
participation in the Treatment Continuation Period.
24
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 or the patient/investigator decision to 
discontinue treatment—whichever occurs later. A follow-up visit should be conducted 
approximately 30 days (±7 days) after the last dose of study treatment. For both visits, the 
information may be collected from tests that were performed for the study or as part of the 
patient’s routine medical care. Patients that do not return to the clinic and attempts to 
contact these patients have been unsuccessful will be considered as lost to follow-up. At 
least three attempts must be made to contact the patient, and must be documented. See 
Section 12.2.2 for further details on discontinuation of patients from study drug. For 
patients continuing on to the optional Treatment Continuation Period, the End-of-
Treatment and subsequent follow-up visits should be performed only after the patient 
discontinues from the optional Treatment Continuation Period.
25
Follow-up Procedures: Safety
All AEs ongoing or starting within 30 days after End-of-Treatment must be recorded on the 
eCRF.  After this time, all ongoing SAEs should be followed at least every 4 weeks until 
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they resolve to baseline (or to NCI CTCAE, v4.0 grade ≤1), stabilize, or are considered to 
be chronic/irreversible.
26
Follow-up Procedures: Survival
Survival data will be collected every 12 weeks ± 14 days, starting after the last dose of 
ponatinib or the investigator/patient decision to discontinue treatment—whichever occurs 
later. These data do not need to be obtained during a visit; phone contact is acceptable. 
Tests and procedures should be performed on schedule, but occasional changes may be allowed 
for holidays, vacation, and other administrative reasons. If the study schedule is shifted, both 
assessments and dosing must be shifted to ensure collection of assessment is completed prior to 
dosing. If extenuating circumstances (such as the COVID-19 pandemic) prevent a patient from 
beginning treatment or completing a scheduled procedure or assessment within this time, the 
patient may continue the study only with the written permission of the sponsor/designee medical 
monitor. Similarly, if extenuating circumstances prevent completion of a scheduled evaluation 
but an acceptable alternative test can be performed, the patient may continue the study only with 
written permission of the sponsor/designee medical monitor. Missed or delayed study visits 
and/or procedures should be recorded as protocol deviations.
12.1.1
Changes to Study Procedures Due to COVID-19 Pandemic 
The following information provides guidance regarding changes to the study procedures that 
could be implemented for study participants or study sites that are affected by the COVID-19 
Public Health Emergency. This guidance takes references from the FDA Guidance on Conduct 
of Clinical Trials of Medical Products during COVID-19 Public Health Emergency - Guidance 
for Industry, Investigators, and Institutional Review Boards, March 2020, updated 02 July 2020, 
and the EMA Guidance on the Management of Clinical Trials During the COVID-19 
(Coronavirus) Pandemic, Version 3 (28 April 2020).
As the COVID-19 pandemic may peak in different regions at different times and restrictions 
implemented by local laws and recommendations may vary, any decision on procedural changes 
should be made on a case-by-case basis by the principal investigator in consultation with the 
study team and the medical team as needed, while maintaining patient safety and confidentiality 
as the priority.
Procedural changes due to COVID-19 may include the following:

All attempts should be made to perform the assessments with the patient present at the 
site. However, in cases where a patient’s visit to the site is not feasible (patient cannot 
travel to the site, the site is temporarily closed for visits, or in cases where the 
investigator believes that is best for patient’s and site staff’s safety not to visit to the site), 
alternative evaluation such as local laboratories and/or TeleHealth (the ability to connect 
a physician to a patient)/Telemedicine (remote clinical assessments) or home healthcare 
(performing some assessments in a patient’s home by a qualified healthcare provider) 
will be allowed if permitted by local regulations. 
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o
For home healthcare visits, collection of clinical laboratory samples (blood 
specimen collection or other diagnostic tests) or ECGs may be performed by the 
investigator or qualified healthcare professional who can visit the study 
participant’s residence.
o
Remote visits via virtual communications (eg, TeleHealth application) may be 
performed as a safety check on patient well-being and to verify correct study drug 
dosing.

Deviations from the protocol-specified procedures (eg, not collecting a protocol-specified 
specimen, such as postdose bloodwork) will be recorded as related to COVID-19.

Missed clinic visits or subject withdrawals due to COVID-19 must be recorded on the 
eCRF (Section 12.4).

Allow the use of alternate means to capture patient-reported outcome/QoL data (eg, a 
paper-based questionnaire mailed to patients) as a back-up only if patients cannot come at 
site for scheduled visit.

Allow transfer of study participants to investigational sites away from risk zones or closer 
to their home to sites already participating in the study or new ones.

Alternate study drug delivery mechanisms, eg, dispensing additional study drug at clinic 
visits or direct-to-patient (DTP) delivery of the study drug from the investigational site to 
patients in compliance with national laws or temporary national emergency measures 
(Section 14.7.2).
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12.2
Patient Registration and Identification
Demographic information on all patients who sign the Informed Consent Form will be recorded 
on the eCRF.  Those patients who complete screening procedures and meet all eligible criteria 
may be enrolled into the study using the enrollment procedure established by the sponsor.  At the 
time of enrollment, the patient will be assigned a unique identification code (number), consisting 
of a study site number and a unique consecutive number.
12.2.1
Screen Failures
Patients who have signed informed consent and subsequently fail to meet the inclusion criteria 
and/or meet the exclusion criteria are defined as screen failures.  For all screen failures, the 
investigator is to maintain a screening log that documents the patient’s initials and reason(s) for 
screen failure.  A copy of the log should be retained in the investigator’s study files.  Any patient 
who is re-screened after screen failure must, in addition to the failed procedure, repeat only those 
screening procedures outlined in the Schedule of Events (Table 7) that have fallen outside the 
specified screening period.
12.2.2
Early Discontinuation from Study Drug Administration or Assessments
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 for withdrawal as thoroughly as possible.  The 
reason for termination must be clearly reported on the appropriate page of the patient’s eCRF.  
An End-of-Treatment reason for discontinuation must be recorded for any patient who is 
randomized.
If a patient is discontinued from the trial for any reason, every effort must be made to perform all 
clinical and laboratory procedures as scheduled for the End-of-Treatment Visit.  In the event that 
the patient fails to return for the necessary visit(s), an effort must be made to contact the patient 
to determine the reason, and this information should be recorded in the appropriate source record 
and the End-of-Treatment eCRF.
12.3
Study Duration
Total study duration is expected to be at least 96 months.  This includes an enrollment period of 
approximately 36 months and a treatment period of approximately 5 years, unless the patient is 
discontinued early.  Following completion of the 24-month Main Treatment Period or following 
early withdrawal from the Main Treatment Period before completing all 24 cycles of the Main 
Treatment Period and upon discussion and agreement with the medical monitor, patients who are 
receiving clinical benefit from and tolerating Ponatinib may continue to receive treatment in the 
optional Treatment Continuation Period.  The study will continue until all patients have been 
discontinued from the study or the study is terminated by the sponsor, whichever comes first.  
Patients will be followed for 30 days after last dose of study drug. 
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12.4
Withdrawal Criteria
12.4.1
Main Treatment Period
Patients will be discontinued from further study drug administration in the Main Treatment 
Period if any of the following occur:

Intolerable toxicity as determined by the investigator and defined in Section 14.2.2

MI, unstable angina, stroke, TIA, or urgent revascularization 

A treatment interruption for study-drug related nonhematologic toxicities lasting longer 
than 28 days  

Absence of CHR by 3 months (see Section 12.4.1.1)

Absence of MCyR at 12 months (see Section 12.4.1.1)

Absence of ≤ 1% BCR-ABL1IS at 12 months (see Section 12.4.1.1)

Loss of ≤ 1% BCR-ABL1IS in the absence of dose re-escalation or continued loss of ≤ 1% 
BCR-ABL1IS, as defined in Section 16.5.1.1, after 6 months following dose re-escalation 
(see Section 12.4.1.1)

Progression of disease to AP- or BP-CML

Entry into another therapeutic clinical trial (e.g., a trial for another investigational product, 
a ponatinib rollover study initiated by the sponsor, etc.) or start of additional anticancer 
therapy 

Significant deviation from the protocol or eligibility criteria, in the opinion of the medical 
monitor or investigator

Noncompliance with study or follow-up procedures

Pregnancy

Patient withdrawal of consent and decision to discontinue participation, including 
withdrawal related to COVID-19

Lost to follow-up 

Termination of the trial by the sponsor

Any other reason that, in the opinion of the investigator, would justify removal of the 
patient from the study
Please ensure that patients discontinuing treatment or assessments early have adequate follow-
up, as described in Section 12.1.
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12.4.1.1
Failure to Meet or Maintain Protocol-Defined Response Criteria in the Main 
Treatment Period
Patients meeting any of the following criteria (requiring discontinuation from the Main 
Treatment Period; see Section 12.4.1) but who are otherwise receiving clinical benefit from 
treatment may enter the optional Treatment Continuation Period upon agreement between the 
investigator and the medical monitor in accordance with Section 10.4.2:

Absence of CHR by 3 months

Absence of MCyR at 12 months 

Absence of ≤ 1% BCR-ABL1IS at 12 months

Loss of ≤ 1% BCR-ABL1IS in the absence of dose re-escalation or continued loss of ≤ 1% 
BCR-ABL1IS, as defined in Section 16.5.1.1, after 6 months following dose re-escalation
These continuation patients will be followed according to the schedule described in Section 12.1.
12.4.2
Treatment Continuation Period
Patients in the Treatment Continuation Period will be followed according to the schedule 
described in Section 12.1.  Patients must be discontinued from further study drug administration 
in the Treatment Continuation Period if any of the following occur:

Intolerable toxicity as determined by the investigator and/or medical monitor

MI, unstable angina, stroke, TIA, or urgent revascularization 

A treatment interruption for study-drug related nonhematologic toxicities lasting longer 
than 28 days  

Progression of disease to AP- or BP-CML

Entry into another therapeutic clinical trial (e.g., a trial for another investigational product, 
a ponatinib rollover study initiated by the sponsor, etc.) or start of additional anticancer 
therapy

Significant deviation from the protocol or eligibility criteria, in the opinion of the medical 
monitor or investigator

Noncompliance with study or follow-up procedures

Pregnancy

Patient withdrawal of consent and decision to discontinue participation, including 
withdrawal related to COVID-19

Lost to follow-up

Termination of the trial by the sponsor

Any other reason that, in the opinion of the investigator, would justify removal of the 
patient from the study
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Please ensure that patients discontinuing treatment or assessments early have adequate 
follow-up, as described in Section 12.1.
12.5
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 participation should be terminated, this action may be 
taken after appropriate consultation between the sponsor and the investigator.  
Conditions that may warrant termination of the study include, but are not limited to:

The discovery of a serious, unexpected, or unacceptable risk to patients 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 Good Clinical Practice (GCP), International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use.
Criteria for removing individual patients from the study are outlined in Section 12.4.
12.6
Sample Collection, Storage, and Shipping
Specific instructions for sample collection, storage, and shipping are included in the Study 
Reference Manual.
13
EFFICACY AND SAFETY ASSESSMENTS
The following sections describe the procedures/tests required for this study.
13.1
Efficacy Assessments
Efficacy assessments are described in Section 12.1 and comprise:

BM aspirates for assessment of cytogenetic response 

BCR-ABL1IS assessment to determine molecular response

Complete blood count for assessment of hematologic response

Survival follow-up
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13.2
Safety Assessments
Safety will be assessed by routine physical and laboratory evaluations, ECGs, and ECHOs, and 
AEs will be recorded and the severity will be graded according to the NCI CTCAE, v.4.0 (see 
Appendix C and Study Reference Manual).
13.2.1
Adverse Events
AE type, incidence, severity (graded in accordance with the CTCAE, v4.0), timing, seriousness 
and relatedness, outcome, action taken with study drug, and treatment will be assessed and 
documented by the investigator continuously throughout the study.
Baseline CML-related signs and symptoms will be recorded as AEs during the study if they 
worsen in severity or increase in frequency.
The number and percentages of patients who developed AOEs and VTEs will be summarized for 
each cohort, as described in Section 16.6.1.
13.3
PK Evaluations
Plasma ponatinib concentration-time data will be obtained to contribute to population PK and 
exposure-response analyses of safety and efficacy. The analysis plan for the population PK and 
exposure-response analyses will be defined separately and the results of these analyses will be 
reported separately.
Upon implementation of Amendment 6, no further PK sample collection will be performed as all 
ongoing patients have completed at least 12 cycles of treatment.
13.4
Exploratory Biomarker Evaluations in Tissue and Plasma
The mutation status of BCR-ABL1 and other genes implicated in tumor biology and/or drug 
metabolism will be determined through analyses of tumor cells collected at study entry, on study, 
and/or at End-of-Treatment.  Analysis methodologies include, but are not limited to, DNA 
sequencing, digital polymerase chain reaction (PCR), and mass spectrometry.  Plasma samples 
collected at study entry, on study, and at End-of-Treatment may be assessed for circulating 
biomarkers (e.g., cytokines, chemokines, and growth factors) to identify associations with 
ponatinib efficacy and safety.
13.5
QoL Assessments
13.5.1
EQ-5D-5L 
The EQ-5D-5L questionnaire is a validated, self-administered general questionnaire of 
health-related quality of life (HR-QoL) issues, developed by EuroQoL Group.  The questionnaire 
asks patients to rate their HR-QoL for 5 dimensions:  mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.  The instrument contains a descriptive element—with 
patients being asked to rate each dimension on a 5-level descriptive severity scale—and a visual 
analog scale, where the same dimensions are rated along a 100-point visual ruler.  Patients for 
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whom a validated translation exists in a language in which they are fluent will complete the 
EQ-5D-5L during study visits, as outlined in the Schedule of Events (Table 7 and Table 8).
13.5.2
FACT-Leu
The FACT-Leu questionnaire is a validated, self-administered questionnaire of HR-QoL, 
developed specifically for patients with leukemia.  The questionnaire contains items divided into 
4 QoL domains:  physical well-being, social/family well-being, emotional well-being, and 
functional well-being.  A fifth category, titled “Additional Concerns,” contains general 
questions.  Patients for whom a validated translation exists in a language in which they are fluent 
will complete the FACT-Leu during study visits, as outlined in the Schedule of Events (Table 7
and Table 8).
Note: Signs and symptoms assessed with the EQ-5D-5L and FACT-Leu questionnaires will be 
analyzed separately as patient-reported outcomes, and will not be considered AEs. 
14
STUDY TREATMENT
14.1
Study Treatment
Patients will be randomized to receive ponatinib at 1 of 3 starting doses (45 mg, 30 mg, or 
15 mg) QD.  Ponatinib will be self-administered by the patient on a daily schedule.  Each 28-day 
dosing period is referred to as 1 cycle.
Study treatment will be administered only to eligible randomized patients at qualified centers 
(e.g., listed on the FDA Form 1572).
14.1.1
Starting Dose Assignment 
The starting dose of ponatinib will be 45 mg (Cohort A), 30 mg (Cohort B), or 15 mg (Cohort 
C), taken orally once daily.  Patients starting at 45 mg or 30 mg will have their daily dose 
reduced to 15 mg if ≤ 1% BCR-ABL1IS has been achieved, as described in Section 14.1.3.
14.1.2
Treatment Administration 
Patients will take the prescribed number of tablets with water, with or without food, at 
approximately the same time each day.  Patients will be provided a diary card or equivalent 
where the date and time of administration will be recorded; complete instructions will be 
provided with the Study Reference Manual.  Patients should be instructed not to take their dose 
on days of visits where they will have plasma samples drawn for PK analyses until after the first 
sample is drawn.  Patients who forget to take their dose more than 6 hours after it is due should 
not make up the missed dose.  Any missed doses should be recorded, and subsequent training of 
patients should be documented in the appropriate source record (e.g., clinic chart) and in the 
eCRF.
14.1.3
Mandatory Dose Reduction for Response Scheme
Patients will be assessed for ≤ 1% BCR-ABL1IS (as defined below) at 3-month intervals, and 
those in the 45 mg QD and 30 mg QD cohorts will have their doses reduced to 15 mg QD upon 
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attainment of ≤ 1% BCR-ABL1IS during the Main Treatment Period (refer to Section 14.1.5 for 
dosing during the Treatment Continuation Period). Dose reduction based upon response can also 
be implemented when an unscheduled response assessment is performed. Dose reduction should 
be implemented as soon as feasible (preferably in 2-3 weeks from the time the response results 
have been communicated to the sites). An unscheduled visit may be required to implement this 
change. No dose reduction for response will be implemented for patients in the 15 mg QD 
cohort.
The primary endpoint of this study will be achievement of ≤1% BCR-ABL1IS at 12 months. This 
incorporates standard CML approaches to patient care and uses patient monitoring. Increasingly, 
patient monitoring is being performed by quantitation of BCR-ABL1 transcripts from a standard 
established by the international scale (IS) (Marin, 2014; NCCN, 2014; Baccarani et al, 2013; 
Marin et al, 2012; Lauseker et al, 2012; Saglio et al, 2012).  
Patients will undergo a baseline BM aspirate and cytogenetic assessment to establish their 
diagnosis and eligibility.  They will then undergo molecular monitoring at 3-month intervals for 
the assessment of response and to inform the decision regarding dose reduction.  Patients will 
undergo a BM aspirate with cytogenetic assessment after 12 cycles, and at additional time points 
as specified in the Schedule of Events (Table 8).  Details of BM acquisition are also listed in 
Section 12.1, Item 16.
Note: Patients who begin therapy at 45 mg or 30 mg may undergo dose reduction for adverse 
events (see Section 14.2.2) prior to the achievement of ≤ 1% BCR-ABL1IS.  This should not 
affect the assessment of response (≤ 1% BCR-ABL1IS) nor the mandated reduction to 15 mg QD 
upon its attainment. 
The schedule of patient assessment for mandatory response-related dose reduction is as 
follows:
Patients in the 45 mg and 30 mg cohorts will have their dose reduced to 15 mg at 3 months if 
they have achieved ≤1% BCR-ABL1IS.  If not, they will continue at their current dose until the 
6-month assessment. 
At 6 months, they will have their dose reduced to 15 mg if they have achieved ≤1% 
BCR-ABL1IS.  If not, they will continue at their current dose until the 9-month assessment.
At 9 months, they will have their dose reduced to 15 mg if they have achieved ≤1% 
BCR-ABL1IS.  If not, they will continue at their current dose until the 12-month assessment.
At 12 months, patients will have their dose reduced to 15 mg if they have achieved ≤1% 
BCR-ABL1IS. 
Patients will discontinue therapy in the Main Treatment Period if they are not in ≤1% 
BCR-ABL1IS at the time of molecular assessment at 12 months.  
14.1.4
Loss of Response after Dose Reduction for ≤1% BCR-ABL1IS
Patients who achieve ≤1% BCR-ABL1IS at any time point, undergo dose reduction, and then 
lose ≤1% BCR-ABL1IS (Section 16.5.1.1), are candidates for dose re-escalation to their starting 
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dose in the absence of AEs requiring dose modification and upon review and agreement with the 
medical monitor.
As described in Section 14.1.3, patients in the cohorts starting at 45 mg (Cohort A) and 30 mg 
(Cohort B) will undergo dose reduction to 15 mg upon achievement of ≤1% BCR-ABL1IS
during the Main Treatment Period.  With continued monitoring at the reduced dose, should 
patients from Cohort A or Cohort B demonstrate loss of ≤1% BCR-ABL1IS as determined by 
molecular assessment, they may be candidates for dose escalation.  Dose escalation can be 
implemented at the discretion of the physician and upon review with the medical monitor. 
Patients will be monitored with molecular response assessments according to the Schedule of 
Events (Table 7 and Table 8).  If the assessment does not demonstrate loss of ≤1% 
BCR-ABL1IS, as defined in Section 16.5.1.1, continued monitoring is indicated.  If the 
assessment indicates loss of ≤1% BCR-ABL1IS, dose escalation may be considered.
Patients may be dose re-escalated as follows:
Patients may only undergo dose re-escalation if they are in Cohort A or Cohort B and do not 
have ongoing AEs necessitating treatment at 10 mg or 15 mg as per Section 14.2.2 (Dose 
Modifications for Adverse Drug Reactions). 
For patients in Cohort A, escalate to the starting dose of 45 mg.  If patients underwent dose 
reduction for AEs and have not yet resumed dosing at 45 mg, escalate to 30 mg.  
For patients in Cohort B, escalate to the starting dose of 30 mg.
For patients in Cohort C, loss of ≤1% BCR-ABL1IS mandates their discontinuation from the 
Main Treatment Period.
If patients regain ≤1% BCR-ABL1IS after dose escalation, continue their therapy at the escalated 
dose and monitor according to the Schedule of Events (Table 7 and Table 8). 
If patients do not regain ≤1% BCR-ABL1IS after 6 months of therapy at the escalated dose, they 
must be discontinued from the Main Treatment Period. 
14.1.5
Treatment during the Treatment Continuation Period
During the Treatment Continuation Period, each patient should be administered the dose and 
most frequent schedule that is both tolerable and continues to provide evidence of clinical benefit 
to the patient, not to exceed the highest dose and frequency (QD) determined from the patient’s 
experience in the Main Treatment Period.  A reduced dose and/or dosing frequency may be 
administered during the Treatment Continuation Period upon discussion and agreement between 
the investigator and the medical monitor.
14.2
Supportive Care
An analysis of baseline risk factors in patients from the phase 2 PACE study assessed the impact 
of hypertension, hypercholesterolemia, diabetes, and obesity, and revealed several risk factors 
that predispose patients to AOEs and VTEs on ponatinib.  Based on an analysis of odds ratios 
(OR), the leading risk factors for serious AOEs are cardiovascular disorders, such as any history 
of myocardial infarction (MI) (OR=6.86), coronary artery disease (OR=7.14), or coronary 
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revascularization (OR=6.19).  The ORs for serious AOEs are 3.53 for history of ischemic 
cerebrovascular disease, 3.78 for diabetes mellitus, 2.49 for hypertension, and 2.07 for 
hypercholesterolemia.  Based on this analysis, the following supportive care recommendations 
are provided to decrease the risk of AOEs and VTEs for patients taking ponatinib.
Antidiabetic Treatment
Patients with diabetes are at increased risk of experiencing arterial occlusive events while being 
treated with ponatinib.  Therefore, as a part of the assessment and management of the patient’s 
cardiovascular risk factors, initiation of or modifications to diabetic care should be considered in 
patients being treated with ponatinib who have elevated glucose levels.  The American Diabetes 
Association guidelines should be followed, and antidiabetic treatment and lifestyle intervention 
(including but not limited to weight loss, decreased fat intake, calorie restriction, increased 
physical activity, and smoking cessation) should be started in any patient with fasting glucose 
> 130 mg/dL (7.2 mmol/L) and/or HbA1c ≥7% (Diabetes Prevention Program Research Group, 
2002; American Diabetes Association, Position Statement 2003).
Hypertension Treatment
Hypertension (HTN) may contribute to risk of arterial occlusive events.  Patients who have HTN 
should be managed appropriately before initiating treatment.  During ponatinib treatment, blood 
pressure elevations should be monitored and managed.  Hypertension should be treated to 
achieve a goal of < 150/90 mmHg.  Initial antihypertensive treatment should generally include a 
thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor 
(ACEI), or angiotensin receptor blocker (ARB) (James et al, 2014).  Ponatinib treatment should 
be temporarily interrupted if HTN is not medically controlled (refer to Section 14.2.1.5 below for 
additional management recommendations).  Patients may require urgent clinical intervention for 
HTN associated with confusion, headache, chest pain, or shortness of breath.
14.2.1
Management of Selected AEs 
Dose reduction guidelines are outlined in Section 14.2.2.  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 course of the study.  Anticipated adverse drug 
reactions that may be experienced are described in the current Investigator’s brochure for 
Ponatinib. 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 associated 
with study drug administration—should be reported on the appropriate concomitant medication 
page of the patient’s eCRF.  The symptoms should be reported on the AE page.
14.2.1.1
Arterial Occlusive and Venous Thrombotic/Embolic Events 
Serious arterial and venous thrombotic and occlusive AEs—including fatal MI, stroke, stenosis 
of large arterial vessels of the brain, severe peripheral vascular disease, renovascular disorders 
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including renal artery stenosis, and the need for urgent revascularization procedures—have 
occurred in ponatinib-treated patients.  Patients with and without cardiovascular risk factors, 
including patients age 50 years or younger, experienced these events.  Vascular occlusive 
adverse events were more frequent with increasing age and in patients with prior history of 
ischemia, hypertension, diabetes, or hyperlipidemia.
14.2.1.1.1 Arterial Occlusion and Thrombosis 
Serious arterial occlusive AEs occurred in ponatinib-treated patients; some patients experienced 
events of more than 1 type.  Serious cardiovascular occlusive AEs included MI and coronary 
artery disease.  Some patients developed CHF concurrent or subsequent to the myocardial 
ischemic event.
Serious cerebrovascular AEs were also reported in ponatinib-treated patients.  Some patients 
developed stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, or middle 
cerebral artery).  
Serious peripheral arterial AEs were reported in ponatinib-treated patients; some developed 
digital or distal extremity necrosis with complications of diabetes mellitus and peripheral arterial 
disease that required amputations.
Monitor and aggressively treat factors that increase cardiovascular risks, such as hypertension, 
smoking, hypercholesterolemia, and hyperglycemia.  Interrupt and consider discontinuation of 
study drug in patients who develop arterial occlusive AEs.  Any patient who experiences a 
serious AE of MI, stroke, or urgent revascularization while on trial must be discontinued from 
the trial unless the investigator believes the potential benefits of ponatinib treatment are likely to 
exceed the risks of continued treatment for that individual patient and the patient has no other 
treatment options.
14.2.1.1.2 Venous Thromboembolism
Serious venous thromboembolic AEs occurred in ponatinib-treated patients, including deep 
venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein 
thrombosis.  Consider dose modification or discontinuation of ponatinib in patients who develop 
serious venous thromboembolic AEs.  Ponatinib should not be restarted in patients with serious 
venous occlusive AEs unless the investigator believes the potential benefit outweighs the risk of 
recurrent venous occlusions and the patient has no other treatment options.
14.2.1.2
Neuropathy
Serious peripheral and cranial neuropathic AEs have occurred in ponatinib-treated patients.  In 
clinical trials, serious peripheral neuropathic AEs reported included peripheral neuropathy, 
paresthesia, hypoesthesia, and hyperesthesia.  Of the patients who developed neuropathy, many 
did so during the first month of treatment.  Monitor patients for symptoms of neuropathy, such as 
hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or 
weakness.  Consider interrupting ponatinib and evaluate if neuropathy is suspected.
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14.2.1.3
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 9.
14.2.1.4
CHF 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.
14.2.1.5
Hypertension
Blood pressure should be monitored at each visit.  HTN detected by at least 2 blood pressure 
measurements should be graded according to NCI CTCAE, v4.0, which defines HTN as a 
disorder characterized by a pathological increase in blood pressure: a repeated elevation in the 
blood pressure exceeding 150 mmHg for systolic and over 90 mmHg for diastolic.  Aggressive 
antihypertensive medication should be initiated or optimized to achieve target blood pressure for 
patients who either develop HTN or experience worsening HTN during study treatment before 
interruption or dose reduction of the study treatment.  HTN may also contribute to renovascular 
disorders, most commonly observed as renal artery stenosis.  Renal artery stenosis has been 
observed in patients taking ponatinib; monitoring for significant or unexplained hypertension 
should therefore include an assessment for renal vascular disease.  If hypertension is persistent 
despite aggressive antihypertensive therapy (i.e., 3 or more medications), or if grade 3 or 4 HTN 
develops, dose interruption and reduction is recommended according to Dose Modification 
Guidelines for general nonhematologic AEs in Table 9.
14.2.1.6
Ocular Toxicity
Serious ocular AE toxicities leading to blindness or blurred vision have occurred in ponatinib-
treated patients.  Retinal toxicities, including macular edema, retinal vein occlusion, and retinal 
hemorrhage, have also occurred in ponatinib-treated patients.  Other ocular toxicities include 
cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis.  Conduct comprehensive eye 
exams at baseline and when clinically indicated.  See Table 9 for details.
14.2.1.7
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.  These events are generally uncomplicated and reversible, and can be managed with 
both a brief interruption of treatment and standard medical therapies. Almost all patients are able 
to continue on with ponatinib treatment at either the same or a reduced dose once the event has 
either improved to grade 1 or resolved.  Patients with low-grade (NCI CTCAE, v4.0 grade 1 or 
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2) elevation in amylase can be continued without dose reduction, but should be monitored 
closely with serial enzyme level determinations.  See Table 9 for details.
14.2.1.8
Hemorrhage
Hemorrhagic events have occurred in patients receiving ponatinib.  Most of these events 
occurred in patients with grade 4 thrombocytopenia.  Interrupt administration in the case of 
serious or severe hemorrhage.
14.2.1.9
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 and 
rapid weight gain should be carefully investigated and appropriate treatment provided.  Interrupt, 
reduce the dose of, or discontinue ponatinib as outlined in Table 9.
14.2.1.10 Cardiac Arrhythmias
Supraventricular tachyarrhythmias were reported in patients treated with ponatinib.  Advise 
patients to report signs and symptoms of rapid heart rate (such as palpitations or dizziness).  
Symptomatic bradyarrhythmias have also been reported. Advise patients to report signs and 
symptoms suggestive of slow heart rate (including fainting, dizziness, or chest pain; see Table 9).
14.2.1.11 Myelosuppression
Neutropenia, anemia, and thrombocytopenia have been observed in clinical studies of ponatinib 
in patients with CML.  While myelosuppression can occur at any time during treatment, its onset 
in CML patients most commonly occurs within the first month of treatment.  Myelosuppression 
can partially be attributed to the CML itself; however, treatment with ponatinib could also 
contribute.  These events can typically be managed with supportive care and, if believed by the 
investigator to be treatment-related, either a reduction or interruption of treatment with ponatinib 
should occur (see Table 9).  Rarely, one or more cytopenias can lead to permanent 
discontinuation of treatment.  The use of hematopoietic growth factors, such as granulocyte 
colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, is permitted on 
study; these agents may be used to support blood counts as clinically indicated to minimize 
treatment interruptions or repeated dose reductions.
The important clinical AE of febrile neutropenia falls under the broad category of 
myelosuppression.  If a patient’s individual risk factors present a high risk of developing febrile 
neutropenia, primary prophylactic use of colony-stimulating growth factors for the prevention or 
reduction of febrile neutropenia is recommended, according to the published NCCN guidelines 
[NCCN Guidelines Version 1.2012 – Myeloid Growth Factors].
14.2.1.12 Tumor Lysis Syndrome (TLS)
The patients at risk of TLS are those with high tumor/leukemic burden prior to treatment.  These 
patients should be monitored closely, especially at the initiation of treatment.  Appropriate TLS 
precautions and prophylactic treatment (such as aggressive hydration with fluids and the 
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initiation of allopurinol at 600 mg/day, or other appropriate treatments) should be initiated prior 
to the start of therapy for those deemed at risk.  Rasburicase and other appropriate treatments for 
hyperuricemia or TLS are permitted.
14.2.1.13 Rash and/or Pruritus
Skin rashes have been commonly reported to be associated with ponatinib.  The vast majority of 
these 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 nonpruritic and 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.
Most patients can be maintained on their current dose of ponatinib, uninterrupted; if necessary, 
their symptoms can be managed with antihistamines, emollients, or topical steroids.  If dose 
interruption is indicated, patients can resume the same dose of ponatinib—typically without 
recurrence of symptoms—once the original episode has improved or resolved.  Interrupt 
administration in the case of serious or severe (grade 3 or 4) rash, and follow the dose 
modification guidelines for nonhematologic toxicity in Table 9.
14.2.1.14 Diarrhea, Nausea, and Vomiting 
Diarrhea is a common side effect of ponatinib, and the use of antidiarrheal medications is 
permitted.  Patients who experience ≥grade 2 diarrhea may begin loperamide at its standard 
treatment schedule (4 mg orally × 1, then 2 mg orally after each loose stool, up to a maximum of 
16 mg/day).
Nausea and vomiting are also reported as side effects of ponatinib.  The use of an antiemetic 
prophylactically is not recommended.  However, if a patient is symptomatic, appropriate 
antiemetic medications may be used as clinically indicated.
14.2.1.15 Constitutional Symptoms/Joint Pain
Certain constitutional symptoms—such as myalgia, arthralgia, headache, weakness, fatigue, 
asthenia, and low-grade fever—have been very commonly reported with ponatinib.  These 
symptoms have been reported mainly at the initiation of treatment, are typically short-lived 
(< 2 weeks), and are seldom, if ever, reported beyond the first month of treatment.  These AEs 
are most commonly low-grade (grade 1 and 2) and are self-resolving, without the need for dose 
interruption or dose reduction, when they do occur.  Most patients can be maintained on their 
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 either improved or resolved.
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14.2.1.16 Compromised Wound Healing and Gastrointestinal Perforation 
Ponatinib may compromise wound healing.  Interrupt ponatinib for at least 1 week prior to major 
surgery.  The decision of when to resume ponatinib after surgery should be based on clinical 
judgment of adequate wound healing.
14.2.1.17 Posterior Reversible Encephalopathy Syndrome (PRES)
PRES, also known as reversible posterior leukoencephalopathy syndrome, is a neurological 
disorder that can present with signs and symptoms such as seizure, headache, decreased 
alertness, altered mental functioning, vision loss, and other visual and neurological disturbances.  
No cases of PRES have been reported in clinical trials, but two postmarketing cases related to 
PRES have been reported in ponatinib-treated patients.  If PRES is diagnosed, interrupt ponatinib 
treatment and resume treatment only once the event is resolved, and if the benefit of continued 
treatment outweighs the risk of PRES.
14.2.2
Dose Modifications for Adverse Drug Reactions
14.2.2.1
Dose Reduction Guidelines 
Dose reduction guidelines for ponatinib are summarized in Table 9, and AEs should be graded 
according to NCI CTCAE, v4.0. These guidelines should be followed by clinical investigators; 
however, for an individual patient, dose interruptions, reductions, and treatment discontinuation 
should also be based on the clinical circumstance. Variation from these guidelines must be 
communicated with the sponsor or sponsor designee, ideally prior to implementation, but no later 
than 72 hours, and must be documented. When the observed toxicity has resolved to ≤grade 1 or 
returned to baseline, the investigator may resume dosing if clinically indicated. Guidance for 
re-escalation after resolution of adverse drug reactions is provided in Section 14.2.2.3.
Dose reduction below 10 mg once-daily is not permitted in the Main Treatment Period (see 
Table 9; a reduced dosing frequency may be permitted in the Treatment Continuation Period in 
accordance with Section 14.1.5).  Doses may be interrupted for study drug-related toxicities for 
up to 28 days.  If a nonhematologic, study drug-related toxicity does not resolve to ≤ grade 1 or 
has not returned to baseline after dose interruption for more than 28 days, the patient must be 
discontinued from study treatment.  If a hematologic study drug-related toxicity does not resolve 
to ≤ grade 1 or has not returned to baseline after dose interruption for more than 28 days, the 
sponsor’s medical monitor must be contacted.  Additionally, the sponsor’s medical monitor must 
be contacted if any AE deemed unrelated to treatment requires dose interruption for more than 
28 days.  
During dose interruptions, continue to observe the study schedule as planned (Table 7 and
Table 8).
Once adverse drug reactions have resolved when the guidelines below are followed, investigators 
are encouraged to re-escalate the dose of ponatinib (Section 14.2.2.3). 
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14.2.2.2
Dose Modifications for AOEs and VTEs
If a serious vascular occlusive adverse reaction occurs, treatment should be interrupted.  
Ponatinib should not be re-administered to patients with arterial or venous occlusive events 
unless the potential benefit outweighs the risk of recurrent arterial or venous occlusions.
AOEs and VTEs include a broad range of nonspecific terms that could meet the criteria for 
diagnosis of this type of event. Investigators should use their clinical judgment and medical 
knowledge of the specific terms in describing these AOEs and VTEs. 
Investigator discretion should be used to judge the event as a vascular pathology when applying 
these dose-modifying schemes. 
14.2.2.2.1 Arterial Occlusive Events
Patients should be discontinued from ponatinib in the event of MI, unstable angina, 
cerebrovascular accident, or TIA, or revascularization procedures. 
For all other arterial occlusive events, dose modification guidelines are outlined in Table 10.  
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Grade 3
Occurrence at 45 mg:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 30 mg 
Occurrence at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 15 mg 
Occurrence at 15 mg: 
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Occurrence at 10 mg: 
Discontinue ponatinib
Any recurrence at any dose level, discontinue ponatinib
Grade 4
Discontinue ponatinib
* “Recurrence” means the second time any AOE, not necessarily recurrence of the same AOE, is encountered by a patient at any 
dose level. 
** “Occurrence” means the first time an AE is encountered by a patient at a given dose level.  
Note: Patients should be discontinued from ponatinib in the event of myocardial infarction (MI), unstable angina, cerebrovascular 
accident or transient ischemic attack (TIA), or revascularization procedures. 
14.2.2.2.2 Venous Thromboembolic Events
Patients should be discontinued from study drug in the event of life-threatening pulmonary 
embolism or retinal vein thrombosis.
For all other venous thromboembolic events, dose modification guidelines are outlined in 
Table 11.
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Patients may receive step-wise dose escalations (e.g., 10 mg QD to 15 mg QD to 30 mg QD) up 
to the starting dose if the above criteria continue to be met.  In no circumstances should a patient 
receive a dose higher than that patient’s starting dose.  
Note:  Patients with grade ≥3 LV dysfunction, CHF, or arterial occlusion are not eligible for 
dose re-escalation after resolution of their symptoms.
14.3
Prior and Concomitant Treatment(s)/Therapy
All concomitant medications administered from the time of informed consent signature through 
30 days after End-of-Treatment (either the last dose of study drug or the investigator/patient 
decision to discontinue, whichever occurs later) are to be reported on the appropriate eCRF for 
each patient.
14.4
Permitted Treatment
All routine and appropriate supportive care (including receipt of blood products and 
hematopoietic growth factors) will be allowed during this study, as clinically indicated, and in 
accordance with standard-of-care practices.  Clinical judgment should be utilized in the treatment 
of any AE experienced by an individual patient.
Information on all concomitant medications, administered blood products, and interventions 
occurring during the study must be recorded on each patient’s eCRF.  Among other treatments 
for concurrent illnesses, the following therapies are allowed:

Medical or surgical treatment necessary for the patient’s well-being 

Where appropriate, treatment with hematopoietic growth factors 

Where appropriate, hydroxyurea or anagrelide during the first cycle of study drug 
administration (concomitant use must be discontinued by the end of the first cycle in all 
patients, and is thereafter prohibited)
14.5
Prohibited Treatment(s)/Therapy
The following concurrent medications and treatments are prohibited: 

Other anticancer therapies

Other investigational drugs or devices

Medications with a known risk of Torsades de Pointes (see Appendix A)

Herbal preparations or related over-the-counter preparations containing herbal 
ingredients 

Elective surgery requiring inpatient care that cannot be postponed until study 
completion
Medications that are potent inhibitors or inducers of CYP3A4 (see Appendix B) should be 
avoided, but are not prohibited (see Section 14.6).
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Medications that prolong the QT interval (see Appendix A), but are not associated with a known 
risk of Torsades de Pointes, should be avoided, but are not prohibited.  If such medications are 
necessary and used while a patient is on study, additional ECG monitoring should be performed 
as clinically indicated.
14.6
Potential Drug Interactions
Based on in vitro studies, drug-drug interactions due to either CYP inhibition or induction by 
ponatinib are highly unlikely in clinical trials using the recommended daily doses of 15-45 mg.  
In vitro studies demonstrate that human CYP3A4 is involved in the metabolism of ponatinib.  In 
light of this, a drug-drug interaction study was performed with a strong CYP3A4 inhibitor in 
healthy subjects, and ketoconazole co-administration was found to increase ponatinib Cmax and 
AUC by 47% and 78%, respectively.  Another drug-drug interaction study was performed with a
strong CYP3A4 inducer in healthy subjects, and co-administration of ponatinib following 
multiple doses of rifampin was found to decrease ponatinib Cmax and AUC by 42% and 62%, 
respectively.  Since CYP3A4 contributes to the metabolism of ponatinib, strong inducers or 
inhibitors of CYP3A4 should be used with caution or avoided altogether.  If co-administration 
with strong inhibitors of CYP3A4 is unavoidable, consider reduction of the ponatinib dose 1 
level from the current dose (that is, 30 mg for a patient receiving 45 mg; 15 mg for a patient 
receiving 30 mg).  Consider an alternative to the strong CYP3A4 inhibitor or, if that is not 
possible, consult the sponsor.  Co-administration of strong CYP3A inducers with ponatinib 
should be avoided unless the benefit outweighs the risk of decreased ponatinib exposure.  
Patients should be monitored for reduced efficacy if co-administration with strong CYP3A 
inducers cannot be avoided.  Selection of concomitant medication with no or minimal CYP3A 
induction potential is recommended.
Medications that are associated with the prolongation of the QT interval may interact with 
ponatinib, as well.  Some medications associated with QT prolongation also interact with 
CYP3A4.  
14.7
Treatment Supply
14.7.1
Formulation, Packaging, and Labeling
Ponatinib investigational drug product is supplied as tablets.  Each tablet contains 10 mg, 15 mg, 
30 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).  Tablets will be supplied as follows:
10 mg tablets: 30 count in white high-density polyethylene (HDPE) bottles with foil 
induction seal and cap
15 mg tablets: 30 count in white HDPE bottles with foil induction seal and cap
30 mg tablets: 30 count in white HDPE bottles with foil induction seal and cap 
45 mg tablets: 30 count in white HDPE bottles with foil induction seal and cap
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Bottle labels will bear the appropriate label text as required by governing regulatory agencies.  
At a minimum, such text will include product name, product strength, number of tablets, and lot 
number.
14.7.2
Treatment Storage, Dispensing, and Accountability
Store ponatinib tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C 
(59°F to 86°F). Keep away from children.  
The study pharmacist or designee at the investigative 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.  Supply shipping will be managed by an interactive voice response system (IVRS).  The 
site must use either an appropriate dispensing log/accountability form provided by the sponsor or 
an acceptable substitute.  Each time study medication is dispensed for a patient, the following 
information is recommended to be recorded: the patient’s 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.  The investigator is responsible for ensuring that the 
patient diary card(s) and study drug provided to the patient and returned from the patient are 
accounted for and noted in source documentation.
In the event that a patient cannot visit the site to obtain the study drug due to unavoidable 
circumstances, such as the COVID-19 pandemic, sites should contact the study monitor/designee 
to arrange for an alternate mechanism (eg, DTP Shipping).
14.7.2.1
Disposition of Used Supplies
All used bottles or packs of study drug must be destroyed in an appropriate manner according to 
the standard practice at each study center.  Destruction of such supplies will be documented, and 
a representative of the sponsor will verify disposition records.
During the trial and at termination, patients must return all unused study drug supplies and the 
return of these unused study drug supplies must be recorded.  Returned supplies must not be 
re-dispensed.
No other utilization of ponatinib intended for use in this study is authorized by the sponsor.  The 
principal investigator or his/her designee will be responsible for the appropriate handling and 
disposition of residual study drug.  Each site is responsible for proper and careful destruction of 
study drug returned by patients.
14.7.2.2
Inventory of Unused Supplies
Periodically throughout and at the conclusion of the study, a representative of the sponsor will 
conduct an inventory of unused study drug.  At the completion of the trial, a final study drug 
accountability review will be conducted.  Any discrepancies must be investigated and all unused 
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study drug must be destroyed on site per the standard operating procedures of the investigative 
site.
15
ADVERSE EVENT REPORTING
15.1
AEs
15.1.1
AE Definition
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have 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 that sign, symptom, or disease is considered related to the medicinal 
product.  Any worsening of a pre-existing condition that is temporally associated with the use of 
the study drug (e.g., occurs after the first dose of study drug), is also defined as an AE.
AEs 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
15.1.2
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 clinically significant by the investigator or sponsor.
15.1.3
Performing AE Assessments
All observed or volunteered AEs, regardless of dose cohort or suspected causal relationship to 
the investigational product, 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 SAE (see 
Section 15.2.1) requiring immediate notification to the Takeda Global Pharmacovigilance 
department or its designated representative.
15.1.4
Reporting Period
All AEs (serious, non-serious, and adverse events of special interest [AESIs]) should be recorded 
on the AE eCRF for all patients beginning at the time of signing the informed consent form and 
concluding 30 days following the last dose of the assigned study treatment in the study or the 
investigator/patient decision to discontinue treatment, whichever occurs later. 
Once a patient is deemed a screen failure, AE collection is no longer required (see Section 12.2.1
Screen Failures). Any SAEs ongoing at the end of the reporting period should be followed until 
they resolve to baseline, stabilize, or are considered to be chronic/irreversible. 
There is no requirement to monitor subjects for SAEs after end of study. Investigators in the 
European Economic Area (EEA) are obligated to report SAEs that they become aware of, to the 
sponsor even after the reporting period (reference European Commission CT-3 Section 4.4). 
Investigators outside the jurisdiction of the EEA are encouraged to report SAEs after the 
reporting period. 
15.1.5
AE Severity
The severity of AEs will be assessed according to the NCI CTCAE, v4.0 (see Appendix C and 
the Study Reference Manual).  If the AE is not defined in the CTCAE, the investigator will 
determine its severity based on the following definitions:

Mild (grade 1): The AE is noticeable to the patient but does not interfere with routine 
activity.  

Moderate (grade 2): The AE interferes with routine activity but responds to symptomatic 
therapy or rest.  

Severe (grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy.  

Life-Threatening (grade 4): The patient is at immediate risk of death.

Death (grade 5): The patient dies as a direct result of the complication or condition induced 
by the AE.
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15.1.6
Causality
The investigator’s assessment of causality must be provided for all AEs (serious and nonserious).  
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. 
The investigator must report such an assessment in accordance with the SAE reporting 
requirements.
The investigator will use both medical consideration and the following categories of causality to 
determine the relatedness of an AE to the study drug (based on the definitions below). Not all 
criteria in each category of relatedness must be present.
Definitely Not Related (not drug-related)

The patient did not receive study drug
OR

The temporal sequence of the AE onset, relative to the administration of 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
AND one of the following:

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
AND one of the following:

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
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Probably Related (drug-related)

There is evidence of exposure to study drug
AND one of the following:

The temporal sequence of the AE onset, relative to administration of study drug, is 
reasonable

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
AND one of the following:

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
15.1.7
Expectedness
The expectedness of an SAE is assessed by the sponsor in the overall classification of SAEs for 
regulatory reportability.  The current Clinical Investigator’s Brochure will be used as the 
reference for determination of expectedness and risk assessment for ponatinib.
15.2
Serious Adverse Events (SAEs) and Adverse Events of Special Interests (AESIs)
The definitions and reporting requirements of ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2A, will be adhered to 
in this study.
15.2.1
Serious Adverse Events Definition
The investigator or sponsor may determine the seriousness of an AE based on the following.
An AE is considered an SAE if at least one of these 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: 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 (i.e., this does not 
include an event that, had it occurred in a more severe form, might have caused death)
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
Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions: Any substantial disruption of a patient’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 this study is considered an 
SAE.  A new cancer is a cancer that is histopathologically different than the cancer 
under study in the trial (i.e., does not include metastatic or progressive disease)

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, that 
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.
15.2.1.1
Progression of the malignancy under study (including signs and symptoms of 
progression)
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.
15.2.1.2
Hospitalizations
AEs (reported from clinical studies) that 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.  AEs that require Emergency Room care but 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:

Care in hospice facilities

Respite care

Care in skilled nursing facilities

Care in nursing homes

Routine Emergency Room admissions

Same-day surgeries (as outpatient/same-day/ambulatory procedures)
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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 (e.g., patient has no place to sleep)

Protocol-specified admission during a clinical study (e.g., for a procedure required by 
the study protocol)

Optional admission not associated with a precipitating AE (e.g., for elective surgery 
that was planned prior to study enrollment [appropriate documentation is required for 
these cases])
15.2.2
AESIs
AOEs and VTEs have been identified as AESIs for ponatinib.  These include arterial and venous 
thrombotic and occlusive adverse events that meet the criteria for SAEs, as defined above in 
Section 15.2.1, as well as those AEs that do not meet the SAE criteria.
AESIs require ongoing monitoring by investigators and rapid identification and communication 
by the investigator to the sponsor.  The sponsor has determined that the events listed below 
should be considered AESIs:

Myocardial infarction (MI): The Third Universal Definition of Myocardial Infarction 
(Thygesen et al, 2012) is used to define MI. The term "Acute MI" is used when there is 
evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia 
including any one of the following: 
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 
one of the following:

Symptoms of ischemia

New or presumed new significant ST-segment T-wave changes or new left bundle 
branch block (LBBB)

Development of pathological Q waves in the ECG

Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality

Identification of an intracoronary thrombus by angiography or autopsy.
o
Cardiac death with symptoms suggestive of myocardial ischemia and presumed new 
ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers 
were obtained or would be increased.
o
Percutaneous coronary intervention-related MI was arbitrarily defined by elevation of 
cTn values (>5 × 99th percentile URL) in patients with normal baseline values 
(≤99th percentile URL) or a rise of cTn values >20% if the baseline values were 
elevated and were stable or falling. In addition, either (1) symptoms suggestive of 
myocardial ischemia, (2) new ischemic ECG changes, (3) angiographic findings 
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consistent with a procedural complication, or (4) imaging demonstration of new loss 
of viable myocardium or new regional wall motion abnormality were required.
o
Stent thrombosis associated with MI when detected by coronary angiography or 
autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac 
biomarker values with at least 1 value above the 99th percentile URL.
o
Coronary artery bypass grafting-related MI was arbitrarily defined by elevation of 
cardiac biomarker values (>10 × 99th percentile URL) in patients with normal 
baseline cTn values (<99th percentile URL). In addition, either (1) new pathological 
Q waves or new LBBB, (2) angiographic documented new graft or new native 
coronary artery occlusion, or (3) imaging evidence of new loss of viable myocardium 
or new regional wall motion abnormality.

Angina (newly diagnosed or worsening of existing or unstable angina)

Coronary artery disease (CAD) (newly diagnosed or worsening of existing CAD) or 
symptoms that may reflect cardiovascular disease (Thygesen et al, 2012)

Cerebrovascular ischemic disease, including ischemic or hemorrhagic stroke, vascular 
stenosis, TIA, cerebrovascular occlusive disease documented on diagnostic neuroimaging, or 
symptoms that may reflect cerebrovascular disease (Easton et al, 2009)  

New onset or worsening of peripheral artery occlusive disease (e.g., of the renal artery, 
mesenteric artery, or femoral artery) or symptoms that may reflect peripheral vascular 
disease 

Retinal vascular thrombosis, both venous and arterial

Venous thromboembolism that could result in significant compromise of organ function or 
other significant consequences (e.g., pulmonary embolism, portal vein thrombosis, or renal 
vein thrombosis), or symptoms that may reflect venous thrombosis.
Additionally, the sponsor has a list of a broad range of nonspecific terms that could meet the 
criteria for AOEs and VTEs. The sponsor will periodically look at the safety data and inform the 
site if any AE qualifies for AOEs/VTEs as per that criteria. Dose modification guidelines for 
AOEs/VTEs are presented in Section 14.2.2.2.
15.2.3
Reporting SAEs 
The investigator or investigator’s designee must notify the Takeda Global Pharmacovigilance 
department or its designated representative immediately (within 24 hours) after becoming aware 
of an SAE.  This timeframe also applies to additional new information (follow-up) on previously 
reported SAEs.  
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15.2.4
Information to be Provided by the Investigator for an SAE 
The sponsor requires all of the following information about the patient and the event:

Investigator identification

Patient identification code (e.g., sex, age, date of birth)

Information on study drug (e.g., 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 

Relationship of the SAE to the study drug

Outcome of the SAE. 
15.2.5
Follow-up Information on a SAE 
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, the investigator is obligated to pursue and provide information to the sponsor.  In addition, 
an investigator may be requested by the sponsor to obtain specific information in an expedited 
manner.  This information may be more detailed than that captured on the AE form.  In general, 
this information will include a description of the AE, provided 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 also be 
provided.
Required Follow-up for SAEs 
Routine follow-up should be conducted through and including 30 days after the last 
administration of assigned study treatment in the trial or the investigator/patient decision to 
discontinue treatment—whichever occurs later—in all patients, in order to monitor for the 
occurrence of SAEs.  If an SAE continues after the 30-day evaluation period, the patient must be 
followed until the event resolves to baseline, stabilizes, or is considered to be 
chronic/irreversible.  The medical monitor may specify a longer follow-up period if required to 
assure the safety of the patient.
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Expedited Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)
Takeda, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions involving the study drug to all regulatory authorities and participating investigators in 
accordance with ICH Guidelines and/or local regulatory requirements, as applicable. In addition, 
Takeda or authorized designee will be responsible for the submission of safety letters to central 
independent ECs (IECs).
The sponsor will notify investigators of all reportable SAEs.  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.
The investigator and IRB/EC will determine whether the informed consent requires revision.  
The investigator should also comply with the 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 will be reported by the sponsor or its designated 
representative—either as expedited safety reports and/or in aggregate reports—to the relevant, 
competent health authorities in all concerned countries.
15.3
Other Safety Issues
15.3.1
Contraception and Pregnancy
Females of childbearing potential and fertile males will be informed as to the potential risk of 
conception while participating in this study. Females of childbearing potential are required to use 
a highly effective form of contraception from randomization through at least 4 months after the 
end of treatment. Birth control methods considered as highly effective are as follows:

systemic hormonal contraceptives used with an additional barrier method:
o
combined (estrogen and progesterone containing) hormonal contraception 
associated with inhibition of ovulation:

oral

intravaginal

transdermal
o
progesterone-only hormonal contraception associated with inhibition of 
ovulation

oral

injectable

implantable
o
intrauterine hormone-releasing system (IUS)

intrauterine device (IUD)

bilateral tubal occlusion

vasectomized sole sexual partner

sexual abstinence (when in agreement with preferred and usual lifestyle of the 
participant)
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A pregnancy test will be performed on each premenopausal female of childbearing potential 
within 7 days prior to first dose of ponatinib, and again at the End-of-Treatment Visit.  A 
negative pregnancy test must be documented prior to administration of study drug.
Females should be advised to take a pregnancy test if their period is late, and to inform their 
investigator of the result.
If a patient is confirmed pregnant during the trial, study drug administration must be 
discontinued immediately.  The investigator must also immediately notify the sponsor medical 
monitor of this event and record the pregnancy on a Pregnancy Form.  Initial information 
regarding a pregnancy must be immediately forwarded to the Takeda Global Pharmacovigilance 
department or its designated representative.
The investigator must immediately report follow-up information to the sponsor regarding the 
course of the pregnancy, including perinatal and neonatal outcomes, regardless of whether the 
patient has discontinued participation in the study.  If the pregnancy results in the birth of a child, 
additional follow-up information may be requested.  If the pregnancy results in spontaneous 
abortion or stillbirth, that event should be reported as an SAE.
Pregnancy outcomes must also be collected for the female partners of any males who took study 
drug in this trial.  Consent to report information regarding these pregnancy outcomes should be 
obtained from the female partner.
15.3.2
Overdose
An overdose is defined as the accidental or intentional ingestion or infusing of any dose of study 
treatment that exceeds the dose described in the protocol.  Overdoses are not considered AEs; 
however, all overdoses should be recorded on an Overdose Form and forwarded to the Takeda 
Global Pharmacovigilance department or its designated representative within 24 hours.  An 
overdose should be reported even if it does not result in an AE.  Overdoses do not need to be 
recorded on the eCRF; dosing information is recorded on the form.  
16
PLANNED STATISTICAL METHODS
16.1
General Considerations
For the purposes of this protocol and all analyses, unless otherwise specified, a month is defined 
as 28 days, the same length as a cycle of treatment for ponatinib. 
Eligible CP-CML patients will be randomized to 3 dose cohorts (45 mg, 30 mg, and 15 mg).  
Patients starting at 45 mg or 30 mg will have their daily dose reduced to 15 mg upon 
achievement of ≤1% BCR-ABL1IS.  Each cohort of patients will be analyzed separately for 
efficacy and safety.
Categorical data will be summarized by the number and percentage of patients in each category.  
Continuous variables will be summarized by descriptive statistics, including mean, standard 
deviation, median, and range.
Statistical inference will be made for each of the 3 cohorts separately—each with the primary 
endpoint of ≤1% BCR-ABL1IS tested at 2-sided 0.05/3=0.0167 significance level, using the 
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Bonferroni method for multiplicity adjustment. The primary analysis of the primary endpoint of 
≤1% BCR-ABL1IS will be performed using a 2-sided exact 98.3% CI for ≤1% BCR-ABL1IS
rate based on the ITT population followed through the Main Treatment Period. Any other 
comparisons will be descriptive. An interim analysis (IA) is planned for this study after all 
patients have been enrolled in the study. The IA data summary will be descriptive in nature. The 
primary analysis is planned to be performed when all patients have at least 12 months of
treatment. A final analysis is planned to be performed after all patients have at least 5 years of 
follow-up. Additional analyses may be performed to develop additional CSRs as per sponsor's 
discretion. In addition, the data will be summarized and reported at least annually.
16.2
Analysis Populations
ITT Population: The ITT population will include all randomized patients, regardless of whether 
they take the assigned study drug.  The primary analyses of efficacy will be based on this 
population.  Randomized patients without response assessments will be considered as non-
responders in the primary efficacy analysis (see Section 16.5.2.1).
Treated Population: The treated population for each cohort includes all patients who have 
received at least one dose of study drug.  The primary analyses of safety will be based on this 
population.
Per-protocol Population: The per-protocol population includes all patients who are 
randomized, receive at least 1 dose of study drug, and have no major protocol violations that 
could be expected to impact response data (such as failure to satisfy 1 or more eligibility criteria, 
administration of other anticancer therapy concurrent with study drug, or administration of 
incorrect dose [e.g., dose that was not the one to which the patient was randomized]).  Major 
protocol violations will be finalized and documented prior to database lock.
16.3
Study Endpoints
Primary Endpoint

≤1% BCR-ABL1IS at 12 months 
Secondary Endpoints

MMR at 12 and 24 months, MCyR by 12 months and duration of MMR

Safety evaluated by rates of AOEs and VTEs, AEs, and SAEs
Other Secondary Endpoints

CCyR at 12 months

Molecular responses: MMR, MR4, and MR4.5 by and at 3-month intervals and MR1 at 
3 months

CHR at 3 months

Tolerability evaluated by discontinuation rate due to AEs, dose reductions due to AE, and 
dose interruptions 
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
Duration of Response:
o
Rates of ≤1% BCR-ABL1IS by 12 months and at and by 6, 18, and 24 months
o
MMR at and by 6 and 18 months; and by 12 and 24 months 

Time to response and duration of response in responders, rate of progression to AP- or 
BP-CML, PFS, and OS
Exploratory Endpoints

Correlation of tumor cell and plasma biomarkers with ponatinib efficacy and safety 

QoL and health outcomes as measured by EQ-5D-5L and FACT-Leu

Efficacy and safety data collected from patients entering the Treatment Continuation 
Period
16.4
Determination of Sample Size
The primary endpoint for this trial is ≤1% BCR-ABL1IS at 12 months.   Consistent with the 
phase 2 PACE trial, the null or uninteresting ≤1% BCR-ABL1IS rate is set at 20%.  The 
alternative ≤1% BCR-ABL1IS rate is set at 35%.  Using the Bonferroni method, the overall 
2-sided significance level for statistical testing in each cohort will be set at 0.0167.  The primary 
analysis of the primary endpoint of ≤1% BCR-ABL1IS will be performed using a 2-sided exact 
98.3% CI for ≤1% BCR-ABL1IS rate based on the ITT population.
A total sample size of 276 patients or 92 patients in each cohort (1:1:1) will distinguish a 
favorable ≤1% BCR-ABL1IS rate of 35% from a null or an uninteresting ≤1% BCR-ABL1IS rate 
of 20% with a nominal 80% power and a 1-sided type I error rate of 0.0083 (equivalent to a 
2-sided 0.0167) using an exact binomial test.  Using the 20% boundary for ≤1% BCR-ABL1IS, 
29 or more ≤1% BCR-ABL1IS responders will be needed for a lower limit of the 2-sided exact 
98.3% CI for the ≤1% BCR-ABL1IS rate to exceed 20%.
16.5
Efficacy Analysis
16.5.1
Definitions of Efficacy Endpoints
The primary and secondary efficacy endpoints are listed in Section 16.3.  This section defines the 
endpoints themselves and the associated conditions defining loss of those endpoints. Additional 
details, including definitions of specific time points and windows for the time point assessments, 
will be provided in the statistical analysis plan (SAP).
16.5.1.1
Molecular Response Definitions
Rate of ≤1% BCR-ABL1IS at 12 months is the proportion of patients achieving ≤1% 
BCR-ABL1IS at 12 months after initiation of study drug. 
Molecular Response: ≤1% BCR-ABL1IS, MMR, MR4, and MR4.5 are defined as ≤1%, 
≤0.1%, ≤0.01%, and ≤0.0032% BCR-ABLIS, respectively.  In the case of undetectable 
BCR-ABL transcript levels, a minimum of 10,000 and 32,000 ABL copies must be present in 
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order to be classified as MR4 and MR4.5, respectively. MR1 at 3 months is the proportion of 
patients achieving a ratio of ≤10% BCR-ABL1 to ABL1 transcripts on the international scale at 
3 months.
Time to ≤1% BCR-ABL1IS is defined as the interval between the first dose date of the study 
treatment and the first date at which the criteria for ≤1% BCR-ABL1IS are met.
Time to MMR is defined as the interval between the first dose date of the study treatment and 
the first date at which the criteria for MMR are met.
Duration of ≤1% BCR-ABL1IS/MMR is defined as the interval between the first assessment at 
which the criteria for ≤1% BCR-ABL1IS/MMR are met until the earliest date at which loss of 
≤1% BCR-ABL1IS/MMR occurs, or the criteria for progression (see Section 16.5.1.4) are met.  
Patients remaining in ≤1% BCR-ABL1IS/MMR will be censored at the last date at which the 
criteria for ≤1% BCR-ABL1IS/MMR are met.
Loss of MMR is defined as an increase to > 0.1% of BCR-ABL1IS.  This result must be 
confirmed at the subsequent visit, unless it is associated with confirmed loss of CHR or loss of 
CCyR or with progression to accelerated or blast phase or death due to CML. 
Loss of ≤1% BCR-ABL1IS is an increase to > 1% of BCR-ABL1IS.  This result must be 
confirmed at the subsequent visit, unless it is associated with confirmed loss of CHR or with 
progression to accelerated or blast phase or death due to CML. 
Loss of MR4 is defined as an increase to > 0.01% of BCR-ABL1IS.  This result must be 
confirmed at the subsequent visit, unless it is associated with confirmed loss of CHR or loss of 
CCyR or with progression to accelerated or blast phase or death due to CML.
Loss of MR4.5 is defined as an increase to > 0.0032% of BCR-ABL1IS.  This result must be 
confirmed at the subsequent visit, unless it is associated with confirmed loss of CHR or loss of 
CCyR or with progression to accelerated or blast phase or death due to CML.
16.5.1.2
Cytogenetic Response Definitions
MCyR by 12 months is the proportion of patients achieving CCyR or PCyR at any time within 
12 months after initiation of study drug. Patients entering the study already in a PCyR must 
achieve a CCyR in order to be considered a success for achieving a MCyR. 
Cytogenetic response is the percentage of Ph+ metaphases in bone marrow (peripheral blood 
may not be used), with a review of a minimum of 20 metaphases.  Responses are defined as 
follows:
Major cytogenetic response (MCyR): CCyR or PCyR

CCyR: 0% Ph+ metaphases

PCyR: > 0 to 35% Ph+ metaphases
CCyR at 12 months is the proportion of patients achieving CCyR at 12 months after initiation 
of study drug.  
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16.5.1.3
Hematologic Response Definitions
CHR rate is defined as the proportion of patients achieving CHR at any time after initiation of 
study treatment.  CHR will be confirmed no earlier than 28 days later.
CHR is defined as achieving all of the following measurements:

White blood cells (WBC) ≤ institutional ULN

Platelets < 450,000/mm3

No blasts or promyelocytes in peripheral blood

< 5% myelocytes plus metamyelocytes in peripheral blood

Basophils in peripheral blood < 5%

No extramedullary involvement (including no hepatomegaly or splenomegaly)
Loss of CHR is defined as the appearance of any of the following, confirmed by a second 
assessment at least 4 weeks later (unless associated with progression [Section 16.5.1.4] or 
CML-related death):

WBC count that rises to > 20,000/mm3

Platelet count that rises to ≥ 600,000/mm3

Splenomegaly progressing to a size ≥5 cm below the left costal margin

Appearance of ≥5% myelocytes plus metamyelocytes in peripheral blood

Appearance of blasts or promyelocytes in the peripheral blood
16.5.1.4
Event-Related Definitions
PFS is defined as the interval between the first dose date of study treatment and the first date at 
which the criteria for progression are met (progression to the accelerated phase or blast phase of 
CML), or death due to any cause, censored at the last response assessment.
Progression to AP is defined as:

≥15% and < 30% blasts in peripheral blood or bone marrow
or

≥20% basophils in peripheral blood or bone marrow
or

≥30% blasts + promyelocytes in peripheral blood or bone marrow (but < 30% blasts)
or

< 100 × 109 platelets/L in peripheral blood unrelated to therapy
or

Cytogenetic, genetic evidence of clonal evolution
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and

No extramedullary disease
Progression to BP is defined as:

≥30% blasts in peripheral blood or bone marrow
or

Extramedullary disease other than hepatosplenomegaly
OS is defined as the interval between the first dose date of study treatment and death due to any 
cause, censored at the last contact date when the patient was alive.
16.5.2
Primary Endpoint Analysis
The primary endpoint for each cohort is ≤1% BCR-ABL1IS rate at 12 months.  The 2-sided type 
I error adjusted for the 3 statistical tests, using the Bonferroni method, will be set at 
0.05/3=0.0167.  Analysis of ≤1% BCR-ABL1IS rate will be performed using a 2-sided 98.3% 
exact CI.  The point estimate of ≤1% BCR-ABL1IS rate and a 98.3% exact CI, based on the 
exact binomial distribution (Clopper-Pearson exact CI), will be presented.  Ponatinib will be 
considered promising if the lower limit of 2-sided 98.3% exact CI for the ≤1% BCR-ABL1IS
rate exceeds 20%.  A 2-sided exact 95% CI will also be provided.
The primary analysis population for the primary efficacy endpoint will be based on the ITT 
population.  The analysis for the primary endpoint will also be performed using the per-protocol 
population.
16.5.2.1
Data Handling Rules for the Primary Analyses of the Primary Endpoint
The following rules will be implemented for the primary analysis of ≤1% BCR-ABL1IS in 
CP-CML patients:

Patients for whom BCR-ABL1IS cannot be determined (i.e., patients with BCR-ABL1 
variants other than b2a2 or b3a2) will be excluded from the primary analysis

Patients who are ≤1% BCR-ABL1IS at baseline will be excluded from the primary 
analysis

Patients will be considered as non-responders if they meet any of the following 
criteria:
o
Are randomized but untreated
o
Do not respond at 12 months after the initiation of study treatment
o
Undergo no baseline PCR assessment
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16.5.3
Secondary Efficacy Endpoint Analyses
16.5.3.1
Secondary Efficacy Endpoints
Analyses of secondary response endpoints, such as MCyR, CCyR, MMR, and CHR, will be 
performed in the same way as the primary endpoint.  For the secondary endpoints of time to 
≤1% BCR-ABL1IS and time to MMR, descriptive statistics will be provided for patients who 
meet the criteria for response.  For the secondary endpoints of duration of ≤1% BCR-ABL1IS, 
and MMR, the Kaplan-Meier method will be used to estimate duration of response among 
patients meeting the criteria for response.  Rates of patients remaining in MCyR, ≤1% BCR-
ABL1IS and MMR at 12, 18, and 24 months, respectively, as well as the proportion of patients 
meeting MCyR by 12 months and CCyR at 12 months by BM cytogenetics, will be presented.  
The rate of progression to AP or BP will be summarized.  PFS and OS will also be estimated, 
using the Kaplan-Meier method.  Median time to event and its 2-sided 95% CI will be provided.  
The analyses of time to event and duration of response will be conducted for each dose cohort, 
and for descriptive purposes only.
The analyses of secondary efficacy endpoints will be performed on the ITT population.  The 
analyses of secondary endpoints may also be performed on the per-protocol population.
16.5.3.2
Data Handling Rules for Secondary Efficacy Endpoint Analyses
The following rules will be implemented for the primary analysis of the secondary endpoints of 
MCyR and CCyR in CP-CML patients:

Patients will be excluded from the analysis if they meet any of the following criteria:
●
Have fewer than 20 metaphases examined at baseline 
●
Are in CCyR at baseline 
●
Undergo no baseline cytogenetic assessment
●
Have a variant translocation that is not assessable for cytogenetic response

Patients will be considered as non-responders if they meet any of the following 
criteria:
o
Are randomized but untreated
o
Do not respond by 12 months after the initiation of study treatment

At any given cytogenetic assessment after baseline, if fewer than 20 metaphases are 
examined, the following rule will apply to the determination of MCyR:
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

Determination of CCyR by cytogenetic assessment will require at least 20 metaphases 
examined.
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For the primary analyses of secondary endpoints of MMR, MR4.5, MR4, and CHR, if patients 
do not have a post-baseline response assessment, they will be considered as non-responders.
16.5.4
Subgroup Analyses of the Primary Endpoint and Secondary Efficacy Endpoints
For the primary endpoint and secondary efficacy endpoints, subgroup analyses will be performed 
by baseline potential prognostic factors when warranted based on numbers of patients in 
subgroups (details will be included in the SAP).  Subgroups may include:

Age (< 60 years, ≥ 60 years)

Gender

Race

Geographic region

T315I (Yes, No) 

Number of prior approved TKI therapies (1, 2, 3, 4)

Other disease-related prognostic factors
16.5.5
Exploratory Analysis on Treatment Continuation Period
For efficacy in patients entering the optional Treatment Continuation Period, analyses will be 
performed by descriptive summary.  PFS and OS will also be estimated based on data collected 
up to 5 years after the last patient enters the study, using the Kaplan-Meier method.  The 
analyses of time to event and duration of response will be conducted for descriptive purposes 
only.
16.6
Safety Analysis
All patients receiving at least 1 dose of study drug will be considered evaluable for safety.  
Safety analyses will be performed, based on the treated population.  All AEs with an initial onset 
date on or after the first dose date, and no later than 30 days after the last dose date of study 
treatment (or events starting after initial consent that worsen in severity on or after the first dose 
date) will be considered treatment-emergent.  AEs and SAEs will be summarized for TEAEs, 
and all AEs will be listed.
16.6.1
Analysis of AOEs and VTEs 
Number and percentages of patients who developed AOEs and VTEs will be summarized for 
each cohort.  These events will be categorized as follows:

Arterial occlusive events
o
Cardiac occlusive/thrombotic events 
o
Cerebral occlusive/thrombotic events
o
Peripheral occlusive/thrombotic events
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
Venous thrombotic events
Details for classification of specific events as AOEs and VTEs are provided in Section 14.2.1.1.
Crude and exposure-adjusted incidence rates of AOEs and VTEs will be calculated for each 
cohort and for all patients.  The exposure-adjusted incidence rate is calculated as number of 
patients with the AE divided by total treatment exposure time.
The following additional descriptive analyses will be performed to characterize AOEs and VTEs:

Time to onset: Calculated as date of first AOE or VTE – first dose date + 1

Dose at onset: Dose of ponatinib taken immediately prior to onset of first AOE or VTE
Detailed data handling rules will be specified in the SAP for incomplete or missing onset dates.
Baseline risk factors for the occurrence of AOEs and VTEs will be evaluated for all patients, and 
will include:

History of ischemic disease 

History of non-ischemic cardiac disease

Hypertension

History of diabetes

History of smoking

Obesity

History of hypercholesterolaemia

Age

Gender

Other risk factors 
16.6.2
Analysis of Categories of AEs
Categories of AEs will be prospectively defined using Standardized MedDRA Queries (SMQs) 
or Modified MedDRA Queries based on SMQs and MedDRA System Organ Classes (SOCs).  
The AE crude rates, as well as the frequency of occurrence by overall toxicity—categorized by 
toxicity grades (severity)—will be described for each cohort.  Events will also be characterized 
by time to onset, dose at onset, and duration, as described above.  Further details will be outlined 
in the SAP.
16.6.3
Other Safety Analyses
For all TEAEs and SAEs, crude rates as well as the frequency of occurrence by overall toxicity, 
categorized by toxicity grades (severity) - will be described for each cohort.  Listings of 
laboratory test results will be generated, and shifts in laboratory parameters from baseline to 
worst post-baseline value (in terms of NCI CTCAE, v.4.0 grades) will be summarized.  
Maximum shift from baseline in blood pressure and mean change from baseline over time will 
be summarized.  Exposure to study drug over time will also be summarized.
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16.6.4
Analyses of Treatment Discontinuation Rate due to AEs, Dose Reductions, and 
Dose Interruptions
For each dose cohort, numbers and percentages of patients who discontinue treatment due to 
AEs; who have any dose reduction from the starting dose due to AEs; or who have dose 
interruption of at least 3 days will be provided.  Number of days at each dose level and time to 
first dose reduction due to AE will be summarized in order to characterize length of dose 
interruptions and reductions.
16.7
Exposure-Response Analysis 
The plasma concentration-time data will be listed and summarized by time point. These data will 
contribute to population PK and exposure-response analyses of safety (e.g., AOE incidence) and 
efficacy (e.g., MMR). The analysis plan for the population PK and exposure-response analyses 
will be defined separately and the results of these analyses will be reported separately. 
16.8
QoL/Health Outcomes Analysis
QoL and health outcomes measures are being collected using the EQ-5D-5L and FACT-Leu 
instruments.  Means and medians of scores of these questionnaires will be summarized for each 
dose cohort by time point, overall, and for each domain.
16.9
Exploratory Biomarker Analyses
The mutation status of BCR-ABL1 and other genes implicated in tumor biology and/or drug 
metabolism will be determined through analyses of tumor cells collected at study entry, on study, 
and/or at End-of-Treatment.  Analysis methodologies include, but are not limited to, DNA 
sequencing, digital PCR, and mass spectrometry.  Plasma samples collected at study entry, on 
study, and at End-of-Treatment may be assessed for circulating biomarkers (e.g., cytokines, 
chemokines, and growth factors) to identify associations with ponatinib efficacy and safety.
16.10
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 dose 
cohort in the Clinical Study Report (CSR).
Protocol deviations related to the COVID-19 pandemic will be assessed and listed 
independently.  Additional sensitivity analyses may be performed to evaluate the impact of 
protocol deviations related to COVID-19 on the primary efficacy and safety endpoints.
17
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, the sponsor or its designee, as well as the 
investigator, will review the protocol; the Clinical Investigator's Brochure; the eCRFs and 
instructions for their completion; the procedure for obtaining informed consent; and the 
procedure for reporting AEs.  A qualified representative of the sponsor will monitor the conduct 
of the study by both visiting the site and contacting it by telephone.  During the visits, 
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information recorded in the eCRFs will be verified against source documents.  The sponsor’s 
medical monitor will review the data for safety information.  The sponsor’s clinical data 
associates or designees will review the data for legibility, completeness, and logical consistency.  
Additionally, the sponsor’s clinical data associates will 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 will be 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 eCRFs against source documents.
17.1
Investigators and Study Administrative Structure
The investigator must provide the sponsor with the following documents before enrolling any 
patients:

An executed Clinical Trial Agreement

FDA Form 1572

Documentation of financial disclosure

Principal investigator’s Curriculum Vitae

IRB/EC approval of the protocol

IRB/EC-approved consent form
If any investigator retires, relocates, or otherwise withdraws from conducting the study, the 
responsibility for maintaining records may be transferred to another person (e.g., sponsor, 
IRB/EC, or other investigators) who accepts the responsibility.  The sponsor must be notified in 
writing of and agree to the change in advance.  An updated FDA Form 1572 will be filed with 
the sponsor and the FDA for any changes in the study personnel reported in the current FDA 
Form 1572.
17.2
Study Monitoring
This study will be monitored by representatives of the sponsor.  Site visits are made before the 
study begins, at regular intervals during the study, and at the study closeout.  Communication by 
telephone, mail, and e-mail may be used, as needed, to supplement site visits.  The investigator 
and study personnel will cooperate with the sponsor, provide all appropriate documentation, and 
be available to discuss the study.  The purpose of the site visits is to verify:

Adherence to the protocol (the investigator should document and explain any deviation 
from the approved protocol)

The completeness and accuracy of the eCRFs and the dispensing and inventory record 
(adequate time and space for these visits should be allocated by the investigator)

Compliance with regulations (the verification will require comparison of the source 
documents to the eCRFs)
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In the event that a monitor cannot visit the site in a timely manner due to the COVID-19 
pandemic, alternative monitoring approaches such as remote source data verification or 
telephone contact may be used to ensure data quality and integrity and maintain patient safety. 
Alternative monitoring approaches should be used as approved by the sponsor, and only where 
allowed by the local Health Authority, local privacy laws (where applicable), and the IRB/IEC.
18
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.
18.1
Institutional Review Board or Ethics Committee 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 (i.e., 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 Clinical Trial Agreement has been signed by the 
sponsor and the clinical site.
18.2
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 study site’s proposed informed consent document should be submitted to the 
sponsor for review and comment before submission to the 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 
information to the patient and/or inclusion of additional information in an informed consent 
document.
Nothing in this protocol or the 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.
18.3
Patient Confidentiality
All unpublished information that the sponsor provides to the investigator, as well as all 
information generated in connection with the study, must be kept confidential and must not be 
disclosed to a third party without the prior written consent of the sponsor.  In addition, this 
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information must not be published prior to the sponsor’s review, in accordance with the terms of 
the Clinical Trial Agreement.  
18.4
Study Committees
18.4.1
Data Monitoring Committee (DMC)
An independent DMC, consisting of 3 to 5 members not associated with the conduct of the study, 
will be established for this trial.  The committee will perform data review quarterly and meet at 
least twice yearly until the final analysis has been performed, as specified in the protocol.  Ad-
hoc DMC meetings may also be held if a significant issue should arise.  
The DMC will be responsible for evaluating the results of safety analyses and making 
recommendations to the sponsor.  Efficacy data can also be requested, if needed, to evaluate 
risk/benefit before making a recommendation.  The DMC will operate under the DMC charter, 
which specifies the data to be included in each review, rules related to study modification, and 
protection of the integrity of the data.  At each meeting, the DMC will make recommendations to 
either continue the study unchanged, to modify the study, or to discontinue the study.  The DMC 
will communicate the recommendations to the sponsor.  The final decision to act on the DMC 
recommendations will be made by the sponsor in consultation with the Study Steering 
Committee.   
18.4.2
Study Steering Committee
A steering committee will be constituted with initiation of the study.  Its purpose is to function in 
an advisory capacity to: 1) provide input on study conduct and progress; 2) ensure scientific and 
ethical integrity of the study; and 3) provide ongoing oversight of safety and efficacy in this 
open-label study.  The steering committee will include clinicians who are experts in the clinical 
care and investigation of the targeted patient population, and will also include sponsor 
representatives.  In addition to general study oversight, the committee will be responsible for 
periodic review of study data to evaluate the safety profile of ponatinib, assess accumulating 
signals of efficacy, evaluate data quality, and provide input on operational aspects of the study.  
The committee may make recommendations for the sponsor’s consideration based on periodic 
review. 
18.4.3
Cardiovascular Endpoint Adjudication Committee
The cardiovascular endpoint adjudication committee (CVEAC) will be composed of independent 
experts with experience and training appropriate for reviews of the CV, AOE, HF, and VTE 
endpoints. They will review all CV events defined as AOEs, HF, and VTEs reported by the sites 
(i.e., initial diagnoses, laboratory values, results of procedures, hospital discharge summaries) to 
determine the occurrence of CV endpoints and sites may be requested to send relevant source 
data to the sponsor representative for this purpose. The adjudication of these events will be 
performed based on the CVEAC adjudication charter, which will document details for 
performing adjudication. The CVEAC’s assessment of each potential CV endpoint will be 
documented in the clinical database and will be used in the endpoint analysis. The process will 
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be coordinated by the contract research organization, and the CVEAC charter will define the 
endpoints and the responsibilities of the committee. 
19
DATA HANDLING AND RECORD KEEPING
19.1
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 screened for the study.  All 
pertinent data records are to be submitted to the sponsor during and/or at completion or 
termination of the study.
19.2
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 the release of the patient’s medical records will be included in the informed consent 
document:
Representatives of regulatory agencies, IRB/EC, the sponsor, and the patient’s 
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.
19.3
Retention of Data
Trial documents (including correspondence related to this clinical study, patient records, source 
documents, eCRFs, study drug inventory records; IRB/EC and sponsor correspondence 
pertaining to the study; and original patient, laboratory, and study drug inventory records relating 
to the study) should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications in 
an ICH region (that is at least 15 years or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product).  Trial documents should be retained for 
a longer period if required by applicable regulatory requirements or by agreement with the 
sponsor.  Thereafter, records will not be destroyed without giving the sponsor prior written 
notice and the opportunity to further store such records, at the sponsor’s cost and expense.
19.4
Termination of Study
The sponsor may terminate the study or a study site at any time for any of the following reasons:

Failure to enroll patients

Protocol violations
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
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.
20
FINANCING AND INSURANCE
A clinical study agreement will be signed by the investigator (and/or, as appropriate, the hospital 
administrative representative) and the sponsor prior to the start of the study, outlining overall 
sponsor and investigator responsibilities in relation to the study.  Financial remuneration will 
cover the cost per included patient, based on the calculated costs of performing the study 
assessments in accordance with the protocol, and the specified terms of payment will be 
described in the contract.  The contract should describe whether costs for pharmacy, laboratory 
and other protocol-required services are being paid directly or indirectly.  Prior to the start of the 
study, investigators and sub-investigators will release sufficient and accurate information that 
permits the sponsor or sponsor-designated agent that an investigator has no personal or 
professional financial incentive regarding the future approval or nonapproval of the study drug 
that his/her research might be biased by such financial incentives.  The financial information is 
exclusive of agreements directly related to fees associated with the study being conducted. All 
information provided will be regarded as strictly confidential and will only be disclosed to the 
respective regulatory authority.
21
PUBLICATION AND DISCLOSURE POLICY
The investigator must notify the IRB/EC of the conclusion of the clinical trial.  This report 
should be made within 3 months of the completion or termination of the study.  The final report 
sent to the IRB/EC should also be sent to the sponsor and, along with the completed eCRFs, 
constitutes the final summary to the sponsor, thereby fulfilling the investigator’s regulatory 
responsibility.
Section 801 of the FDA Amendments Act mandates the 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 (icmje.org [Accessed: 21 March 2014]).
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The institution and principal investigator acknowledge that the study is a multi-center study, and, 
as such, agree that they will not publish a manuscript, abstract, poster or other disclosures 
(“Publication”) before a combined paper that identifies all the sites that participated in the study 
(“Multi-Center Publication”) is published.  If the Multi-Center Publication has not been 
submitted within one (1) year from the date of the completion, termination, or abandonment of 
the multi-center study, the institution may publish or present its individual results in accordance 
with the provisions stated below.
In order to balance institution’s right to publish with Takeda’s proprietary interests, the 
institution will submit to Takeda material intended for publication, manuscripts, abstracts, 
posters and other disclosures (“Proposed Disclosures”) at least forty-five (45) days prior to 
submitting for publication or other disclosure to allow for expeditious review by Takeda.  If 
Takeda believes that any Proposed Disclosure contains any information relating to any 
patentable invention, the disclosure of such Proposed Disclosure shall be delayed for up to sixty 
(60) days from the date Takeda receives the Proposed Disclosure to permit Takeda to file patent 
applications.  If Takeda believes that any Proposed Disclosure contains Confidential 
Information, Takeda shall have the right to require that the institution delete any reference to 
Confidential Information, excluding the results of the study or other Permitted Research (as 
defined in Section 11).  If the institution and principal investigator choose not to publish, Takeda
reserves the right to publish the results of the study, and, if appropriate, to include its medical 
staff in the author list of such publication in accordance with academic publication standards.
Subject to applicable copyright law, if an institution and/or principal investigator publishes the 
results of the study, the institution and/or principal investigator hereby grant Takeda an 
irrevocable, royalty-free license to make and distribute copies of such publication under any 
copyright privileges that the institution and/or principal investigator may have.
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22
REFERENCES
American Diabetes Association. Standards of medical care for patients with diabetes mellitus. 
Diabetes Care. 2003 Jan;26 Suppl 1:S33-50. 
Baccarani M, Deininger MW, Rosti G, et al. European Leukemia Net recommendations for the 
management of chronic myeloid leukemia: 2013. Blood. 2013; 122(6): 872-84.
Bradeen HA, Eide CA, O'Hare T, et al. Comparison of imatinib, dasatinib (BMS-354825), and 
nilotinib (AMN107) in an n-ethyl-n-nitrosourea (ENU)-based mutagenesis screen: high efficacy 
of drug combinations. Blood. 2006;108:2332-2338.
Cortes J, Kantarjian H, Shah N, et al. Ponatinib in refractory philadelphia chromosome-positive 
leukemias. N Engl J Med. 2012; 367(22):2075-88.
Diabetes Prevention Program Research Group. Reduction in the Incidence of Type 2 Diabetes 
with Lifestyle Intervention or Metformin. N Engl J Med. 2002;346:393-403.
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.
ICLUSIG® (ponatinib) film-coated tablets. Summary of Product Characteristics. MAH: ARIAD 
Pharmaceuticals Ltd., Surrey, UK. 2015. Available at: 
ema.europa.eu/docs/en_GB/document_library/EPAR_-
Product_Information/human/002695/WC500145646.pdf [Accessed: 15 November 2016].
James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high 
blood pressure in adults: report from the panel members appointed to the Eighth Joint National 
Committee (JNC 8). JAMA. 2014; 311(5):507-520. 
Lauseker M, Hanfstein B, Haferlach C, et al. Equivalence of BCR-ABL transcript levels <1% 
according to the international scale with complete cytogenetic response in chronic phase CML 
patients. Abstract 2495. Presented at the 54th American Society of Hematology annual meeting. 
Atlanta, GA. Dec 8-11, 2012. 
Marin D. Patient with chronic myeloid leukemia in complete cytogenetic response: what does it 
mean, and what does one do next? J Clin Oncol. 2014; 32(5):379-84. 
Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript levels at 3 months is 
the only requirement for predicting outcome for patients with chronic myeloid leukemia treated 
with tyrosine kinase inhibitors. J Clin Oncol. 2012; 30(3): 232-8.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: 
Myeloid Growth Factors. Available at:
nccn.org/professionals/physician_gls/f_guidelines.asp. Version 1, 2012 [Accessed 21 March 
2014].
O’Brien S, Radich JP, Abboud CN, et al. NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines®). Chronic Myelogenous Leukemia. Version 3.2014. National 
Comprehensive Cancer Network, Inc. 2014.  
For non-commercial use only

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O'Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic 
myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. 
Cancer Cell. 2009;16 (5):401-412.
Saglio G, Kantarjian H, Shah N, et al. Early response (molecular and cytogenetic) and long-term 
outcomes in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): 
exploratory analysis of DASISION 3-year data. Abstract 1675. Presented at the 54th American 
Society of Hematology annual meeting. Atlanta, GA. Dec 8-11, 2012. 
Thygesen K, Alpert JS, Jaffe AS. Third Universal Definition of Myocardial Infarction. 
Circulation. 2012;126:2020-2035.
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23
APPENDICES
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APPENDIX A
Drugs with a Risk of Torsades de Pointes
Four categories of QT-prolonging drugs that may be used as a guide for this protocol can be 
accessed at crediblemeds.org/everyone/composite-list-all-qtdrugs/ [Accessed: 
04 September 2020].  Categories include “Drugs with Known TdP Risk,” “Drugs with Possible 
TdP Risk,” “Drugs with Conditional TdP Risk,” and “Drugs to be Avoided by Congenital Long 
QT Patients.”  The investigator site should register (under the “For Healthcare Providers” tab) to 
access these categories.  If the investigator site does not wish to register, a composite list, 
including all categories, is available.  
Drugs with a known risk of Torsades de Pointes are listed in the table below, and are the only 
category of QT-prolonging drugs that are prohibited in this study.
Note: The website and table are only to be used as a guideline and are not comprehensive.  It is 
the investigator’s responsibility to ensure that any drugs under consideration have not been 
newly identified as causing Torsades de Pointes.
Table A-1
Drugs Generally Accepted by the QTDrugs.org Advisory Board of the 
Arizona CERT to have a Known Risk of Causing Torsades de Pointes; 
Prohibited in this Study
Generic Name
Brand Name
Class/Clinical Use
Aclarubicin
Aclacin®, 
Aclacinomycine®, 
Aclacinon®, Aclaplastin®, 
Jaclacin®
Anticancer/cancer
Amiodarone 
Cordarone®, Pacerone®, 
Nexterone®
Antiarrhythmic/arrhythmia
Anagrelide
Agrylin®, Xagrid®
Phosphodiesterase 3 inhibitor/thrombocythemia
Arsenic trioxide 
Trisenox®
Anticancer/leukemia
Astemizole 
Hismanal®
Antihistamine/allergic rhinitis
Azithromycin
Zithromax®, Zmax®
Antibiotic/bacterial infection
Bepridil 
Vascor®
Antianginal/angina pectoris (heart pain)
Cesium chloride
Energy Catalyst
Toxin/cancer
Chloroquine
Aralen®
Antimalarial/malaria
Chlorpromazine 
Thorazine®, Largactil®, 
Megaphen®
Antipsychotic/Antiemetic/schizophrenia, nausea, others
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Generic Name
Brand Name
Class/Clinical Use
Chlorprothixene
Truxal®
Antipsychotic/schizophrenia
Cilostazol
Pletal®
Phosphodiesterase 3 inhibitor/intermittent claudication
Ciprofloxacin
Cipro®, Cipro-XR®, 
Neofloxin
Antibiotic/bacterial infection
Cisapride
Propulsid®
GI stimulant/increase GI motility
Citalopram
Celexa®, Cipramil®
Antidepressant, SSRI/depression
Clarithromycin
Biaxin®, Prevpac®
Antibiotic/bacterial infection
Cocaine
Cocaine
Local anesthetic/topical anesthetic
Disopyramide 
Norpace®
Antiarrhythmic/arrhythmia
Dofetilide 
Tikosyn®
Antiarrhythmic/ arrhythmia
Domperidone
Motilium®, Motillium®, 
Motinorm Costi®, Nomit®
Antiemetic/nausea, vomiting
Donepezil
Aricept®
Cholinesterase inhibitor/Dementia (Alzheimer’s 
disease)
Dronedarone
Multaq®
Antiarrhythmic/ arrhythmia
Droperidol 
Inapsine®, Droleptan®, 
Dridol®, Xomolix®
Antipsychotic/Antiemetic/anesthesia (adjunct), nausea
Erythromycin 
E.E.S.®, Robimycin®, 
EMycin®, Erymax®, Ery-
Tab®, Eryc Ranbaxy®, 
Erypar®, Eryped®, 
Erythrocin Stearate 
Filmtab®, Erythrocot®, E-
Base®, Erythroped®, 
Ilosone®, MY-E®, 
Pediamycin®, Abboticin®, 
Abboticin-ES®, Erycin®, 
PCE Dispertab®, 
Stiemycine®, Acnasol®, 
Tiloryth®
Antibiotic /bacterial infection, increase GI motility
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Generic Name
Brand Name
Class/Clinical Use
Escitalopram
Cipralex®, Lexapro®, 
Nexito®, Anxiset-E®, 
Exodus®, Esto®, 
Seroplex®, Elicea®, 
Lexamil®, Lexam®, 
Entact®, Losita®, 
Reposil®, Animaxen®, 
Esitalo®, Lexamil®
Antidepressant, SSRI/major depression, anxiety 
disorders
Flecainide
Tambocor®, Almarytm®, 
Apocard®, Ecrinal®, 
Flécaine®
Antiarrhythmic/arrhythmia
Fluconazole
Diflucan®, Trican®
Antifungal/fungal infection
Gatifloxacin
Tequin®
Antibiotic/bacterial infection
Grepafloxacin
Raxar®
Antibiotic/bacterial infection
Halofantrine 
Halfan®
Antimalarial/malaria
Haloperidol 
Haldol®, Aloperidin®, 
Bioperidolo®, Brotopon®, 
Dozic®, Duraperidol®, 
Einalon S®, Eukystol®, 
Halosten®, Keselan®, 
Linton®, Peluces®, 
Serenace®, Serenase®, 
Sigaperidol®
Antipsychotic/schizophrenia, agitation
Hydroquinidine 
(dihydroquinidine)
Serecor®
Antiarrhythmic/arrhythmia
Hydroxychloroquine Plaquenil®, Quineprox®
Antimalarial, Antiinflammatory/malaria, SLE, 
rheumatoid arthritis
Ibogaine
Psychedelic/narcotic addiction, unproven
Ibutilide
Corvert®
Antiarrhythmic/arrhythmia
Levofloxacin
Levaquin®, Tavanic®
Antibiotic/bacterial infection
Levomepromazine 
(methotrimeprazine)
Nosinan®, Nozinan®, 
Levoprome®
Antipsychotic/schizophrenia
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Generic Name
Brand Name
Class/Clinical Use
Levomethadyl 
acetate
Orlaam®
Opioid agonist/narcotic dependence
Levosulpiride
Lesuride®, Levazeo®, 
Enliva®
Antipsychotic/schizophrenia
Mesoridazine
Serentil®
Antipsychotic/schizophrenia
Methadone
Dolophine®, Symoron®, 
Amidone®, Methadose®, 
Physeptone®, Heptadon®
Opioid agonist/pain, narcotic dependence
Moxifloxacin
Avelox®, Avalox®, 
Avelon®
Antibiotic/bacterial infection
Nifekalant
Shinbit®
Antiarrhythmic/arrhythmia
Ondansetron
Zofran®, Anset®, 
Ondemet®, Zuplenz®, 
Emetron®, Ondavell®, 
Emeset®, Ondisolv®, 
Setronax®
Antiemetic/nausea, vomiting
Oxaliplatin
Eloxatin®
Anticancer/cancer
Papaverine HCl 
(intracoronary)
Vasodilator, Coronary/diagnostic adjunct
Pentamidine 
Pentam®
Antifungal/fungal infection (pneumocystis pneumonia)
Pimozide
Orap®
Antipsychotic/Tourette's disorder
Probucol
Lorelco®
Antilipemic/hypercholesterolemia
Procainamide 
Pronestyl®, Procan®
Antiarrhythmic/arrhythmia
Propofol
Diprivan®, Propoven®
Anesthetic, general/anesthesia
Quinidine
Quinaglute®, Duraquin®, 
Quinact®, Quinidex®, 
Cin-Quin®, Quinora® 
Antiarrhythmic/arrhythmia
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Generic Name
Brand Name
Class/Clinical Use
Roxithromycin
Rulide®, Xthrocin®, Roxl-
150®, Roxo®, Surlid®, 
Rulide®, Biaxsig®, 
Roxar®, Roximycinv®, 
Roxomycin®, Rulid®, 
Tirabicin®, Coroxin®
Antibiotic/bacterial infection
Sevoflurane
Ulane®, Sojourn®
Anesthetic, general/anesthesia
Sotalol 
Betapace®, Sotalex®,
Sotacor®
Antiarrhythmic/arrhythmia
Sparfloxacin
Zagam® 
Antibiotic/bacterial infection
Sulpiride
Dogmatil®, Dolmatil®, 
Eglonyl®, Espiride®, 
Modal®, Sulpor®
Antipsychotic, atypical/schizophrenia
Sultopride
Barnetil®, Barnotil®, 
Topral®
Antipsychotic, atypical/schizophrenia
Terfenadine
Seldane®
Antihistamine/Allergic rhinitis
Terlipressin
Teripress®, Glypressin®, 
Terlipin®, Remestyp®, 
Tresil®, Teriss®
Vasoconstrictor/septic shock
Terodiline
Micturin®, Mictrol®
Muscle relaxant/bladder spasm
Thioridazine
Mellaril®, Novoridazine®, 
Thioril®
Antipsychotic/schizophrenia
Vandetanib
Caprelsa®
Anticancer/thyroid cancer
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Takeda Development Center Americas, Inc.
AP24534-14-203
07 April 2021
Confidential and Proprietary
Page 116 of 117
APPENDIX B
Drugs that Interact with CYP3A4, 5, and 7
The list of drugs that interact with CYP3A4, 5, and 7 can be found online at 
medicine.iupui.edu/clinpharm/ddis/table.aspx [Accessed 21 March 2014].  Drugs listed as strong 
inhibitors and inducers of CYP3A should be avoided, if possible. 
Note:  The website should be used as a guideline and is not necessarily comprehensive.  It is the 
investigator’s responsibility to ensure that any drugs under consideration have not been newly 
identified as strong CYP3A4/5 inhibitors or inducers.
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Takeda Development Center Americas, Inc.
AP24534-14-203
07 April 2021
Confidential and Proprietary
Page 117 of 117
APPENDIX C
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, v4.0) can be found on the following website:
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 [Accessed 21 Mar 
2014].
This version of CTCAE is compatible at the AE term level where each CTCAE term is a 
Medical Dictionary for Regulatory Activities Terminology Lowest Level Term (MedDRA 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).
For non-commercial use only

For non-commercial use only

Ponatinib
Study No. AP24534-14-203
Clinical Study Report
Page 50 of 133
CONFIDENTIAL
9.8
Changes in the Conduct of the Study or Planned Analyses
9.8.1
Protocol Changes
At the time of the primary analysis, this protocol had 6 amendments (excluding country-specific 
amendments), producing 7 versions of the protocol. Protocol Amendment 5 (Version 6.0) was in 
effect at the data cutoff date for the primary analysis. Key changes to each version are 
summarized below.
Protocol Amendment 1 (Dated 17 December 2015)
This amendment served the following purposes:

Imposed more stringent and detailed guidelines for contraception requirements of patients on
the study.

Excluded patients with hypersensitivity to the ponatinib active substance or to any of its
inactive ingredients.
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Ponatinib
Study No. AP24534-14-203
Clinical Study Report
Page 51 of 133
CONFIDENTIAL

Added hepatitis B virus serology as a screening requirement.

Clarified the requirements for screening eye examination.

Updated the SOE to allow another option (brain natriuretic peptide testing) for sites unable to
perform N-terminal pro-brain natriuretic peptide testing.

Corrected an administrative error to correctly characterize this study’s ICH GCP compliant,
expedited safety reporting process for Suspected Unexpected Serious Adverse Reactions.

Included an administrative update to ensure alignment with European Union Commission
CT3 Guidance.

Updated sponsor contact information.
Protocol Amendment 2 (Dated 30 March 2016)
This amendment served the following purposes:

Updated the criteria for resistance to prior TKI therapy, reflecting the current European
LeukemiaNet recommendations for the management of CML [1].

Increased blood count monitoring frequency (additional screens on Day 15 during Cycles 2
and 3) in adherence to the ponatinib investigator’s brochure.

Increased lipase monitoring frequency (additional screens on Day 15 during Cycles 2 and 3)
to align with blood count frequency and to increase monitoring of an early-onset AE
(pancreatitis).

Clarified testing for hepatitis B serology.
Protocol Amendment 3 (Dated 30 May 2017)
This amendment was a modification to reflect current real-world clinical practices. The changes 
were relevant in the context of the ponatinib clinical study being conducted and aligned with 
investigator feedback and expert opinion.
The amendment served the following purposes:

Modified the primary endpoint from a cytogenetic response to a molecular response
(≤1% BCR-ABL1IS at 12 months) as per FDA recommendation and current clinical practice.

Modified the sample size from 450 to 276 patients.

Modified inclusion and exclusion criteria to reflect the appropriate current clinical practice.

Allowed for a dose reduction if the patient achieved a response at an unscheduled response
assessment, taking into consideration a risk-benefit approach.

Globally updated terminology of “MR2” to “≤1% BCR-ABL1IS” to align with and reflect the
nomenclature used in literature and current clinical practice.
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Ponatinib
Study No. AP24534-14-203
Clinical Study Report
Page 52 of 133
CONFIDENTIAL
Protocol Amendment 4 (Dated 01 March 2018)
The purpose of this amendment was to clarify continued access to ponatinib for study patients, 
described as “continuation patients,” who tolerated treatment and obtained clinical benefit. Prior 
protocol language had already enabled the option for a patient to continue ponatinib upon 
agreement between the investigator and medical monitor, given evidence of tolerance and 
clinical benefit.
The amendment served the following purposes:

Clarified the access and follow-up of patients who continued ponatinib in the study beyond
24 cycles of treatment as continuation patients if they were receiving clinical benefit from
treatment, allowed on a case-by-case basis upon agreement between the investigator and
medical monitor.

Clarified the access and follow-up of patients who continued on ponatinib in the study as
continuation patients if they did not achieve protocol-defined response criteria designed to
support statistical analyses of deep molecular or cytogenetic responses in the 3 dosing
cohorts; these patients had the option to continue on ponatinib on a case-by-case basis if they
were tolerating and receiving clinical benefit from treatment, upon agreement between the
investigator and medical monitor.

Specified the SOE for patients continuing in the study beyond 24 cycles of treatment.
Protocol Amendment 5 (Dated 18 April 2019)
The amendment served the following purposes:

Included the plan to conduct an IA after all patients had been enrolled in the study.

Specified that the mandatory dose reduction based on response should be implemented by the
sites as soon as feasible.

Removed requirements of reporting nonserious AESIs within 24 hours to the sponsor.

Included a detailed definition of acute MI.

Included “lost to follow-up” as a withdrawal criterion.

Clarified the PK objective of the study to reflect collection of sparse PK data to contribute to
population PK and exposure-response analyses of safety and efficacy data, which will be
reported separately.
There were 2 country-specific amendments for Norway (Amendment 1.1, dated 
18 December 2015; Amendment 2.1, dated 06 June 2016) and 1 for Germany (Amendment 1.2, 
dated 16 February 2016).
Refer to Appendix 16.1.1 for full versions of the protocols and more details on the summary of 
changes.
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Ponatinib 
Study No. AP24534-14-203 
Clinical Study Report Addendum 1 
Page 12 of 89
CONFIDENTIAL 
9.8 
Changes in the Conduct of the Study or Planned Analyses 
9.8.1 
Protocol Changes 
Two additional protocol amendments were implemented between the PA data cutoff (31 May 
2020) and the 5-year follow-up data cutoff (15 May 2024). Key changes implemented by each of 
these amendments are summarized below. 
Protocol Amendment 6 (Dated 05 October 2020) 
This amendment served the following purposes: 
•
To provide guidance on the management of alternate strategies for conducting study
procedures, collecting data, and managing investigational product(s) during unavoidable
circumstances, such as the coronavirus disease 2019 (COVID-19) pandemic.
•
To provide guidance on how to record deviations from protocol-specified procedures and
missed clinic visits or patient withdrawals due to the COVID-19 pandemic and indicate how
these protocol deviations would be accounted for in the statistical analyses of the study data.
•
To clarify that no additional pharmacokinetic (PK) samples would be collected during the
study because all ongoing patients had completed at least 12 cycles of treatment.
•
To update the list of prohibited medications known to have a risk of causing Torsades de
Pointes.
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Ponatinib 
Study No. AP24534-14-203 
Clinical Study Report Addendum 1 
Page 13 of 89
CONFIDENTIAL 
Protocol Amendment 7 (Dated 07 April 2021) 
This amendment served the following purposes: 
•
To state that patients would be followed for a treatment period of approximately 5 years.
•
To reduce contact between the patient and the site from at least once every 3 months (odd and
even cycles) to once every 6 months for patients who have completed at least 24 cycles of
treatment.
•
To provide an updated Schedule of Events for the assessments to be conducted at the 6 month
study visits.
•
To update the sponsor information from ARIAD Pharmaceuticals to Takeda Development
Center Americas Inc.
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