Clinical trial NCT02627677
Conditions: Chronic Phase Chronic Myeloid Leukemia
Keywords: CML CP-CML Leukemia Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Neoplasms by Histologic Type Neoplasms Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases
Sponsor: Ariad Pharmaceuticals
Start date: 2015-12-31; Completion date: 2021-01-20
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy and safety of 2 starting doses of ponatinib compared to nilotinib in participants with imatinib-resistant chronic myeloid leukemia (CML) in chronic phase (CP).

Detailed description:
This is a multi-center, randomized study to demonstrate the efficacy and safety of 2 starting doses of ponatinib as a treatment for CP-CML compared to nilotinib. Eligible participants must have chronic phase chronic myeloid leukemia (CP-CML), be resistant to first-line imatinib treatment and have received no other tyrosine kinase inhibitors (TKIs).

Arms: arm 1: Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to 42 months. arm 2: Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to 45 months. arm 3: Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Interventions: intervention 1: Ponatinib 30 mg QD intervention 2: Ponatinib 15 mg QD intervention 3: Nilotinib 400 mg BID
Intervention descriptions: intervention 1: Ponatinib 30 mg, taken orally once daily. intervention 2: Ponatinib 15 mg, taken orally once daily. intervention 3: Nilotinib 400 mg, taken orally twice daily.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 2/3 Open-label Study to Evaluate Safety and Efficacy of Ponatinib, Followed by a 
Randomized Study of Ponatinib Versus Nilotinib in Patients with Chronic Myeloid Leukemia in 
Chronic Phase (CP-CML) Resistant to Imatinib
NCT Number: NCT02627677
Protocol Approve Date: 10 March 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


ARIAD Pharmaceuticals, Inc.
AP24534-15-303
EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 1 of 109
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 2/3 Open-label Study to Evaluate Safety and Efficacy 
of Ponatinib, Followed by a Randomized Study of Ponatinib 
Versus Nilotinib in Patients with Chronic Myeloid Leukemia in 
Chronic Phase (CP-CML) Resistant to Imatinib
Protocol Number:
AP24534-15-303
Study Phase:
2/3
Product Name:
Ponatinib
ClinicalTrials.gov Identifier:
NCT02627677
EudraCT Number:
2015-001318-92
Sponsor:
ARIAD Pharmaceuticals, Inc.
125 Binney Street
Cambridge, MA 02142
USA
Telephone: +1 (617) 494-0400
Protocol Issue Date:
10 March 2017
Version Number:
3.0 
PROTOCOL REVISION HISTORY:
Amendment Number
Protocol Version Number
Date
Original Protocol
Version 1.0
29 April 2015
Amendment 1 (Canada only)
Version 1.1
08 September 2015
Amendment 2
Version 2.0
30 March 2016
Amendment 3
Version 3.0
10 March 2017
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


ARIAD Pharmaceuticals, Inc.
AP24534-15-303
EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 2 of 109
1
DISCLOSURE STATEMENT
This document is the exclusive property of ARIAD Pharmaceuticals, Inc. (“ARIAD”). This 
document and the information contained herein is confidential and proprietary to ARIAD and is 
intended solely for the guidance of this clinical investigation. This information is provided to you 
solely for the purpose of evaluation and/or conducting a clinical study for ARIAD. You may 
disclose the contents of this document only to study personnel under your supervision or to your 
Institutional Review Board(s) who need to know the contents solely for purposes of this clinical 
study. No part of this document may be used for any other purpose, including any other clinical 
study. This document may not be disclosed to any other person or entity or reproduced, 
referenced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, 
mechanical, photocopying, recording, or otherwise, without the prior written authorization of 
ARIAD. The foregoing shall not apply to disclosure required by applicable laws or governmental 
regulations; however, you will give notice to ARIAD of any such disclosure as soon as 
practicable.
Any information that may be added to this document is confidential and proprietary to ARIAD 
and subject to the same confidentiality obligations and use restrictions described above.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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ARIAD Pharmaceuticals, Inc.
AP24534-15-303
EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 4 of 109
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)
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


ARIAD Pharmaceuticals, Inc.
AP24534-15-303
EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 5 of 109
2.3
Sponsor Representative Signature
ARIAD Pharmaceuticals, Inc. has approved of this protocol and assures that this study will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality. 
Sponsor Representative’s Signature 
Date (dd-mmm-yyyy)
Sponsor Representative’s Name and Title (print)
Clinical Research & Development
ARIAD Pharmaceuticals, Inc.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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ARIAD Pharmaceuticals, Inc.
AP24534-15-303
EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 7 of 109
4
PROTOCOL SYNOPSIS
Sponsor
ARIAD Pharmaceuticals, Inc.
125 Binney Street
Cambridge, MA 02142
USA
Study Treatment
Investigational medicinal product: Ponatinib
Active comparator: None (phase 2); Nilotinib (phase 3)
Study Title
A Phase 2/3 Open-label Study to Evaluate Safety and Efficacy of Ponatinib, Followed 
by a Randomized Study of Ponatinib versus Nilotinib in Patients with Chronic Myeloid 
Leukemia in Chronic Phase (CP-CML) Resistant to Imatinib
Development Phase
Phase 2/3
Eligible Population
Patients with chronic phase chronic myeloid leukemia (CP-CML) who are resistant 
following first-line treatment with imatinib and have not received other tyrosine kinase 
inhibitors (TKIs)
Summary and Study 
Rationale
Most patients with newly diagnosed CML are initially treated with an imatinib regimen 
with good results (Henk et al, 2015). However, 30% to 50% of all newly diagnosed 
CP-CML patients who are treated in the first-line setting with imatinib are in need of 
another treatment, either because they become resistant to imatinib (20%-25%) or 
because they become intolerant of imatinib (15%-20%) (Baccarani et al, 2009). A 
review of efficacy in the second-line setting demonstrates that there is potential for 
improvement. Among the available second-line therapies (nilotinib, dasatinib, or 
bosutinib), major cytogenetic response (MCyR) rates in second-line CP-CML range 
from 51% with nilotinib therapy (n=321) (Nilotinib SmPC, 2016) to 62% in dasatinib 
treated patients (n=387) indicating that second-line therapy initially fails to achieve a 
response in a substantial fraction of patients. Additionally, none of the available 
second-line agents have activity against all of the known mutants and the T315I 
mutation is refractory to all TKIs with the exception of ponatinib. Thus, both with 
regard to response rates and activity against resistant mutants, an unmet need remains 
in many patients who fail first-line TKI therapy.
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.
This protocol describes a phase 2/3, open-label study of ponatinib for the treatment of 
patients with chronic myeloid leukemia (CML) in chronic phase (CP) whose imatinib 
therapy has failed. The goal of the phase 2 portion of this study is to generate efficacy 
and safety data to inform the design and sample size of the randomized phase 3 portion 
of this study. The goal of the phase 3 portion of this study is to test the hypothesis that 
ponatinib will be efficacious and safe in treating second-line CP-CML patients, that it 
will be superior to nilotinib, that each of the starting doses will demonstrate the 
continued efficacy of ponatinib, and that the dose reduction strategy will lessen arterial 
occlusive complications.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


ARIAD Pharmaceuticals, Inc.
AP24534-15-303
EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 8 of 109
Study Design
This is a multi-center study to demonstrate the efficacy and safety of 1 dose of 
ponatinib during the phase 2 portion, and 2 starting doses of ponatinib as compared to 
nilotinib during the phase 3 portion. Eligible patients must have CP-CML, be resistant 
to first-line imatinib treatment and have received no other TKIs.
During the phase 2 portion, all patients will receive ponatinib 15 mg once daily (QD). 
Upon achievement of major molecular response (MMR) as defined in the protocol, 
patients will have their daily dose of ponatinib reduced to 10 mg.
Based on accumulating data from the 15 mg cohort in phase 2, the phase 3 design 
(including number of ponatinib cohorts) and/or sample size may be amended prior to 
enrollment of patients into the phase 3 portion of the study.
During the phase 3 portion, patients will be randomized to receive once daily oral 
administration of either 30 mg ponatinib QD (Cohort A), 15 mg ponatinib QD (Cohort
B), or 400 mg nilotinib BID (twice daily) (Cohort C). They will be randomized in a 
ratio of 1:2:1, respectively. Upon achievement of MMR as defined in the protocol, 
patients in Cohort A will have their daily dose of ponatinib reduced to 15 mg and 
patients in cohort B will have their daily dose of ponatinib reduced to 10 mg. The dose 
of nilotinib for patients in Cohort C will not be adjusted based on response. 
Ponatinib dose reduction upon achievement of MMR can also be implemented when
an unscheduled response assessment is performed.
The primary endpoint of MMR by12 months is defined according to standard criteria 
as ≤0.1% BCR-ABL1/ABL1IS.
The study will assess hematologic response, cytogenetic response, and molecular 
response, as well as additional measures of efficacy including time to responses, and 
duration of responses by starting dose and after dose reduction. Assessments will be 
according to standard international criteria. Progression-free survival (PFS) and overall 
survival (OS) data will also be collected and analyzed. Adverse event (AE) rates and 
rates of arterial occlusive events (AOEs) and venous thrombotic/embolic events 
(VTEs), in particular, will be measured. The duration of patient participation will be 
60 months for all patients, unless they withdraw prior to that based on the withdrawal 
criteria defined within the protocol.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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EudraCT Number: 2015-001318-92
Protocol Version 3.0
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Page 11 of 109
vi At any time after the initiation of therapy, the loss of CHR, the loss of 
CCyR, or the confirmed loss of MMR in 2 consecutive tests, one of 
which has a BCR-ABL1IS transcript level of ≥1%.
[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
or 1.
4.
Have adequate renal function as defined by the following criterion:
a.
Serum creatinine ≤1.5 × upper limit of normal (ULN) for institution.
5.
Have adequate hepatic function as defined by all of 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 a negative pregnancy test documented prior to enrollment (for females of 
childbearing potential).
8.
Agree to use a highly effective form of contraception with sexual partners from 
the time of randomization through at least four (4) months after end of study 
treatment (for female and male patients who are fertile).
9.
Provide written informed consent. 
10.
Be willing and able to comply with scheduled visits and study procedures.
11.
Have recovered from toxicities related to prior anticancer therapy to NCI CTCAE 
grade ≤1 except for alopecia or peripheral neuropathy.
Main Exclusion Criteria
Patients are not eligible for participation in the study if they meet any of the following 
exclusion criteria:
1.
Have previously been treated with any approved or investigational TKIs 
other than imatinib or treated with imatinib within 14 days prior to 
receiving study drug.
2.
Have previously been treated with any anti-CML therapy other than 
hydroxyurea, including interferon, cytarabine, immunotherapy, or any 
cytotoxic chemotherapy, radiotherapy, or investigational therapy.
3.
Underwent autologous or allogeneic stem cell transplant. 
4.
Are in ≤1% BCR-ABL1 (in phase 2) or in MMR (in phase 3). 
5.
Have a known history of T315I mutation in phase 3.
6.
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 
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EudraCT Number: 2015-001318-92
Protocol Version 3.0
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Page 12 of 109
infarction
c.
Any history of a revascularization procedure, including vascular 
surgery or the placement of a stent
d.
History of venous thromboembolism, including deep venous 
thrombosis, superficial venous thrombosis, or pulmonary embolism, 
within 6 months prior to enrollment
e.
Congestive heart failure (New York Heart Association [NYHA] class 
III or IV) within 6 months prior to enrollment or left ventricular 
ejection fraction (LVEF) less than 45% or less than the institutional 
lower limit of normal (whichever is higher) within 6 months prior to 
enrollment
7.
Have cardiac conduction abnormalities as follows: 
a.
QTcF >450 msec on the average of 3 serial baseline ECGs (using the 
QTcF formula); congenital long QT syndrome, or a known family 
history of long QT syndrome; or inability to determine the QTcF
b.
Presence of a complete left bundle branch block
c.
Use of a ventricular pacemaker
d.
History of clinically significant (as determined by the treating 
physician) atrial arrhythmia 
e.
Resting bradycardia <50 beats per minute
f.
Any history of ventricular arrhythmia 
8.
Are taking medications with a known risk of Torsades de Pointes or that 
have the potential to prolong the QT interval (Appendix A), unless the 
medication can be discontinued or be substituted by another without the 
risk.
9.
Are taking medicines that are strong CYP3A4 inhibitors, unless the 
medication can be discontinued or be substituted by another that is not an 
inhibitor (Appendix B)
10.
Are taking medicines that are strong CYP3A4 inducers, unless the 
medication can be discontinued or be substituted by another that is not an 
inducer (Appendix B)
11.
Have uncontrolled hypertension (i.e., >150 and >90 mmHg 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.
12.
Have poorly controlled diabetes defined as HbA1c values of > 7.5%.
Patients with preexisting, well-controlled, diabetes are not excluded.
13.
Have uncorrected hypokalemia or hypomagnesemia.
14.
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. A history of CNS involvement itself is not an 
exclusion if the CNS has been cleared of disease with a documented 
negative lumbar puncture.
15.
Have a significant bleeding disorder unrelated to CML. 
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Protocol Version 3.0
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Page 13 of 109
16.
Have a history of thrombophilia (eg, Protein C deficiency)
17.
Have a history of alcohol abuse. 
18.
Have a history of acute pancreatitis within 1 year of study entry or history 
of chronic pancreatitis. 
19.
Have history of malabsorption syndrome or other gastrointestinal condition 
that could affect oral absorption of study drug.
20.
Have a history of a different malignancy, other than cervical cancer in situ 
or basal cell or squamous cell carcinoma of the skin, except if patient has
been disease-free for at least 5 years, and are deemed by the investigator to 
be at low risk for recurrence of that malignancy.
21.
Are pregnant or lactating.
22.
Have undergone major surgery within 14 days prior to first dose of study 
treatment. Minor surgical procedures, such as catheter placement or bone 
marrow biopsy are allowed.
23.
Have an ongoing or active infection. This includes but is not limited to the 
requirement for intravenous antibiotics. 
24.
Have any surgical or medical condition / illness that, in the opinion of the 
investigator, would compromise patient safety or interfere with the 
evaluation of the study drug.
25.
Have hypersensitivity to the active substance in ponatinib and nilotinib or
to any of the inactive ingredients listed in Section 14.9.1.1 for ponatinib 
and in Section 14.9.1.2 for nilotinib.
Approximate Number of 
Patients
For the phase 2 portion, the overall total enrollment will be approximately 75 patients; 
all patients will be enrolled to the ponatinib 15 mg dose. For the phase 3 portion, the 
overall total enrollment will be approximately 600 patients randomized in a 1:2:1 
fashion with approximately 150 patients in the ponatinib 30 mg starting dose cohort 
(Cohort A), approximately 300 patients in the ponatinib 15 mg starting dose cohort 
(Cohort B), and approximately 150 patients in the nilotinib cohort (Cohort C). Based 
on accumulating data from the 15 mg cohort in phase 2, the sample size for the phase 3 
portion may be amended.
Approximate Duration of 
Patient Participation
The duration of patient participation will be 60 months for all patients. Each patient 
will undergo a period of up to 3 weeks for screening prior to treatment. The duration of 
therapy will be determined by the patient’s response and toxicity, and patients will 
remain on assigned study treatment for 60 months if they are responding.
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Protocol Version 3.0
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Approximate Duration of 
Study
The estimated duration of the phase 2 portion of the study is approximately 68 months, 
including 8 months for enrollment and 60 months of treatment/follow-up.
The estimated duration of the phase 3 portion of the study is approximately 84 months
(7 years), including 24 months for enrollment and 60 months of treatment/follow-up.
The estimated duration of the study overall (both phases) is approximately 104 months, 
consisting of:

Approximately 20 months for phase 2 until the primary endpoint:
o
8 months for enrollment, and
o
12 months for treatment/follow-up to the primary endpoint, 
followed by

84 months for phase 3 up to the end of the study:
o
24 months for enrollment, and
o
60 months of treatment/follow-up to the end of the study.
Patients in both phases will be followed up to 60 months as defined in the protocol 
after they are evaluated for the primary endpoint at 12 months; however, enrollment in 
phase 3 will begin after patients in phase 2 are evaluated for the primary endpoint at 12 
months.
The overall study design may be modified based on the data from phase 2 that will 
inform the phase 3 portion of the study.
Approximate Number of 
Study Centers
Approximately 90 centers; multi-national. 
Dosage and 
Administration
For the phase 2 portion, all patients will receive ponatinib 15 mg once daily (QD). 
Patients will have their daily dose of ponatinib reduced to 10 mg upon achievement of 
response as defined in Section 14.2.1.
For the phase 3 portion, patients will be randomized to receive once daily oral 
administration of 1 of 2 starting doses of ponatinib: 30 mg (Cohort A), 15 mg (Cohort 
B), or twice daily oral administration of 400 mg of nilotinib (Cohort C) in a 1:2:1 ratio 
for Cohorts A, B, and C, respectively. Patients in Cohort A will have their daily dose 
reduced to 15 mg upon achievement of response as defined in Section 14.2.1, and 
patients in Cohort B will have their daily dose reduced to 10 mg upon achievement of 
response as defined in Section 14.2.1. The dose of nilotinib will not be adjusted based 
on response.
Dose interruptions or reductions should be implemented for patients who experience 
treatment-related adverse events in phase 2 and in all 3 cohorts in phase 3, upon 
clinical judgment of the investigator. Guidelines for management of treatment-related 
adverse events are described in Section 14.4. 
For the phase 3 portion with nilotinib as the comparator, the current SmPC for Tasigna 
(nilotinib) should be used as the reference safety information for the nilotinib drug.
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. 
Both ponatinib and nilotinib are associated with the potential for AOEs whereas 
ponatinib is also associated with potential for VTEs. Attention should be paid to 
appropriate medical management of conditions that contribute to risk of AOEs and 
VTEs.
Treatment of Hypertension 
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Protocol Version 3.0
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Page 15 of 109
Hypertension (HTN) may contribute to risk of arterial occlusive events. Patients who 
have HTN should be managed appropriately before initiating treatment. During study 
treatment, blood pressure should be monitored and elevations 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). Specific management of an individual patient should be determined by the 
treating physician. Study 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.
Treatment of Diabetes 
Patients with diabetes are at increased risk of experiencing arterial occlusive events. 
Initiation of or modifications to diabetic care should be considered in patients receiving 
study treatment who have elevated glucose levels or evidence of prior elevated glucose 
levels (eg, HbA1c). The American Diabetes Association guidelines should be 
followed, and diabetes treatment and lifestyle intervention (including but not limited to 
weight loss, decreased fat intake, calorie restriction, increased physical activity, and 
smoking cessation) should be started in any patient with fasting glucose >130 mg/dL 
(7.2 mmol/L) and/or HbA1c ≥7% (Diabetes Prevention Program Research Group, 
2002; American Diabetes Association, Position Statement 2013).
Prohibited Treatments
The following concurrent medications and treatments are prohibited:

Other anticancer therapies, including other TKIs

Other investigational drugs or devices

Medications with a known risk of Torsades de Pointes or that prolong the QTcF 
interval (Appendix A)

Strong CYP3A4 inhibitors (Appendix B)

Strong CYP3A4 inducers (Appendix B)

Herbal preparations or related over-the-counter preparations containing herbal 
ingredients

Stem cell transplantation
Elective surgery requiring inpatient care should be postponed until study completion 
if possible.
Efficacy Evaluation
MMR rates, other molecular response rates, cytogenetic response rates, hematologic 
response rates, and disease progression will be assessed according to standard criteria 
using the following measures:

BCR-ABL1 transcript assessment to determine molecular responses

Bone marrow aspirates for assessment of cytogenetic responses

Complete blood count for assessment of hematologic responses

Survival follow-up
All patients remaining on study treatment will be followed for 60 months unless they 
withdraw sooner. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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ARIAD Pharmaceuticals, Inc.
AP24534-15-303
EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 17 of 109
(≥60 versus <60 years) and best response to prior imatinib therapy (CCyR or 
≤1% BCR-ABL1IS or better, yes/no) to compare the MMR rate by 12 months between 
patients receiving either dose level of ponatinib (initial dose: 30 mg QD or 15 mg QD) 
and patients receiving nilotinib (initial dose: 400 mg BID) and will follow a testing 
procedure to ensure an overall 2-sided Type I error rate of <0.05. An efficacy interim 
analysis is planned after the first 300 randomized patients have at least 12 months of 
follow-up. To maintain an overall Type I error rate of 0.05 (2-sided), an O’Brien-
Fleming approach will be used which requires a 2-sided p-value <0.0052 at the interim 
(at 50% of information time). Thus, with 2 treatment comparisons significance will be 
declared for any arm where the 2-sided p-value is <0.0026 . For each dose comparison, 
if this boundary is not crossed at the time of the interim analysis, then the primary 
analysis will be conducted 12 months following the last patient randomized. A 
Bonferroni procedure will be used to adjust for comparisons of Cohorts A and B to 
Cohort C, with a dose considered significant if the 2-sided p-value is <0.024.
The primary analysis will be based on the Full Analysis Set (all patients randomized to 
a treatment group for whom a BCR-ABL1IS ratio can be determined at baseline). A 
sensitivity analysis of the primary endpoint will be performed on the ITT population, 
with patients not evaluable treated as nonresponders.
The following patients will be analyzed as responders in the primary analysis:

Patients who meet the criteria for MMR by 12 months after randomization
All other patients will be analyzed as non-responders in the primary analysis, including 
randomized patients without follow up and any patients who meet the criteria for 
MMR at study entry.
Comparisons of molecular key secondary endpoints and cytogenetic key secondary 
endpoints will be performed separately. Analyses of molecular key secondary 
endpoints will be performed on the Full Analysis Set. Analyses of cytogenetic key 
secondary endpoints will be performed on the ITT population. For each dose 
comparison (within a given set of key secondary endpoints) that is significant in the 
primary analysis, formal statistical comparisons of key secondary endpoints will be 
performed using a closed testing procedure according to the ranking below and will 
take place only if comparisons of all other secondary efficacy endpoints with a smaller 
rank are significant at the 2-sided 0.025 level (molecular endpoints and cytogenetic 
endpoints will be tested separately, thus the significance level has been halved). Note 
that at some analysis time points not all key secondary endpoints will be mature (eg, 
molecular key secondary endpoints will not be mature at interim analysis or 12 month 
analysis – see Section 16.5.3.3 for the statistical handling of these key secondary 
endpoints). Each sequence of key efficacy endpoints will be tested separately for each 
treatment comparison (Cohort A versus Cohort C, Cohort B versus Cohort C), within 
the sets of molecular and cytogenetic endpoints, respectively.
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. Subgroups may include:

Age

Gender

Race

Geographic region (North America, Europe, Other)

T315I mutation history (Yes, No)

Best response to prior imatinib therapy (CCyR, ≤1% BCR-ABL1IS or better)

Other disease-related prognostic factors
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Safety Analyses:
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. Analyses 
will also be performed on adverse events of special interest (AESIs); further detail will 
be outlined in the Statistical Analysis Plan. Patients will be analyzed for safety 
according to the treatment they received. The AE incidence rates, as well as the 
frequency of occurrence of overall toxicity, categorized by toxicity grades (severity) 
will be described for each treatment arm. Listings of laboratory test results will also be 
generated, and descriptive statistics summarizing the changes in laboratory tests over 
time will be presented. Exposure to study drug over time will also be summarized.
Quality of Life / Health Outcomes Analysis:
Means and medians of raw scores of the EQ-5D-5L and FACT-Leu patient-reported 
outcome questionnaires will be summarized for each treatment group by time point, 
overall, and for each domain.
Sample Size Determination - Phase 2: 
The primary endpoint for the phase 2 portion of the study will be MMR rate by 12 
months. A sample size of 75 patients will distinguish a favorable MMR by 12 month 
rate of 40% from a null or an uninteresting MMR rate of 25%, with a nominal 80% 
power and a 2-sided type I error rate of 0.05 (equivalent to a 2-sided 0.025) using an 
exact binomial test.
Sample Size Determination - Phase 3:
Based on accumulating data from the 15 mg cohort in phase 2, the phase 3 design 
(including number of ponatinib cohorts) and/or sample size may be amended prior to 
enrollment of patients into the phase 3 portion of the study.
The primary endpoint for the phase 3 portion of the study will be MMR rate by 12 
months. The primary analysis of the primary endpoint of MMR will be performed 
using a 2-sided alpha = 0.024 for each comparison.
A sample size of 150 patients each in Cohort A and C (ponatinib 30 mg and nilotinib, 
respectively) will distinguish a favorable MMR rate of 45% for ponatinib from a null 
or an uninteresting MMR rate of 25% for nilotinib with a nominal 90% power to detect 
an improvement in MMR of 20%. 
The sample size of 300 patients in Cohort B and 150 patients in Cohort C will 
distinguish a favorable MMR rate of 40% for ponatinib from a null or an uninteresting 
MMR rate of 25% for nilotinib with approximately 80% power to detect an 
improvement in MMR of 15%. 
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 (675 patients). Based 
on accumulating data from the 15 mg cohort in phase 2, the phase 3 design (including 
number of ponatinib cohorts) and/or sample size may be amended prior to enrollment 
of patients into the phase 3 portion of the study.
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5
TABLE OF CONTENTS
1
DISCLOSURE STATEMENT.....................................................................................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............................................................................................19
6
LIST OF ABBREVIATIONS ....................................................................................24
7
DEFINITIONS OF TERMS ......................................................................................26
8
INTRODUCTION.......................................................................................................28
8.1
Unmet Need in Second-Line CP-CML Therapy ..........................................28
8.2
Ponatinib Background....................................................................................29
8.2.1
Preclinical Summary...........................................................................29
8.2.2
Ponatinib Use in Refractory CP-CML patients ...............................29
8.2.3
Ponatinib Results in Earlier Lines of Therapy.................................30
8.3
Selection of Ponatinib Dose ............................................................................31
8.4
Selection of Nilotinib as a Comparator.........................................................32
8.5
Selection of Endpoints ....................................................................................32
8.6
Selection of Study Design ...............................................................................33
9
STUDY OBJECTIVES...............................................................................................34
9.1
Primary Objectives .........................................................................................34
9.2
Key Secondary Objectives..............................................................................34
9.3
Other Secondary Objectives...........................................................................35
9.4
Exploratory Objectives...................................................................................35
10
INVESTIGATIONAL PLAN.....................................................................................35
10.1
Overall Study Design and Plan......................................................................35
10.1.1
Primary Endpoint ...............................................................................36
10.1.2
Key Secondary Endpoints ..................................................................36
10.1.3
Other Secondary Endpoints...............................................................36
10.1.4
Exploratory Endpoints .......................................................................37
10.2
Description of Treatment ...............................................................................37
10.3
Randomization ................................................................................................37
11
SELECTION OF STUDY POPULATION...............................................................38
11.1
Inclusion Criteria ............................................................................................38
11.2
Exclusion Criteria ...........................................................................................40
12
STUDY PROCEDURES.............................................................................................42
12.1
Schedule of Events ..........................................................................................42
12.2
Patient Registration and Identification.........................................................50
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12.2.1
Screen Failures ....................................................................................50
12.2.2
Early Discontinuation from Study Drug Administration or 
Assessments..........................................................................................50
12.3
Study Duration ................................................................................................50
12.4
Withdrawal Criteria .......................................................................................51
12.5
Study or Site Termination..............................................................................52
12.6
Sample Collection, Storage, and Shipping....................................................52
13
EFFICACY AND SAFETY ASSESSMENTS..........................................................52
13.1
Efficacy Assessments.......................................................................................52
13.2
Safety Assessments..........................................................................................52
13.2.1
Adverse Events ....................................................................................52
13.3
Exploratory Biomarker Evaluations in Tissue and Plasma........................53
13.4
Quality of Life Assessments............................................................................53
13.4.1
EQ-5D-5L.............................................................................................53
13.4.2
FACT-Leu............................................................................................53
14
STUDY TREATMENT ..............................................................................................53
14.1
Study Treatment .............................................................................................53
14.1.1
Treatment Administration .................................................................54
14.2
Ponatinib Treatment for Patients in Cohorts A and B................................54
14.2.1
Mandatory Dose Reduction for Response Scheme in Ponatinib 
Cohorts A and B..................................................................................54
14.2.2
Loss of Response after Dose Reduction for MMR or MCyR in 
Cohorts A and B..................................................................................56
14.3
Nilotinib Treatment for Patients in Cohorts C ............................................57
14.4
Adverse Event Management ..........................................................................57
14.4.1
Management of Selected Adverse Events .........................................58
14.4.1.1
Adverse Events Common to Ponatinib and Nilotinib.............58
14.4.1.2
Ponatinib-Specific Adverse Events..........................................62
14.4.1.3
Nilotinib-Specific Adverse Events ...........................................63
14.4.2
Dose Modifications for Adverse Drug Reactions .............................63
14.4.2.1
Dose Reduction Guidelines for Adverse Events......................63
14.4.2.2
Dose Modifications for Arterial Occulusive Events and 
Venous Thrombotic/Embolic Events.......................................71
14.4.2.3
Dose Re-Escalation after Resolution of Adverse Drug 
Reactions ..................................................................................74
14.5
Prior and Concomitant Treatment(s)/Therapy............................................75
14.6
Permitted Treatment ......................................................................................75
14.7
Prohibited Treatment(s)/Therapy .................................................................75
14.8
Potential Drug Interactions............................................................................75
14.8.1
Potential Interactions with Ponatinib ...............................................75
14.8.2
Potential Interactions with Nilotinib.................................................76
14.9
Treatment Supply ...........................................................................................76
14.9.1
Formulation, Packaging, and Labeling.............................................76
14.9.1.1
Ponatinib ..................................................................................76
14.9.1.2
Nilotinib....................................................................................77
14.9.2
Treatment Storage, Dispensing, and Accountability .......................77
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14.9.2.1
Disposition of Used Supplies ...................................................77
14.9.2.2
Inventory of Unused Supplies..................................................77
15
ADVERSE EVENT REPORTING............................................................................78
15.1
Adverse Events ................................................................................................78
15.1.1
Adverse Event Definition....................................................................78
15.1.2
Abnormal Test Findings.....................................................................78
15.1.3
Performing Adverse Events Assessments .........................................79
15.1.4
Reporting Period.................................................................................79
15.1.5
Adverse Event Severity.......................................................................79
15.1.6
Causality ..............................................................................................80
15.1.7
Study Drug Action Taken...................................................................81
15.1.8
Adverse Event Outcome .....................................................................81
15.1.9
Expectedness........................................................................................82
15.2
Serious Adverse Events and Adverse Events of Special Interest................82
15.2.1
Serious Adverse Event Definition......................................................82
15.2.1.2
Progression of the malignancy under study............................83
15.2.1.3
Hospitalizations........................................................................83
15.2.2
Adverse Events of Special Interest ....................................................83
15.2.3
Reporting SAEs and AESI .................................................................84
15.2.4
Information to be Provided by the Investigator for an SAE or 
AESI .....................................................................................................84
15.2.5
Follow-up Information on an SAE or AESI.....................................84
15.3
Expedited Reporting of SUSARs...................................................................85
15.4
Other Safety Issues..........................................................................................85
15.4.1
Pregnancy, Contraception and Breastfeeding..................................85
15.4.2
Overdose ..............................................................................................86
16
PLANNED STATISTICAL METHODS..................................................................86
16.1
General Considerations ..................................................................................86
16.2
Analysis Populations.......................................................................................87
16.3
Study Endpoints ..............................................................................................87
16.4
Determination of Sample Size........................................................................88
16.5
Efficacy Analysis .............................................................................................89
16.5.1
Definitions of Efficacy Endpoints ......................................................89
16.5.1.1
Molecular Response Definitions..............................................89
16.5.1.2
Cytogenetic Response Definitions ...........................................90
16.5.1.3
Hematologic Response Definitions..........................................90
16.5.1.4
Event-Related Definitions........................................................91
16.5.2
Primary Endpoint Analysis................................................................92
16.5.2.1
Data Handling Rules for the Primary Analyses of the 
Primary Endpoint.....................................................................92
16.5.3
Secondary Efficacy Endpoint Analyses.............................................92
16.5.3.1
Key Secondary Efficacy Endpoints..........................................92
16.5.3.2
Analysis Methods for Secondary Efficacy Endpoints.............94
16.5.3.3
Data Handling Rules for Secondary Efficacy Endpoint 
Analyses....................................................................................94
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16.5.4
Subgroup Analyses of the Primary Endpoint and Secondary 
Efficacy Endpoints ..............................................................................94
16.6
Safety Analysis.................................................................................................95
16.6.1
Analysis of Arterial Occlusive and Venous 
Thrombotic/Embolic Events ..............................................................95
16.6.2
Analysis of Categories of Adverse Events.........................................96
16.6.3
Other Safety Analyses.........................................................................96
16.6.4
Analysis of Treatment Discontinuation Rate due to AEs, Dose 
Reductions, and Dose Interruptions..................................................96
16.7
Exposure-Response Analysis..........................................................................96
16.8
Quality of Life / Health Outcomes Analysis .................................................97
16.9
Exploratory Biomarker Analyses..................................................................97
16.10
Protocol Deviations/Violations.......................................................................97
16.11
Interim Analysis ..............................................................................................97
17
QUALITY CONTROL AND QUALITY ASSURANCE........................................98
17.1
Investigators and Study Administrative Structure......................................98
17.2
Study Monitoring ............................................................................................99
18
ETHICAL CONDUCT OF THE STUDY ................................................................99
18.1
Institutional Review Board or Ethics Committee Approval.......................99
18.2
Patient Information and Consent ..................................................................99
18.3
Patient Confidentiality..................................................................................100
18.4
Study Committees .........................................................................................100
18.4.1
Data Monitoring Committee............................................................100
18.4.2
Study Steering Committee................................................................100
19
DATA HANDLING AND RECORD KEEPING...................................................101
19.1
Case Report Forms and Study Records......................................................101
19.2
Access to Source Documentation.................................................................101
19.3
Retention of Data...........................................................................................101
19.4
Termination of Study....................................................................................101
20
FINANCING AND INSURANCE ...........................................................................102
21
PUBLICATION AND DISCLOSURE POLICY ...................................................102
22
REFERENCES..........................................................................................................104
23
APPENDICES ...........................................................................................................107
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TABLE OF TABLES
Table 1
Fixed or Cumulative Molecular Response for Ponatinib and Nilotinib as Second-
Line Therapy following Imatinib...............................................................................30
Table 2
Response Rate by Dose Tertile in CP-CML Patients (AP24534-10-201)...............31
Table 3
Schedule of Events Through Cycle 12.......................................................................48
Table 4
Schedule of Events after Cycle 12, End-of-Treatment Visit, and Survival 
Follow-Up.....................................................................................................................49
Table 5
Mandatory Study Drug Dose Modifications Based on Responsea..........................55
Table 6
Ponatinib Dose Re-escalation Following Loss of MMR After Dose Reduction.....56
Table 7
Dose Modifications for Adverse Drug Reactions for Patients on Ponatinib..........64
Table 8
Modifications for Adverse Drug Reactions in Patients on Nilotinib......................67
Table 9
Dose Modifications for Arterial Occlusive Events for Patients on Ponatinib .......72
Table 10 Dose Modifications for Arterial Thrombotic or Occlusive Events in Patients on 
Nilotinib........................................................................................................................73
Table 11 Dose Modifications for Venous Thromboembolic Events for Patients on 
Ponatinib......................................................................................................................74
Table 12 Determination of MCyR by Cytogenic Assessment.................................................94
LIST OF APPENDICES
APPENDIX A Drugs with a Risk of Torsade de Pointes.......................................................107
APPENDIX B Drugs that Interact with CYP3A4, 5, and 7..................................................108
APPENDIX C National Cancer Institute Common Terminology Criteria for Adverse 
Events................................................................................................................109
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6
LIST OF ABBREVIATIONS
Abbreviation
Term
ABL
Abelson
AE
adverse event
AESI
adverse event of special interest
ALL
acute lymphoblastic leukemia / acute lymphocytic leukemia
ALT
alanine aminotransferase
AML
acute myelogenous leukemia / acute myeloid leukemia
ANC
absolute neutrophil count
AOEs
Arterial occlusive events
AP
accelerated phase
ARIAD
ARIAD Pharmaceuticals, Inc.
AST
aspartate aminotransferase
AUC
area under the curve
β-HCG
beta-human chorionic gonadotropin
BCR
Breakpoint Cluster Region
BCR-ABL1
Breakpoint Cluster Region-Abelson
BCR-ABL1IS
BCR-ABL transcript level as measured by the International Scale
BID
twice daily
BM
bone marrow
BP
blast phase
BUN
blood urea nitrogen
CBC
complete blood count
CcyR
complete cytogenetic response
CHF
congestive heart failure
CHR
complete hematologic response
CI
confidence interval
Cmax
maximum plasma concentration
CML
chronic myelogenous leukemia / chronic myeloid leukemia
CP
chronic phase
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
cTn
cardiac troponin
CYP
cytochrome P450
DLT
dose-limiting toxicity
EC
Ethics Committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EMA
European Medicines Agency 
FACT-Leu
Functional Assessment of Cancer Therapy – Leukemia
FDA
Food and Drug Administration (United States)
FISH
fluorescence in situ hybridization
GCP
Good Clinical Practice
HR-QoL
health-related quality of life
HSCT
hematopoietic stem cell transplantation
HTN
hypertension
IB
investigator brochure
ICMJE
International Committee of Medical Journal Editors
INR
International Normalized Ratio
IRB
Institutional Review Board
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Abbreviation
Term
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LV
left ventricular
LVEF
left ventricular ejection fraction
MCyR
major cytogenetic response
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MMR
major molecular response
MR
molecular response
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute (of the United States)
OS
overall survival
PCR
polymerase chain reaction
PCyR
partial cytogenetic response
PFS
progression-free survival
Ph+
Philadelphia chromosome positive
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
QD
once daily
QT
QT interval; a measure of the time between the start of the Q wave and the end of the T wave in 
the heart's electrical cycle
QTc
heart rate-corrected QT interval (calculated)
QTcF
QT interval corrected (Fridericia)
R/I
resistant or intolerant
SAE
serious adverse event
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SMQ
Standardized MedDRA Query
SOC
System Organ Class
TIA
transient ischemic attack
TKI
tyrosine kinase inhibitor
TLS
tumor lysis syndrome
ULN
upper limit of normal
URL
upper reference limit
VTEs
Venous thrombotic/embolic events
WBC
white blood cell
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7
DEFINITIONS OF TERMS
Term
Definition
Suspected Adverse 
Reaction
A suspected adverse reaction is any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, "reasonable possibility" means there is evidence to suggest a causal 
relationship between the drug and the adverse event.
Clinically Significant
A clinical observation or laboratory result that leads to a new intervention or change in 
therapy is defined in the context of this study as clinically significant.
Data Monitoring 
Committee
An independent committee consisting of 3 to 5 members not associated with the conduct 
of the study. The data monitoring committee will be responsible for evaluating the results 
of safety and efficacy interim analyses and will make recommendations to the sponsor on 
the conduct of the study.
Cycle
For the purposes of this study, a cycle consists of 28 days and is equivalent to a month in 
the measurement of study endpoints.
End-of-Treatment
The end of treatment occurs at the last dose of study treatment or when the investigator 
and patient decide that the patient will receive no further study treatment, whichever 
occurs later.
End-of-Study
The end-of-study (completion) date is when all patients have completed all study visits or 
have otherwise discontinued from the study.
Enrolled Patient
An enrolled patient is a patient who has signed the informed consent form, completed all 
screening evaluations, and has been randomized to a treatment group.
Ethics Committee
Throughout this document the term Ethics Committee (EC) refers to all appropriate 
properly constituted committees or boards recognized by the appropriate regulatory 
agencies for approving clinical studies. These include independent EC and Institutional 
Review Boards.
Evaluable for Safety
Any patient who receives study drug is considered evaluable for safety analyses.
Follow-up Period
The follow-up period for survival begins at the end of treatment and continues until 
patient contact discontinues.
Institutional Review 
Board
Throughout this document the term Institutional Review Board (IRB) refers to all 
appropriate properly constituted committees or boards recognized by the appropriate 
regulatory agencies for approving clinical studies. These include independent ECs and 
IRBs.
Patient
Throughout this document the term patient refers to a patient in this clinical research 
study.
Regulation
Throughout this document the term regulation refers to all appropriate regulations, laws, 
and guidelines. This study will be conducted according to all appropriate regulations. The 
regulations may be international, national, or local and may include but not be limited to 
the Code of Federal Regulations (United States); The Rules Governing Medicinal 
Products in the European Union; Ministry of Health, Labor, and Welfare (MHLW): 
Ethical Guidelines for Clinical Research (Japan); MHLW: Good Clinical Practice 
Guidelines (Japan); Japan Pharmaceuticals Affairs Law; the International Conference on 
Harmonisation (ICH) Guideline for Good Clinical Practice; and the World Medical 
Association Declaration of Helsinki: Ethical Principles for Medical Research Involving 
Human Patients.
Regulatory Agency
Throughout this document the term regulatory agency refers to all appropriate health and 
regulatory agencies. These may be international, national, or local and may include but 
not be limited to Ministry of Health, Labor, and Welfare (Japan), Pharmaceuticals and 
Medical Devices Agency (PMDA), European Medicines Agency (EMA), and the Food 
and Drug Administration (FDA; United States).
Sponsor
Throughout this document the term sponsor refers to all applicable departments within 
ARIAD Pharmaceuticals, Inc., or its designee.
Study Reference 
Manual
In the context of this study, Study Reference Manual is a general term for the information 
provided to sites on technical aspects of the study. 
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Term
Definition
Study Drug
A study drug is any drug, device, biological agent, or comparator (including placebo) 
used in the sponsor’s clinical research and development studies. For the purposes of this 
protocol, the study drugs are ponatinib (investigational medicinal product) and nilotinib 
(active control).
Study Start Date
The study start date is the date that the first patient signs the informed consent form.
Study Steering 
Committee
The study steering committee consists of clinician experts and sponsor representatives. 
The committee will be responsible for evaluating the results of safety and efficacy 
analyses and will make recommendations to the sponsor on the conduct of the study.
Treatment Period
The treatment period is from time of first dose until 30 days past last dose. 
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8
INTRODUCTION
This protocol describes a phase 2/3, open-label study of ponatinib for the treatment of patients 
with chronic myeloid leukemia (CML) in chronic phase (CP) whose imatinib therapy has failed. 
The phase 2 portion of the study will consist of a single treatment arm in which all patients will 
receive 15 mg ponatinib once daily. The goal of the phase 2 portion of this study is to generate
efficacy and safety data to inform the design and sample size of the phase 3 portion of this study. 
In the phase 3 portion of the study, patients will be randomized to one of 2 doses of ponatinib 
(30 mg [Cohort A] and 15 mg [Cohort B] once daily) or nilotinib (400 mg twice daily; Cohort 
C). The goal of the phase 3 portion of this study is to test the hypothesis that ponatinib will be 
efficacious and safe in treating second-line CP-CML patients, that it will be superior to nilotinib, 
that each of the starting doses will demonstrate the continued efficacy of ponatinib, and that the 
dose reduction strategy will lessen arterial occlusive complications. While ponatinib is approved 
in the United States (US) and the European Union (EU) for patients who have become resistant 
or intolerant to available treatments [Iclusig® (ponatinib) Package Insert, 2016; Iclusig®
(ponatinib) Summary of Product Characteristics, 2016], there is a strong rationale for testing 
ponatinib in patients who have become resistant after initial imatinib therapy. 
8.1
Unmet Need in Second-Line CP-CML Therapy
Targeted therapy of Philadelphia chromosome-positive (Ph+) CML using the tyrosine kinase 
inhibitor (TKI) imatinib has been one of the most striking achievements in modern cancer 
medicine. Most patients with newly diagnosed CML are initially treated with an imatinib 
regimen with good results (Henk et al, 2015). However, 30% to 50% of all newly diagnosed 
CP-CML patients who are treated in the first-line setting with imatinib are in need of another 
treatment, either because they become resistant to imatinib (20%-25%) or because they become 
intolerant of imatinib (15%-20%) (Baccarani et al, 2009). Patients who experience failure of
imatinib are treated second-line with available second generation agents, namely nilotinib and 
dasatinib [Tasigna® (nilotinib) Summary of Product Characteristics, 2014; Sprycel® (dasatinib) 
Summary of Product Characteristics, 2015, Sprycel® (dasatinib) Package Insert, 2010; Tasigna®
(nilotinib) Package Insert, 2010]. In the US, an additional second generation TKI, bosutinib, may 
also be considered [Bosulif® (bosutinib) Package Insert, 2012]. Ponatinib may be an option if 
failure is the result of the T315I mutation [Iclusig® (ponatinib) Package Insert, 2016; Iclusig®
(ponatinib) Summary of Product Characteristics, 2016]. 
A review of efficacy in the second-line setting demonstrates that there is potential for 
improvement. Major cytogenetic response (MCyR) rates in second-line CP-CML range from 
51% with nilotinib therapy (n=321) (Nilotinib SmPC, 2016) to 62% in dasatinib treated patients 
(n=387) indicating that second-line therapy initially fails to achieve a response in a substantial 
fraction of patients. Additionally, none of the available second-line agents have activity against 
all of the known mutants and the T315I mutation is refractory to all TKIs with the exception of 
ponatinib.
Thus, both with regard to response rates and activity against resistant mutants, an unmet need 
remains in many patients who fail first-line TKI therapy. Ponatinib offers the potential to 
improve upon existing second-line therapy as it is the TKI with the most potent activity against 
BCR-ABL1, has activity against all resistant single mutants, and is effective in patients who have 
failed second-line treatments. 
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8.2
Ponatinib Background
8.2.1
Preclinical Summary
Ponatinib is a novel, synthetic, orally active TKI specifically designed to optimally inhibit native 
BCR-ABL1. 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. Pharmacokinetic 
analysis of samples from the ongoing phase 1 clinical study (AP24534-07-101) showed that the 
threshold for pan-BCR-ABL1 activity is surpassed with ≥15 mg once daily dosing (Cmax) and 
with ≥30 mg once daily (steady-state trough).
8.2.2
Ponatinib Use in Refractory CP-CML patients 
The phase 1 study of ponatinib (AP24534-07-101) is a dose escalation study in 81 patients with 
refractory hematologic malignancies (65 with Ph+ leukemia) designed to determine the 
recommended phase 2 dose (RP2D) and assess anti-leukemic activity of ponatinib. Doses from 
2 mg to 60 mg were investigated. The 45 mg daily dose was chosen as the recommended phase 2 
dose and was determined to be the maximum tolerated dose (MTD). With a median follow-up of 
49.9 months, MCyR, MMR, and MR4.5 were achieved by 31/43 (72.1%), 24/43 (55.8%), and 
12/43 (28%) CP-CML patients, respectively. Median dose intensity was 28.3 mg daily for the 
CP-CML population. The most common treatment-emergent AEs (TEAEs) (≥40%) were rash 
(49.4%), nausea (45.7%), abdominal pain (44.4%), fatigue (44.4%), and headache (43.2%). 
Arterial occlusive events were observed: 13/43 (30%) CP-CML patients experienced 
cardiovascular occlusion, 4/43 (9%) experienced cerebrovascular occlusion, and 6/43 (14%) 
experienced peripheral vascular occlusive events. Pancreatitis was determined to be the dose-
limiting toxicity (DLT).
The phase 2 study of ponatinib (AP24534-10-201, PACE) enrolled 449 patients with refractory 
CML or Ph+ ALL that was either resistant or intolerant to dasatinib or nilotinib or with the 
T315I mutation. The most recent 4-year data from this study confirmed that treatment with 
ponatinib continued to provide clinically meaningful responses. This includes the observation of 
maintenance of responses over time after dose reductions. Patients received a starting dose of 
45 mg ponatinib daily and the median dose intensity was 29.4 mg daily (ranging from 3 to 45 mg 
daily) for CP-CML patients. The majority of CP-CML patients (252/270, 93%) enrolled in the 
study had been treated with 2 or more prior TKIs. With a median follow-up of 48.24 months, 
55.4% of CP-CML patients achieved MCyR and 39.3% achieved MMR, and 85.7% remained in 
the primary end-point for ≥548 days at 30 mg. For maintenance of response over time after a 
dose reduction, among the 7 CP-CML patients who had dose reductions from 45 mg to 30 mg 
only, all patients maintained a MCyR for at least 548 days at the reduced dose. Of the 53 patients 
who had a dose reduction from 45 mg to 15 mg, 98.1% maintained a MCyR. Maintenance of 
responses was similar in the patients who had achieved a MCyR at the 30-mg dose and 
subsequently received a dose reduction to 15 mg. The median PFS and OS had not been reached 
for CP-CML patients, but the probability of remaining progression-free at 1, 2, 3, and 4 years 
was estimated as 79.2%, 68.3%, 60.5%, and 56.4%, respectively. The probability of overall 
survival at comparable times was estimated as 94.0%, 86.0%, 81.2%, and 76.8%, respectively.
The most common TEAEs (≥40%) seen in the overall safety population (n=449) were 
thrombocytopenia (43.9%), abdominal pain (42.5%), and rash (41.6%). Continuing analyses of 
the phase 2 trial have demonstrated a higher cumulative incidence of arterial occlusive events 
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(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. The overall rate of arterial occlusive events after 48 months of follow-up was 23.2%, 
including the subsets of cardiovascular (12.5%), cerebrovascular (8.7%), and peripheral vascular 
(8.9%) events. The overall rate of venous thromboembolic events was 5.6%. Refer to the 
Investigator’s Brochure for a complete evaluation of the ponatinib safety profile.
8.2.3
Ponatinib Results in Earlier Lines of Therapy
In an analysis of the phase 2 study, ponatinib elicits higher response rates in earlier lines of 
therapy. In particular, response rates observed in CP-CML patients who were previously treated 
with only one approved TKI (n=19) demonstrate 79% of patients achieved MCyR and 58% 
achieved MMR. This is in comparison to third-line CP-CML patients (n=98) in which 67% 
achieved MCyR and 42% achieved MMR. The MMR response in second-line patients is durable 
with 75% of patients estimated to remain in response at 1 year using Kaplan-Meier methodology. 
In the ponatinib phase 2 study, second-line post- imatinib MMR rates at 45 mg were higher than 
those seen in nilotinib-treated patients post-imatinib, although the number of patients treated 
second-line with ponatinib treated is small (N=13) (Table 1).
Table 1
Fixed or Cumulative Molecular Response for Ponatinib and Nilotinib as Second-
Line Therapy following Imatinib 
Landmark
Response
Ponatinib After Imatinib
Nilotinib After Imatinib
At 3 months
MR1
9/13 = 69% (39%-91%) [4]
117/321 = 36% (31%-42%) [1]
MR2
6/13 = 46% (19%-75%) [4]
61/321 = 19% (15%-24%) [1]
MMR (MR3)
2/13 = 15% (1.9%-46%) [4]
At 6 months
MR1
9/13 = 69% (39%-91%) [4]
124/321 = 39% (33%-44%) [1]
MR2
8/13 = 61% (32%-86%) [4]
84/321 = 26% (21%-31%) [1]
MMR (MR3)
4/13 = 31% (9.1%-61%) [4]
By 12 months
MMR
8/13 = 61% (32%-86%) [5]
41/163 = 25% (19%-33%) [2]
By 24 months
MMR
9/13 = 69% (39%-91%) [4]
82/294 = 28% (23%-33%) [3]
[1] Giles et al; 2012 (1-6) [2] Hughes et al; 2009 [3] Kantarjian et al, 2011 [4] 06Jan2014 data cut [5] 09Nov2012 data cut 
MR1= molecular response 1 (≤10% BCR-ABL1IS); MR2= molecular response 2 (≤1% BCR-ABL1IS); MR3= molecular response 
3(≤0.1% BCR-ABL1IS); MMR= major molecular response (≤0.1% BCR-ABL1IS)
Ponatinib (45 mg once daily) was also evaluated in newly diagnosed CP-CML patients in the 
phase 3 study (AP25434-12-301, EPIC) compared to imatinib (400 mg twice daily). In response 
to an increasing accumulation of arterial occlusive events throughout the clinical program, the 
phase 3 study was terminated prior to completion. Upon study termination, 307 patients were 
enrolled in the study (155 in ponatinib arm, 152 in imatinib arm; 58% of target enrollment). At 
that time, ponatinib-treated patients had a median follow-up of 5.0 months (range 0.03-
17.6 months) and imatinib-treated patients had a median follow-up of 5.3 months (range 0.5-
14.1 months). Preliminary findings based on data up until the early termination suggest there are 
differences in efficacy between ponatinib and imatinib therapy, favoring ponatinib, as measured 
by MMR at 3, 6, and 9 months and by MR4 and MR4.5 for all time points through 12 months. 
With 288 patients (148 ponatinib, 140 imatinib) with a post-baseline assessment of molecular 
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response, the rates of MMR at any time (41% vs. 18%), MR4 at any time (21% vs. 1%), and 
MR4.5 at any time (15% vs. 0%) were significantly higher for patients on the ponatinib arm than 
the imatinib arm (all p-values <0.001).
8.3
Selection of Ponatinib Dose
This clinical study will test two modulations of ponatinib dose: lower starting doses and dose 
reduction after achievement of response (as described below and in Section 10.2). The data that 
support these approaches derive from univariate and multivariate analyses of the relationship of 
dose with efficacy and safety, along with analyses of the effects of dose reductions on response 
and safety.
The impact of dose on achievement of MCyR in patients with CP-CML has been evaluated using 
a multivariate analysis of data from the phase 2 study adjusting for covariates and an analysis of 
response by dose tertile. Both analyses show that increasing dose intensity is associated with 
higher response rates in this predominantly fourth-line population of CP-CML patients. The 
multivariate analysis indicates that dose intensity is associated with achievement of MCyR by 
12 months in CP-CML patients with an odds ratio of 3.222 (p<0.0001). An analysis of CP-CML 
patients shows a decrease in MCyR and MMR from the highest dose-intensity tertile to the 
lowest dose-intensity tertile (Table 2). Nevertheless, response rates are still high in the lowest 
tertile, with the understanding that this is not a second-line patient population.
Table 2
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).
CCyR=complete cytogenetic response, MCyR=major cytogenetic response, MMR=major molecular response.
Multivariate analyses on data from the phase 2 study showed increasing dose intensity correlated 
with an increased probability of experiencing AEs. The relationship between dose intensity and 
arterial occlusive 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. Additionally, dose reduction by 15 mg/day was predicted to lead to an 
approximate 33% risk reduction in the incidence of arterial occlusive events.
Analyses in patients who underwent dose reduction due to AEs show that patients can maintain 
response on doses lower than 45 mg daily. Of patients who achieved response at 45 mg and 
subsequently had their dose reduced to either 30 mg or 15 mg, 6/7 (85.7%) and 52/53 (98.1%)
maintained MCyR, respectively, compared to 15/21 (71%) patients who did not dose reduce. 
Patients who had achieved a MCyR at the 30 mg dose and received a dose reduction to 15 mg 
showed similar maintenance of responses, with 7 patients maintaining a MCyR for ≥1095 days 
at the reduced dose of 15 mg. Similar results were obtained with regard to patients who achieved 
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MMR. Among patients who achieved MMR at 45 mg, 4/5 (80.0%) and 36/40 (90.0%) patients 
who dose reduced to 30 mg or 15 mg, respectively, maintained their response while 11/18 
(61.1%) patients who did not dose reduce, maintained their response. 
Taken together, these data underpin the rationale for investigating lower doses of ponatinib in 
conjunction with dose reduction following response. This study will employ starting doses of 
15 mg (in phase 2) and 30 mg and 15 mg (in phase 3) to achieve response and then reduce dosing 
to lower the risk of AEs while maintaining response.
8.4
Selection of Nilotinib as a Comparator
Nilotinib is approved in the US and EU for adult CP-CML patients who are resistant to or 
intolerant of prior therapy that included imatinib [Gleevec® (imatinib) Package Insert, 2012; 
Glivec® Summary of Product Characteristics, 2015). The approved dose in both the US and the 
EU is 400 mg twice daily for this indication. Both NCCN (O’Brien et al, 2014) and ELN 
(Baccarani et al, 2013) guidelines recommend consideration of the use of nilotinib in patients 
initially treated with imatinib whose disease develops resistance to therapy.
The efficacy of nilotinib as a second-line therapy post imatinib in studies with long follow-up 
has been clearly established and extensively studied. Data in a phase 2 study of CP-CML patients 
whose disease was resistant or intolerant to imatinib demonstrated that 59% (190/321) of 
CP-CML patients achieved MCyR by 24 months (Giles et al, 2013). At 48 months, PFS and OS 
in CP-CML patients were predicted to be 57% and 78%, respectively. Data regarding MMR rates 
in the second-line population are less certain. The rates of MMR by 12 months have been 
estimated to be 25% (Hughes et al, 2009) and by 24 months 28% (Kantarjian et al, 2011) but 
these analyses involve subset analyses of patients with available samples in the nilotinib second-
line experience.
Like ponatinib, nilotinib-treated patients have experienced peripheral vascular events. At 5 years 
of follow up, 15.2% of newly diagnosed CP-CML patients treated with nilotinib experience 
arterial occlusive events (Note: this rate cannot be compared directly with ponatinib since 
individual event terms are not provided) (Tasigna® Package Insert, 2016; Tasigna® Summary of 
Product Characteristics, 2016). In both the ponatinib and nilotinib development programs, most
of these patients had additional risk factors for cardiovascular disease. The use of nilotinib as a 
comparator thus offers the opportunity to compare these agents directly in a single patient 
population.
8.5
Selection of Endpoints
The depth of and time to molecular response is well correlated with clinical outcome, and this 
provides the rationale for utilizing MMR as a measure of outcome in the patient population 
studied here. Marin and colleagues have shown that a strong predictor of OS is the attainment of 
BCR-ABL1 transcript levels below 10% by 3 months after the initiation of therapy (Marin et al, 
2012). This observation supports continued use of molecular response endpoints and suggests 
that the rapidity and depth of molecular response may be an important indicator of treatment 
success.
Time to achieve response is also important. In a study by the German CML Study Group of over 
1,300 patients starting treatment with a TKI (Hanfstein et al, 2012), the estimated OS at 5 years 
for those who achieved a 1-log reduction in the first three months was 94%. For patients who had 
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a 2-log reduction at three months, the estimated survival was 97%. If patients didn’t have this 
degree of early leukemia suppression, the estimated 5-year survival dropped to 87%. 
In ponatinib-treated patients in the phase 2 study, molecular response at 3, 6, and 12 months had 
a significantly positive association with long-term PFS and OS. Patients who achieved MMR at 
12 months had a PFS of 93% and OS of 100% at 2 years. This is in contrast to patients who did 
not achieve MMR at 12 months who had a probability of PFS of 74% and probability of OS of 
93% at 2 years (Muller et al, 2014).
This benchmark of response is reflected in the ELN guidelines. The goals of therapy outlined are 
to achieve a 1-log reduction within the first 3 months of treatment, a 2-log reduction within the 
first 6 months, and a 3-log reduction (that is, MMR) within 12 months (Baccarani et al, 2013).
This supports the choice of MMR by 12 months as the primary endpoint of this study.
8.6
Selection of Study Design
8.6.1
Phase 2
The single arm phase 2 portion of the study will estimate the efficacy, as measured by MMR rate 
by 12 months, of a 15 mg starting ponatinib dose, in patients with CP-CML following resistance 
to imatinib. The ponatinib dose chosen is based on the current molecular response rates with 
ponatinib therapy. A sample size of 75 patients will distinguish a favorable MMR by 12 month 
rate of 40% from a null or an uninteresting MMR rate of 25%, with a nominal 80% power and a 
2-sided type I error rate of 0.05 (equivalent to a 2-sided 0.025) using an exact binomial test.
Interim analyses will also be performed after 50 patients reach 6 months of treatment during the 
phase 2 portion of the study. A sample size of 50 patients will distinguish a favorable 
≤1% BCR-ABL1IS by 6 month rate of 50% from a null or an uninteresting ≤1% BCR-ABL1IS
rate of 25%, with a nominal 96% power and a 2-sided type I error rate of 0.05 (equivalent to a 2-
sided 0.025) using an exact binomial test. At the interim analysis, the CI for ≤1% BCR-ABL1IS
will be calculated. Based on the observation from the phase 2 study of ponatinib 
(AP24534-10-201; PACE), ≤1% BCR-ABL1IS at 6 months is considered to be a good surrogate 
for the primary endpoint of this study - MMR by 12 months. 
8.6.2
Phase 3
The phase 3 portion of this study will evaluate the superiority of a ponatinib dosing strategy
compared with the current approved dosing regimen for nilotinib. The study will also compare 
arterial occlusive event rates by dose and treatment. 
Two-thirds of the patients will have a minimum follow-up of at least 18 months at the time of the 
primary analysis and the data will enable the efficacy and safety comparison of ponatinib versus
nilotinib. The safety profile will be further characterized by secondary analyses until all patients 
have reached the end of the study, which is planned to last 60 months.
Patients will be randomized 1:2:1 to 30 mg ponatinib QD (Cohort A), 15 mg ponatinib QD 
(Cohort B), or 400 mg nilotinib BID (Cohort C), taken orally. A sample size of 150 patients in 
each Cohort A and C (ponatinib 30 mg and nilotinib) will distinguish a favorable MMR rate of 
45% for ponatinib from a null or an uninteresting MMR rate of 25% for nilotinib with a nominal 
90% power to detect an improvement in MMR of 20%. The sample size of 300 patients in 
Cohort B and 150 patients in Cohort C will distinguish a favorable MMR rate of 40% for 
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ponatinib from a null or an uninteresting MMR rate of 25% for nilotinib with approximately 
80% power to detect an improvement in MMR of 15%. Thus, the larger cohort size utilizing 
ponatinib at a lower dose will enable the detection of a smaller improvement in efficacy with 
adequate power.
8.6.2.1
Rationale for Phase 3 Design Based on Phase 2
Based on accumulating data from the 15 mg cohort and supportive clinical data evolving from 
additional studies highlighted below, the phase 3 design (including number of ponatinib cohorts) 
and/or sample size may be amended prior to enrollment of patients into the phase 3 portion of the 
study.
8.6.2.2
Rationale for Phase 3 Design Based on Additional Supportive Data
In addition to data from phase 2, evolving cumulative safety data from the OPTIC study will be 
evaluated to inform the design of the phase 3 portion of the study. OPTIC is an ARIAD-
sponsored randomized, open-label, phase 2 study of ponatinib in patients with resistant CP-CML 
to characterize the efficacy and safety of a range of doses including 45, 30 and 15 mg.
Additionally, supportive clinical data evolving from the currently active phase 2 investigator 
initiated study conducted by Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) 
evaluating the activity and risk profile of ponatinib at 30 mg QD in CP-CML (refer to 
ClinicalTrials.gov Identifier: NCT02398825 for further details) will be considered.
9
STUDY OBJECTIVES
9.1
Primary Objectives
Phase 2
The primary objective of the phase 2 portion of this study is to demonstrate the efficacy of 
ponatinib administered at a dose of 15 mg in patients with CP-CML who are resistant to 
imatinib, as measured by MMR by 12 months, with the goal of generating efficacy and safety 
data to inform the design and sample size of the phase 3 portion of this study.
Phase 3
The primary objective of the phase 3 portion of this study is to demonstrate the efficacy of 
ponatinib administered at 2 starting doses (30 and 15 mg QD) compared to nilotinib administered 
at 400 mg BID in patients with CP-CML who are resistant to imatinib, as measured by MMR by 
12 months.
9.2
Key Secondary Objectives in Phase 2 and Each Cohort in Phase 3
The key secondary objectives of this study are:
●
To characterize, according to each arm and ponatinib starting dose, the rate of AOEs 
and VTEs, AEs, and serious adverse events (SAEs).
●
To characterize, according to each arm and ponatinib starting dose, the rate of 
cytogenetic responses and molecular responses other than MMR. 
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EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 36 of 109
The study will assess hematologic response, cytogenetic response, and molecular response, as 
well as additional measures of efficacy including time to responses, and duration of responses by 
starting dose and after dose reduction. PFS and OS data will also be collected and analyzed. 
Adverse event rates and the rates of vascular occlusive events, in particular, will be measured. 
Assessments will be according to standard international criteria. The duration of patient 
participation will be 60 months for all patients, unless they withdraw prior to that based on the 
withdrawal criteria defined within the protocol. 
10.1.1
Primary Endpoint in Phase 2 and Each Cohort in Phase 3
The primary endpoint for this study is major molecular response (MMR) by 12 months for each 
cohort. 
10.1.2
Key Secondary Endpoints in Phase 2 and Each Cohort in Phase 3
The key secondary endpoints for this study are:
●
Cytogenetic response rates: 
i.
MCyR, as defined in Section 16.5.1.2, by 12 months
ii.
CCyR by 12 months
●
Molecular response rates: ≤1% BCR-ABL1IS, MR3/MMR, MR4, MR4.5 at 3-month 
intervals until end-of-treatment and MR1 (≤10% BCR-ABL1IS) at 3 months
●
Safety
i.
Arterial occlusive and venous thrombotic/embolic events in each cohort
ii.
AEs in each cohort
iii.
SAEs in each cohort
●
Time to response
●
Duration of response:
i.
≤1% BCR-ABL1IS and MMR at 3, 6, 9, and 12 months, and then at 3-month 
intervals until completion of treatment
ii.
MCyR at 12 and 24 months, by cytogenetic analysis
iii.
Duration of response in responders
iv.
Duration of therapy
●
Progression-free survival 
●
Overall survival
10.1.3
Other Secondary Endpoints in Phase 2 and Each Cohort in Phase 3
Other secondary endpoints for this study include:
●
Hematologic response rates: CHR
●
Tolerability:
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s of Use
plicable Terms 


ARIAD Pharmaceuticals, Inc.
AP24534-15-303
EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 38 of 109
In the phase 3 portion, patients will be randomized in a 1:2:1 ratio to receive either ponatinib in 
one of 2 starting doses or nilotinib. 
Cohort A: 30 mg ponatinib QD with reduction to 15 mg at 3, 6, 9, or 12 months upon 
achievement of MMR. 
Cohort B: 15 mg ponatinib QD with reduction to 10 mg at 3, 6, 9, or 12 months upon 
achievement of MMR. 
Cohort C: 400 mg nilotinib BID. 
A cycle of therapy will comprise 28 days of treatment, regardless of dose.
The randomization for phase 3 will be stratified based on the patient’s baseline age (≥60 vs 
<60 years) and best response to prior imatinib therapy (CCyR or ≤1% BCR-ABL1IS or better, 
yes/no). Specific instructions for randomization will be supplied in the Study Reference Manual. 
Randomization procedures should be performed following confirmation of eligibility. This study 
is open-label; patients, investigators, and the sponsor will know the identity of each patient’s 
study treatment.
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 3. Documentation from the screening period is required for each inclusion 
and exclusion criterion.
Patients must meet all of the following criteria in order to be eligible for the study:
1. Have CP-CML resistant to first-line imatinib treatment. 
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 accelerated phase (AP) or blast phase (BP) CML
b.
Cytogenetic assessment must demonstrate the BCR-ABL1 fusion by presence of 
the t(9;22) Philadelphia chromosome.
i
Conventional chromosome banding must be performed
ii
A minimum of 20 metaphases must be assessable at entry. If  < 20 metaphases are 
assessable, a real time PCR with > 1% of BCR-ABL1IS is required to be eligible 
iii Variant translocations are not allowed
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Protocol Version 3.0
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c.
BCR-ABL1 transcript levels must be assessable using the International Scale (ie, 
patients must have either the b2a2 or b3a2 transcript type)
d. Resistance is defined as follows. Patients must meet at least 1 criterion. 
i
Three months after the initiation of therapy: No cytogenetic response (>95% Ph+) 
or failure to achieve CHR.
ii
Six months after the initiation of therapy: BCR-ABL1IS >10% and/or >35% Ph+.
iii Twelve months after the initiation of therapy: BCR-ABL1IS >1% and/or Ph+ >0.
iv At any time after the initiation of therapy, the development of new BCR-ABL1
kinase domain mutation(s). 
v
At any time after the initiation of therapy, the development of new clonal 
evolution.
vi At any time after the initiation of therapy, the loss of CHR, the loss of CCyR, or 
the confirmed loss of MMR in 2 consecutive tests, one of which has a 
BCR-ABL1IS transcript level of ≥1%.
[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 or 1.
4.
Have adequate renal function as defined by the following criterion:
a.
Serum creatinine ≤1.5 × upper limit of normal (ULN) for institution.
5.
Have adequate hepatic function as defined by all of 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 a negative pregnancy test documented prior to enrollment (for females of childbearing 
potential).
8.
Agree to use a highly effective form of contraception with sexual partners from the time of 
randomization through at least four (4) months after the end of treatment (for female and 
male patients who are fertile).
9.
Provide written informed consent. 
10. Be willing and able to comply with scheduled visits and study procedures.
11.
Have recovered from toxicities related to prior anticancer therapy to NCI CTCAE grade ≤1
except for alopecia or peripheral neuropathy.
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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 previously been treated with any approved or investigational TKIs other than 
imatinib or treated with imatinib within 14 days prior to receiving study drug.
2.
Have previously been treated with any anti-CML therapy other than hydroxyurea, 
including interferon, cytarabine, immunotherapy, or any cytotoxic chemotherapy, 
radiotherapy, or investigational therapy.
3.
Underwent autologous or allogeneic stem cell transplant.
4.
Are in ≤ 1% BCR-ABL1 (in phase 2) or in MMR (in phase 3). 
5.
Have a known history of T315I mutation in phase 3.
6.
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 history of revascularization procedure, including vascular surgery or the 
placement of a stent
d. Any history of venous thromboembolism including deep venous thrombosis, 
superficial venous thrombosis, or pulmonary embolism, within 6 months prior to 
enrollment
e.
Congestive heart failure (New York Heart Association [NYHA] class III or IV) 
within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less 
than 45% or less than the lower limit of normal per local institutional standards 
(whichever is higher) within 6 months prior to enrollment
7.
Have cardiac conduction abnormalities as follows: 
a.
QTcF >450 msec on the average of 3 serial baseline ECGs (using the QTcF formula); 
congenital long QT syndrome, or a known family history of long QT syndrome; or 
inability to determine the QTcF 
b. Presence of a complete left bundle branch block
c.
Use of a ventricular pacemaker
d. History of clinically significant (as determined by the treating physician) atrial 
arrhythmia
e.
Resting bradycardia <50 beats per minute
f.
Any history of ventricular arrhythmia
8.
Are taking medications with a known risk of Torsades de Pointes or that have the potential 
to prolong the QT interval (Appendix A), unless the medication can be discontinued or be 
substituted by another without the risk.
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9.
Are taking medicines that are strong CYP3A4 inhibitors, unless the medication can be 
discontinued or be substituted by another that is not an inhibitor (Appendix B).
10.
Are taking medicines that are strong CYP3A4 inducers, unless the medication can be 
discontinued or be substituted by another that is not an inducer (Appendix B).
11.
Have uncontrolled hypertension (i.e., >150 and >90 mmHg 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.
12.
Have poorly controlled diabetes defined as HbA1c values of > 7.5%.  Patients with 
preexisting, well-controlled, diabetes are not excluded.
13.
Have uncorrected hypokalemia or hypomagnesemia. 
14.
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. A history of CNS 
involvement is not itself exclusionary if the CNS has been cleared of disease with a 
documented negative lumbar puncture.
15.
Have a significant bleeding disorder unrelated to CML. 
16.
Have a history of thrombophilia (eg, Protein C deficiency).
17.
Have a history of alcohol abuse. 
18.
Have a history of acute pancreatitis within 1 year of study entry or a history of chronic 
pancreatitis.
19.
Have malabsorption syndrome or other gastrointestinal illness that could affect oral 
absorption of study drug.
20.
Have a history of another malignancy, other than cervical cancer in situ, basal cell or 
squamous cell carcinoma of the skin, except if patient has been disease-free for at least
5 years, and are deemed by the investigator to be at low risk for recurrence of that 
malignancy.
21.
Are pregnant or lactating.
22.
Have undergone major surgery within 14 days prior to first dose of study treatment. Minor 
surgical procedures, such as catheter placement or bone marrow biopsy, are allowed.
23.
Have an ongoing or active infection. This includes but is not limited to the requirement for 
intravenous antibiotics. 
24.
Have any surgical or medical condition or illness that, in the opinion of the investigator, 
would compromise patient safety or interfere with the evaluation of the study drug.
25.
Have hypersensitivity to the active substance in ponatinib and nilotinib or to any of the 
inactive ingredients listed in Section 14.9.1.1 for ponatinib and in Section 14.9.1.2 for 
nilotinib.
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EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 42 of 109
12
STUDY PROCEDURES
12.1
Schedule of Events
Table 3 lists the screening and study procedures to be done through Cycle 12 for both the phase 2 
and phase 3 portions of the study. Table 4 lists the procedures to be done after Cycle 12 through 
the end of both the phase 2 and phase 3 portions 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:
1
Screening Period Procedures
Screening tests and procedures are used to establish eligibility of the patient for the study. 
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 done within 21 days prior to randomization with the exception of 
the screening bone marrow (BM) aspirate (within 42 days) and screening pregnancy test 
(within 7 days of first dose of 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 study begins with the signing and dating of the informed 
consent form.
3
Randomization (Phase 3 Only)
Specific instructions for randomization will be supplied in the Study Reference Manual. 
Randomization procedures should be performed within the 21 day screening period following 
completion of 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 includes diagnoses, therapies, medical and surgical treatments, lifestyle 
factors, and family history.
Special attention should be paid to documenting risk factors for arterial cardiovascular 
cerebrovascular, peripheral vascular, and venous thromboembolic disease, and the history 
must include any history of ischemic heart disease (including 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 transient ischemic attacks [TIA], cerebral atherosclerosis, 
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Protocol Version 3.0
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revascularization procedures), diabetes mellitus, hypertension, hypercholesterolemia, 
hyperlipidemia, deep venous thrombosis, pulmonary embolism, any other coagulopathy (eg, 
protein S or protein C deficiency, anticardiolipin antibody), physical inactivity, obesity, and 
smoking. Note that a history of a prior myocardial infarction, unstable angina, stroke, transient 
ischemic attack, any ischemic infarct, or a revascularization procedure is exclusionary. 
Family medical history will be collected and should include history of coronary artery disease, 
early death from myocardial infarction or cerebrovascular accident, sudden death, and 
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).
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 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, and the reason for 
failure of or intolerance to each regimen. As described in Section 11.2, previous treatment
with any approved or investigational TKIs other than imatinib or treatment with any anti-
CML therapy other than hydroxyurea, including interferon, cytarabine, immunotherapy, or 
any cytotoxic chemotherapy, radiotherapy, stem cell transplant, or investigational therapy are 
exclusionary criteria.
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
Complete Physical Exam 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 every 6 months thereafter as 
indicated in Table 3 and Table 4) 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 
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any signs of serious vascular occlusion (both venous and arterial) in the retina. Also, clinically 
evaluate for photophobia, conjunctival disease, uveitis, and cataracts. Additional exams at 
screening or thereafter should be performed as clinically indicated. 
10
Complete Blood Count with Differential
Complete blood count (CBC) with differential is defined as peripheral blood total white blood 
cell (WBC) count, hemoglobin, hematocrit, platelet count, absolute neutrophil count (ANC),
and WBC differential reported individually for each cell type. Cell types required for 
diagnosis and response assessment must be quantified including basophils, myelocytes, 
metamyelocytes, promyelocytes, and blasts, when present. Hematologic assessments must be 
obtained at screening and at every subsequent assessment, as specified in the Schedule of 
Events (Table 3 and Table 4) or more frequently as clinically indicated (eg, to confirm 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 3 and Table 4) or more frequently as 
clinically indicated.
b) 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.
c) Fasting Cholesterol/Lipid Assessment
Fasting serum lipid panel (total, HDL, LDL) including triglycerides must be collected during 
screening and at subsequent time points as specified in the Schedule of Events (Table 3 and 
Table 4) or more frequently as clinically indicated.
d) 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) or BNP must be performed at 
screening. Additionally, HbA1c, CRP, cTn, and NT-proBNP (or BNP) must be performed at 
the times specified in the Schedule of Events (Table 3 and Table 4) or more frequently as 
clinically indicated.  If the investigative site is unable to perform NT-proBNP testing, a BNP 
test can be performed instead.
12
Pregnancy Test
The pregnancy test must be a beta-human chorionic gonadotropin (β-HCG) test, and either 
urine or serum can be used. Women who are not of childbearing potential (status post-
hysterectomy, status post-bilateral oophorectomy, or postmenopausal [defined as amenorrhea 
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Protocol Version 3.0
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for at least 12 months]) do not need to have the test performed. The test 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
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 in 
cycles 3, 6, 12, 18, every 6 cycles thereafter, and at end-of-treatment, as specified in the 
Schedule of Events, or more frequently if clinically indicated. If prolongation of the QTcF 
interval is observed ECG monitoring should be utilized as described in Section 12 and as 
clinically indicated.
14
Echocardiogram
An echocardiogram (ECHO) for assessment of left ventricular ejection fraction (LVEF) must 
be performed within the 21-day screening window and every 12 cycles and at end of 
treatment, as specified in the Schedule of Events. Additional ECHOs need only be performed 
if clinically indicated.
15
Adverse Events and Concomitant Medications
Adverse events and concomitant medications are to be recorded continuously throughout the 
treatment period, starting on date of signed informed consent, and at the 30-day follow-up 
visit, as indicated in the Schedule of Events (Table 3 and Table 4). 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 CTCAE grade ≤1), stabilize, or are 
considered to be chronic or irreversible.
16
Bone Marrow Aspirate/Cytogenetics
The BM aspirate results must include the components required for assessing response of the 
patient. All BM aspirates must quantify cell types required for diagnosis and response 
assessment, including promyelocytes and blasts. Examination must include cytogenetic 
assessment by conventional banding. Bone marrow cytogenetics requires examination of at 
least 20 metaphases. If less than 20 metaphases are examined, a real time PCR with > 1% of 
BCR/ABL1IS is required to be eligible, within the same time window.
The BM aspirate with or without an optional biopsy or real time PCR must occur within 42 
days prior to randomization and ± 7 days of the subsequent scheduled assessment at cycle 12. 
A BM aspirate with cytogenetic assessment of 20 metaphases is required in all patients on 
study after the first 12 cycles, and for patients who are not in CCyR, every 12 cycles
thereafter.
For patients documented to be in MCyR by the protocol definition of ≤1% BCR-ABL1IS, and 
who have not yet undergone a post-screening BM aspirate, if ≤1% BCR-ABL1IS is lost prior 
to a scheduled BM aspirate, a BM aspirate and cytogenetics must be obtained.
At the end of cycle 12, all patients must undergo a BM aspirate and cytogenetic assessment. 
After cycle 12, patients documented to be in CCyR after any BM aspirate and cytogenetics 
assessment, and also in MMR, are not required to have any further BM aspirates. As outlined 
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21
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 is 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. See Section 12.2.2 for further details on discontinuation of 
patients from study drug.
22
Follow-up Procedures: Safety
All AEs ongoing or starting within 30 days after the End-of-Treatment must be recorded on 
the eCRF. After this time, 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 CTCAE grade ≤1), stabilize, or are considered to be chronic or irreversible.
23
Follow-up Procedures: Survival
Survival data will be collected every 12 weeks ± 2 weeks starting after the last dose of study 
treatment 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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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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 eligibility criteria 
may be enrolled into the study using the enrollment procedure established by the sponsor. 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 and/or 
exclusion criteria are defined as screen failures. Once the Investigator determines that screening 
will not continue for a patient and the patient will not be enrolled in the study, the screen failure 
should be documented on the Eligibility Criteria eCRF within 5 days. 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 3) 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 
enrolled (phase 2) or randomized (phase 3).
If a patient is discontinued from the study 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
The estimated duration of the phase 2 portion of the study is approximately 68 months, including 
8 months for enrollment and 60 months of treatment/follow-up.
Total maximum study duration of the phase 3 portion of the study is expected to be 
approximately 84 months (7 years). This includes an enrollment period of approximately 
24 months and a treatment period of 60 months (5 years), unless the patient is discontinued early. 
The duration of therapy will be determined by the patient’s response and toxicity. Patients will 
be followed for 30 days after last dose of study drug. 
The estimated duration of the study overall (both phases) is approximately 104 months, 
consisting of:

Approximately 20 months for phase 2 until the primary endpoint:
o
8 months for enrollment, and
o
12 months for treatment/follow-up to the primary endpoint, followed by
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
84 months for phase 3 up to the end of the study:
o
24 months for enrollment, and
o
60 months of treatment/follow-up to the end of the study.
Patients in both phases will be followed up to 60 months as defined in the protocol after they are 
evaluated for the primary endpoint at 12 months; however, enrollment in phase 3 will begin after 
patients in phase 2 are evaluated for the primary endpoint at 12 months.
The overall study design may be modified based on the data from phase 2 that will inform the 
phase 3 portion of the study.
12.4
Withdrawal Criteria
Patients will be discontinued from further study drug administration if any of the following
occur:
●
Intolerable toxicity as determined by the investigator and defined in Section 14.4.2.1
●
Myocardial infarction, 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
●
Absence of MCyR by 12 months
●
For patients in the ponatinib arms, confirmed loss of MCyR in the absence of dose re-
escalation (in patients unable to dose escalate due to toxicity) or continued loss of 
MCyR after 6 months following dose re-escalation
●
For patients in the nilotinib arm, loss of MCyR 
●
Progression of disease to AP- or BP-CML
●
Entry into another therapeutic clinical study or start of additional anticancer therapy
●
Significant deviation from the protocol or eligibility criteria, in the opinion of the 
medical monitor or investigator
●
Noncompliance with study or follow-up procedures
●
Pregnancy
●
Patient withdrawal of consent and decision to discontinue participation
●
Termination of the study by the sponsor
●
Any other reason that, in the opinion of the investigator, would justify removal of the 
patient from the study
Please ensure that patients discontinuing treatment or assessments early have adequate follow up 
as described in Section 12.1.
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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 (PHASE 2 AND PHASE 3)
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:
●
BCR-ABL1 transcript assessment to determine molecular response
●
Bone marrow aspirates for assessment of cytogenetic response 
●
Complete blood count for assessment of hematologic response
●
Survival follow-up
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 NCI CTCAE v.4.0), timing, 
seriousness and relatedness, outcome, action taken with study drug, and treatment will be 
assessed and documented by the investigator continuously throughout the study.
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For the phase 3 portion, the starting dose of study drug will be 30 mg ponatinib QD (Cohort A), 
15 mg ponatinib QD (Cohort B), or 400 mg nilotinib BID (Cohort C), taken orally. Study drug 
will be self-administered by the patient on a daily schedule. As described in Section 14.2, 
patients in Cohort A will have their daily dose of ponatinib reduced to 15 mg and patients in 
Cohort B will have their daily dose of ponatinib reduced to 10 mg if MMR has been achieved.
Study treatment will be administered only to eligible (and, for the phase 3 portion, randomized)
patients at qualified centers (eg, listed on the FDA Form 1572).
14.1.1
Treatment Administration 
Patients in the phase 2 portion and in Cohorts A and B of the phase 3 portion will take the 
prescribed number of ponatinib tablets with water, with or without food, at approximately the 
same time each day. Patients in Cohort C will take the prescribed number of nilotinib capsules 
approximately 12 hours apart at approximately the same time each day. Nilotinib capsules should 
be swallowed with water and must not be taken with food. Patients should not consume food 2 
hours before or 1 hour after the dose of nilotinib is taken. Patients in all cohorts 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 who forget to take their 
dose more than 6 hours after it is due should not make up the missed dose. Any missing doses 
should be recorded, and subsequent training of patients should be documented in the appropriate 
source record (eg, clinic chart) and in the eCRF.
14.2
Ponatinib Treatment for Patients in Phase2 and Cohorts A and B in Phase 3
The starting dose of study drug will be 15 mg ponatinib QD (phase 2), 30 mg ponatinib QD 
(Cohort A of phase 3), 15 mg ponatinib QD (Cohort B of phase 3). Each 28-day dosing period is
referred to as 1 cycle. Patients will be assessed for MMR and MCyR as described below, and 
doses will be modified according to response. Doses may also be modified to manage AEs, also 
described below. 
14.2.1
Mandatory Dose Reduction for Response Scheme in Phase 2 and Ponatinib 
Cohorts A and B in Phase 3
Patients will be assessed for molecular and cytogenetic response at 3-month intervals. Patients in 
the ponatinib cohorts will have their doses reduced upon attainment of MMR at 3, 6, 9, or 12 
months or MCyR at 12 months, as defined below and in Sections 16.5.1.1 and 16.5.1.2. No dose 
reduction for response will be implemented for patients in the nilotinib cohort. The dose 
reduction scheme is described in Table 5. 
MMR is defined as a ≤0.1% ratio of BCR-ABL1 to ABL1 transcripts on the IS (BCR-ABL1IS), 
measured by real-time quantitative PCR.
MCyR is defined according to standard criteria as ≤35% Ph+-containing metaphases (typically 
<7/20 involved metaphases), that is, as either a PCyR or a CCyR. Increasingly, patient 
monitoring is being performed by quantitation of BCR-ABL1 transcript from a standard 
according to the international scale (IS) (Marin, 2014; Baccarani et al, 2013; Marin et al, 2012; 
Lauseker et al, 2012; Saglio et al, 2012). This is in fact the recommendation of the National 
Comprehensive Cancer Network (NCCN; O’Brien et al, 2014). Using such monitoring, ≤1% 
BCR-ABL1/ABL1IS is taken to be equivalent to CCyR (Marin, 2014). 
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Patients will undergo a baseline BM aspirate and cytogenetics to establish the diagnosis and 
eligibility. They will then undergo molecular monitoring at 3-month intervals (or when an 
unscheduled assessment is performed) for the assessment of response. In the ponatinib arms 
(phase 2 and Cohorts A and B of phase 3), the assessment will also inform the decision regarding 
dose reduction. They will undergo a BM aspirate with cytogenetics after 12 cycles, which will be 
used to assess cytogenetic response at 12 months and to inform the decision regarding dose 
reduction, at end of treatment as specified in the Schedule of Events (Table 4), and other time 
points depending on response. Details of BM acquisition are also listed in Section 12.1, item 15.
Note: patients may undergo dose reduction for adverse events (see Section 14.3) prior to the 
achievement of MMR. This should not affect the assessment of response and the mandated dose 
reduction in patients enrolled in the ponatinib cohorts upon its attainment. 
The schedule of patient assessment for mandatory response-related dose reduction in phase 
2 and Cohorts A and B in phase 3 is as follows:
At 3 months, patients in Cohorts A and B will have their dose reduced to 15 mg and 10 mg, 
respectively, if they are in MMR; if not, they will continue at their current dose until the 6-month 
assessment.
At 6 months, patients in Cohorts A and B will have their dose reduced to 15 mg and 10 mg, 
respectively if they are in MMR. If not, they will continue at their current dose until the 9-month 
assessment.
At 9 months, patients in Cohorts A and B will have their dose reduced to 15 mg and 10 mg, 
respectively, if they are in MMR. If not, they will continue at their current dose until the 
12-month assessment.
At 12 months, all patients will undergo a BM aspirate and cytogenetics. Patients in phase 2 will 
have their dose reduced to 10 mg and patients in Cohorts A and B of phase 3 will have their dose 
reduced to 15 mg and 10 mg, respectively, if they are in MMR, and will continue therapy. 
At 12 months, dose reduction upon achieving an MCyR may occur following discussion with the 
Medical Monitor. If not in MCyR at 12 months, patients will discontinue therapy.
Ponatinib dose reduction upon achievement of MMR can also be implemented when an 
unscheduled response assessment is performed.
Table 5
Mandatory Study Drug Dose Modifications Based on Responsea
Response Criteria
Time Point
Value
Cohort
Action
MMR (≤0.1%)
3 months and every 
subsequent 3 months or 
when an unscheduled 
response assessment is 
performed
MMR
Phase 2
Reduce dose to 10 mg
Phase 3
A
Reduce dose to 15 mg
B
Reduce dose to 10 mg
C
No change in dose
MCyR by BM 
cytogenetics (upon 
discussion with 
Medical Monitor)
12 months
MCyR
Phase 2
Reduce dose to 10 mg
Phase 3
A
Reduce dose to 15 mg
B
Reduce dose to 10 mg
C
No change in dose
Not in MCyR
All
Discontinue from study
a
Once a patient re-escalates due to loss of response, that patient should not be dose-reduced again upon re-
achievement of MMR or MCyR by BM cytogenetics
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Refer to Section 12.4 for additional criteria for discontinuation for patients not achieving 
response.
14.2.2
Loss of Response after Dose Reduction for MMR or MCyR in Phase 2 and in 
Cohorts A and B of Phase 3
Patients being treated with ponatinib who achieve MMR at any time point, undergo dose 
reduction, and then lose MMR, as determined by real-time quantitative PCR assessment 
(Section 16.5.1.1), are candidates for dose re-escalation to their starting dose, in the absence of 
AEs requiring dose modification. Patients who achieve MCyR, but not MMR, at 12 months also 
will undergo dose reduction. These patients who subsequently lose MCyR are also candidates for 
dose escalation at the discretion of the physician. 
Patients will be monitored with a cytogenetic assessment at 12 months and molecular response 
assessments every 3 months according to the Schedule of Events (Table 3 and Table 4, or in the 
case of an unscheduled assessment). Any patient who has a greater than 1-log increase in 
transcript level should also have a BM cytogenetic assessment performed unless the patient 
remains at ≤1% BCR-ABL1IS. If the cytogenetic assessment indicates loss of MCyR, dose 
escalation may be considered. If the cytogenetic assessment does not demonstrate loss of MCyR, 
continued monitoring is indicated. 
Patients may be dose re-escalated as follows:
Patients may only undergo dose re-escalation if they do not have ongoing AEs necessitating 
treatment at 10 mg or 15 mg as per Section 14.4.2 (Dose Modifications for Adverse Drug 
Reactions). 
For patients in Cohort A of phase 3, re-escalate to the starting dose of 30 mg. For patients in 
phase 2 and Cohort B of phase 3, escalate to the starting dose of 15 mg.
If patients regain MCyR after dose escalation, continue their therapy at the escalated dose and 
monitor according to the Schedule of Events (Table 3 and Table 4). 
If patients do not regain MCyR after 6 months of therapy at the escalated dose, they must be 
discontinued from the study. 
The dose re-escalation scheme is described in Table 6.
Table 6
Ponatinib Dose Re-escalation Following Loss of Response After Dose Reduction
Current Response Criteria
Time Point
Cohort
Action
Loss of MCyR by cytogenetics
12 months or later
Phase 2
Re-escalate to 15 mga
Phase 3
A
Re-escalate to 30 mga
B
Re-escalate to 15 mga
If 

Loss of ≤1% BCR-ABL1IS (ie, 
≥1% BCR-ABL1) and >10-fold 
↑in BCR-ABL1 from nadir 
Any time after 
achievement of 
MCyR or MMR
Phase 2
Perform BM cytogenetics; if loss of MCyR 
then re-escalate to 15 mga; if no loss of 
MCyR, continue to monitor according to 
SOE
Phase 3
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or 

BCR-ABL1 >10%
A
Perform BM cytogenetics; if loss of MCyR 
then re-escalate to 30 mga; if no loss of 
MCyR, continue to monitor according to 
SOE
B
Perform BM cytogenetics; if loss of MCyR 
then re-escalate to 15 mga; if no loss of 
MCyR, continue to monitor according to 
SOE
a
unless dose-reduction was due to AEs
14.3
Nilotinib Treatment for Patients in Cohorts C
The starting dose of study drug will be 400 mg nilotinib BID (Cohort C). Each 28-day dosing 
period is referred to as 1 cycle. Patients will be assessed for MMR and MCyR as described
above, but in contrast to the ponatinib arms, doses will not be modified according to achievement 
of response. Doses may be modified to manage AEs, as described below. 
14.4
Adverse Event Management
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 this analysis, the leading risk 
factors for serious AOEs and VTEs are cardiovascular disorders such as any history of 
myocardial infarction, coronary artery disease, coronary revascularization, and history of 
ischemic cerebrovascular disease, diabetes mellitus, hypertension, and hypercholesterolemia. 
The following supportive care recommendations are provided to address these conditions and the
risk of AOEs and VTEs for patients taking ponatinib.
Nilotinib also is associated with AOEs. Less is known about the contribution of risk factors to 
nilotinib-associated AOEs but the literature suggests that similar risk factors contribute to these 
events in the course of nilotinib therapy (Valent et al, 2015).
The following supportive care recommendations are provided to address these conditions and the
risk of AOEs and VTEs for patients taking ponatinib and the risk of AOEs for patients taking 
nilotinib. At this time, there are no data that demonstrate that these recommendations are 
effective in lessening the risk of AOEs and VTEs but they constitute standard care for patients 
with these contributing conditions. 
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 who have elevated glucose levels. The American Diabetes Association guidelines should 
be followed, and diabetic 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 2013).
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Hypertension Treatment
Hypertension (HTN) may contribute to the risk of arterial occlusive events. Patients who have 
HTN should be managed appropriately before initiating treatment. During study treatment, blood 
pressure elevations should be monitored and elevations 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). Specific management of an 
individual patient should be determined by the treating physician. Study treatment should be 
temporarily interrupted if HTN is not medically controlled (refer to Section 14.4.1.1.5 below for 
additional management recommendations). Patients may require urgent clinical intervention for 
HTN associated with confusion, headache, chest pain, or shortness of breath.
14.4.1
Management of Selected Adverse Events 
Dose reduction guidelines are outlined in Section 14.4.2.1. This section provides additional 
guidance for management of selected AEs for both ponatinib and nilotinib.
Comprehensive assessments of any study drug-related AEs (adverse drug reactions) experienced 
by the patient will be performed throughout the course of the study. Adverse drug reactions that 
may be experienced are described in the current Investigator’s Brochure for ponatinib and the 
current SmPC for Tasigna (Nilotinib SmPC, 2016) for nilotinib. 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 diagnoses should be reported on the AE page.
The current SmPC for Tasigna (nilotinib) should be used as the reference safety information for 
the nilotinib drug.
14.4.1.1
Adverse Events Common to Ponatinib and Nilotinib
14.4.1.1.1 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, 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. AOEs were more frequent with increasing age and in patients with prior history of 
ischemia, hypertension, diabetes, or hyperlipidemia.
Similar events have been observed in nilotinib-treated patients.
Arterial Occlusion 
Serious arterial occlusive AEs occurred in ponatinib-treated patients; some patients experienced
events of more than one type. Serious cardiovascular occlusive AEs included MI and coronary 
artery disease. Some patients developed CHF concurrent or subsequent to the myocardial 
ischemic event.
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Serious cerebrovascular occlusive AEs were also reported in ponatinib-treated patients. Some 
patients developed stenosis of large arterial vessels of the brain (eg, carotid, vertebral, or middle 
cerebral artery).
Serious peripheral arterial occlusive 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.
Similar events occur in nilotinib-treated patients. Ischemic cardiac AEs, peripheral arterial 
occlusive disease, and cerebral arterial events were observed in newly diagnosed patients.
Monitor and aggressively treat factors that increase cardiovascular risk, 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 adverse event of MI, unstable angina, stroke, or urgent revascularization while on study
must be discontinued from the study unless the investigator believes that the potential benefits of 
ponatinib or nilotinib treatment are likely to exceed the risks of continued treatment for that 
individual patient and the patient has no other treatment options.
Venous Thromboembolism
Serious venous thromboembolic AEs occurred in ponatinib- and nilotinib-treated patients, 
including deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and 
retinal vein thrombosis. Consider dose modification or discontinuation of treatment in patients 
who develop serious venous thromboembolic AEs. Neither ponatinib nor nilotinib should be 
restarted in patients with serious venous occlusive AEs unless the investigator believes that the 
potential benefit outweighs the risk of recurrent venous occlusions and the patient has no other 
treatment options.
14.4.1.1.2 Electrolyte abnormalities
Both ponatinib and nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, 
hypocalcemia, and hyponatremia. These should be monitored periodically and corrected during 
therapy. 
14.4.1.1.3 Neuropathy
Serious peripheral and cranial neuropathic AEs have occurred in ponatinib-treated patients. In 
clinical studies, 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. Peripheral neuropathy is also reported as a common 
adverse reaction for nilotinib. Monitor patients for symptoms of neuropathy, such as 
hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or 
weakness. Consider interrupting study treatment and evaluate if neuropathy is suspected.
14.4.1.1.4 Hepatotoxicity
Hepatotoxicity, most commonly manifested by reversible transaminase and alkaline phosphatase 
elevation and hyperbilirubinemia, has been observed with ponatinib. Elevations of 
transaminases, alkaline phosphatase, and bilirubin have also been associated with nilotinib. 
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Monitoring of hepatic function is recommended, and laboratory abnormalities should be 
managed with dose interruption and/or dose reduction according to Table 7 and Table 8.
14.4.1.1.5 Hypertension
Hypertension is associated with both ponatinib and nilotinib therapy. Blood pressure should be 
monitored at each visit. Hypertension (HTN) detected by at least 2 blood pressure measurements 
should be graded according to NCI CTCAE version 4.0, which defines HTN as a disorder 
characterized by a pathological increase in blood pressure, a repeated elevation in the blood 
pressure exceeding 140 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. 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 7 and Table 8.
14.4.1.1.6 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 and nilotinib. Most 
cases of pancreatitis or elevated pancreatic enzymes occur within the first 2 months of treatment. 
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 improved to 
grade 1 or resolved. Patients with low-grade (NCI CTCAE version 4.0 grade 1 or 2) elevation in 
amylase can be continued without dose reduction but should be monitored closely with serial 
enzyme level determinations. See Table 7 for details.
14.4.1.1.7 Hemorrhage
Hemorrhagic events have occurred in patients receiving ponatinib. Most of these events occurred 
in patients with grade 4 thrombocytopenia. Hemorrhagic events, including gastrointestinal and 
CNS hemorrhage, have also been reported in studies of nilotinib. Interrupt administration in case 
of serious or severe hemorrhage. 
14.4.1.1.8 Fluid Retention and Edema
Both ponatinib and nilotinib are 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 therapy as outlined in Table 7 and Table 8.
14.4.1.1.9 Cardiac Arrhythmias
Supraventricular tachyarrhythmias have been reported in patients treated with ponatinib or 
nilotinib. 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 7 and Table 8).
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14.4.1.1.10
Myelosuppression
Neutropenia, anemia, and thrombocytopenia have been observed in clinical studies of ponatinib 
and nilotinib in patients with CML. While myelosuppression can occur 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 or nilotinib should occur (Table 7 and Table 8). 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).
14.4.1.1.11
Tumor Lysis Syndrome (TLS)
Tumor lysis syndrome occurs in patients treated with both ponatinib and nilotinib. 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 
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.
14.4.1.1.12
Rash and/or Pruritus
Skin rashes have been commonly reported to be associated with both ponatinib and nilotinib.
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 or nilotinib, 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 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 7.
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14.4.1.1.13
Diarrhea, Nausea, and Vomiting 
Diarrhea is a common side effect of both ponatinib and nilotinib, 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, than 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 both ponatinib and nilotinib. The use of 
an antiemetic prophylactically is not recommended. However, if a patient is symptomatic,
appropriate antiemetic medications may be used as clinically indicated.
14.4.1.1.14
Constitutional Symptoms/Joint Pain
Certain constitutional symptoms such as myalgia, arthralgia, headache, weakness, fatigue, 
asthenia, and low-grade fever have been commonly reported with both ponatinib and nilotinib. In 
studies of ponatinib, these symptoms were reported mainly at the initiation of treatment, were
typically short lived (<2 weeks), and were seldom, if ever, reported beyond the first month of 
treatment. These AEs are most commonly low grade (grade 1 and 2) and are self-resolving 
without the need for dose interruption or dose reduction when they do occur. Most patients can 
be maintained on the current dose of ponatinib or nilotinib, uninterrupted, and their symptoms 
can be managed with a short course of oral analagesics, corticosteroids, and/or anti-pyretics as 
clinically indicated. If dose interruption is indicated, patients can resume the same dose of 
ponatinib or nilotinib, typically without recurrence of symptoms, once the original episode has 
improved or resolved.
14.4.1.2
Ponatinib-Specific Adverse Events 
14.4.1.2.1 Congestive Heart Failure and Left Ventricular Dysfunction
Severe congestive heart failure (CHF) and left ventricular (LV) dysfunction have been reported
in patients taking ponatinib. Patients with cardiac disease or risk factors for cardiac disease 
should be monitored carefully and any patient with signs or symptoms consistent with cardiac 
failure should be evaluated and treated. Consider discontinuation of therapy in patients who 
develop serious CHF.
14.4.1.2.2 Ocular Toxicity
Serious ocular adverse event toxicities leading to blindness or blurred vision have occurred in 
ponatinib-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and 
retinal hemorrhage have also occurred in ponatinib-treated patients. Other ocular toxicities 
include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. If decreased vision or 
blurred vision occurs, an ophthalmic examination (including fundoscopy) should be performed 
and ponatinib should be interrupted if arterial occlusive events or venous thrombotic/embolic 
events are suspected.
14.4.1.2.3 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.
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14.4.1.3
Nilotinib-Specific Adverse Events 
14.4.1.3.1 QT Prolongation
Nilotinib prolongs the QT interval, which can lead to arrhythmia and sudden death. Patients with 
prolonged QT interval at baseline are excluded from this study, as are those with uncorrected 
electrolyte imbalances such as hypokalemia or hypomagnesemia (which also prolong the QT 
interval). The use of concomitant medicines that prolong the QT interval is prohibited. Patients 
on study will undergo periodic ECG monitoring.
14.4.1.3.2 Sudden Death
Sudden deaths have been reported in patients receiving nilotinib. As noted above, patients with 
prolonged QT or with electrolyte abnormalities, which may be risk factors for sudden death, are 
excluded from the study. 
14.4.2
Dose Modifications for Adverse Drug Reactions
14.4.2.1
Dose Reduction Guidelines for Adverse Events
Dose reduction guidelines for ponatinib are summarized in Table 7, and for nilotinib in Table 8.
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. Deviation from 
these guidelines must be documented and communicated with the sponsor. 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 14.4.2.3.
Ponatinib dose reduction below 10 mg once daily is not permitted (see Table 7). Nilotinib dose
reduction below 400 mg once daily is not permitted. 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 3 and Table 
4).
Once adverse drug reactions have resolved when the guidelines below are followed, investigators 
are encouraged to re-escalate the dose of study drug (Section 14.4.2.3).
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Table 7
Dose Modifications for Adverse Drug Reactions for Patients on Ponatinib
Toxicity
Modification
Nonhematologic Toxicity
General 
Grade 1 or transient grade 2
No intervention
Grade 2 lasting ≥7 days with optimal 
care
First occurrencea at any dose level:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at current dose level 
Recurrenceb at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 15 mg 
Recurrenceb at 15 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Recurrenceb at 10 mg:
Discontinue ponatinib
Grade 3 or 4
Occurrencea at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 15 mg 
Occurrencea at 15 mg: 
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Occurrencea at 10 mg: 
Discontinue ponatinib
Pancreatitis and Elevation of Lipase
Asymptomatic grade 1 or 2 elevation 
of serum lipase
Consider interruption or dose reduction of ponatinib
Asymptomatic grade 3 or 4 elevation 
of lipase (>2 × ULN) or asymptomatic 
radiologic pancreatitis (grade 2 
pancreatitis)
Occurrencea at 30 mg:
Hold until event is ≤ grade 1 (≤ 1.5 x ULN), or has returned to baseline 
Resume at 15 mg 
Occurrencea at 15 mg: 
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Occurrencea at 10 mg:
Discontinue ponatinib
Symptomatic grade 3 pancreatitis 
(severe pain, vomiting, medical 
intervention indicated [eg, analgesia, 
nutritional support])
Occurrencea at 30 mg:
Hold until complete resolution of symptoms and after recovery of lipase 
elevation to ≤ grade 1
Resume at 15 mg 
Occurrencea at 15 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Occurrencea at 10 mg:
Discontinue ponatinib
Grade 4 pancreatitis
Discontinue ponatinib
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Toxicity
Modification
Hepatic Toxicity
Elevation of liver transaminase >3 × 
ULN (grade 2 or higher)
Occurrencea at 30 mg:
Hold ponatinib and monitor hepatic function until event is ≤ grade 1 
(≤3 ×ULN), or has returned to baseline
Resume at 15 mg 
Occurrencea at 15 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Occurrencea at 10 mg:
Discontinue ponatinib
Elevation of AST or ALT ≥3 × ULN 
concurrent with an elevation of 
bilirubin >2 × ULN and alkaline 
phosphatase < 2 × ULN
Discontinue ponatinib
LVEF/CHFc
Grade 1
No dose adjustment
Grade 2 
Monitor by ECHO
First occurrencea at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level 
Recurrenceb at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrenceb at 15 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg
Recurrenceb at 10 mg:
Discontinue ponatinib
Grade 3
Monitor by ECHO
Occurrencea at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Occurrencea at 15 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg
Occurrencea at 10 mg:
Discontinue ponatinib
Grade 4
Discontinue ponatinib
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Toxicity
Modification
Skin rash
Grade 1
No intervention
Grade 2 persistent despite optimal 
symptomatic therapy
First occurrencea at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level 
Recurrenceb at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrenceb at 15 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Recurrenceb at 10 mg:
Discontinue ponatinib
Grade 3 persistent despite optimal 
symptomatic therapy
First occurrencea at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level 
Recurrenceb at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrenceb at 15 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Recurrenceb at 10 mg:
Discontinue ponatinib
Hematologic Toxicity
Drug-Related ANC/platelets
Grade 1 or 2
No dose adjustment
Grade 3 or 4
First occurrencea at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level 
Recurrenceb at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrenceb at 15 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Recurrenceb at 10 mg:
Discontinue ponatinib
ANC = absolute neutrophil count; CHF = congestive heart failure; CT = computed tomography; LVEF = left ventricular ejection 
fraction.
a 
“Occurrence” means the first time an AE is encountered by a patient at a given dose level. 
b
“Recurrence” means the second time an AE is encountered by a patient at a given dose level. 
c
Note: CTCAE criteria should be used to interrupt or discontinue study drug for grade 2, 3, or 4 events considered to be study
drug related. 
For grade 2: LVEF <50% - 40%, grade 3: LVEF <39 - 20%, grade 4: refractory CHF or LVEF <20%.
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Dose modifications for patients being treated with nilotinib are below in Table 8.
Table 8
Modifications for Adverse Drug Reactions in Patients on Nilotinib
Toxicity
Modification
Nonhematologic Toxicity
General 
Grade 1 or transient grade 2
No intervention
Grade 2 lasting ≥7 days with optimal 
care
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at current dose level 
Recurrenceb at 400 mg BID:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Grade 3 or 4
Occurrencea at 400 mg BID:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 400 mg QD
Occurrencea at 400 mg QD: 
Discontinue nilotinib
Pancreatitis and Elevation of Lipase
Asymptomatic grade 1 or 2 elevation 
of serum amylase or lipase
Consider interruption or dose reduction of nilotinib
Asymptomatic grade 3 or 4 elevation 
of amylase or lipase (>2 × ULN) 
Occurrencea at 400 mg BID
Hold therapy and perform abdominal CT with contrast
If positive for pancreatic pathology, continue to hold therapy and repeat at 
investigator’s discretion
If CT is negative, 
Hold until event is ≤ grade 1 (≤ 1.5 x ULN), or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Grade 2 or 3 pancreatitis 
Occurrencea at 400 mg BID
Hold therapy and perform abdominal CT with contrast
If positive for pancreatic pathology, continue to hold therapy and repeat at 
investigator’s discretion
If CT is negative, 
Hold until event is ≤ grade 1 (≤ 1.5 x ULN), or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Grade 4 pancreatitis
Discontinue nilotinib
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Toxicity
Modification
Hypophosphatemia
Grade 2
Continue 400 mg BID and start phosphate supplementation
Grade 3 or 4
First occurrencea at 400 mg BID:
Hold, start phosphate supplementation until event is ≤grade 2, or has 
returned to baseline 
Resume at current dose level 
Recurrenceb at 400 mg BID:
Hold until event is ≤grade 2, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Serum creatinine
Grade 2
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at current dose level 
Recurrenceb at 400 mg BID:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Grade 3 or 4
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Hepatic toxicity (rule out hemolysis or Gilbert’s syndrome)
Grade 2 elevation of bilirubin or 
hepatic transaminases (AST and/or
ALT)
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at current dose level 
Recurrenceb at 400 mg BID:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Grade 3 or 4 elevation of bilirubin or 
hepatic transaminases (AST and/or
ALT)
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
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Toxicity
Modification
Diarrhea
Institute symptomatic therapy
Grade 3 or 4
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Vomiting
Institute symptomatic therapy
Grade 3 or 4
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Skin Rash
Institute symptomatic therapy
Grade 2
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at current dose level 
Recurrenceb at 400 mg BID:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Grade 3 or 4
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
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Toxicity
Modification
QT prolongation
QTcF > 480 ms
Hold nilotinib and correct any abnormalities of serum potassium and 
magnesium
Verify concomitant medications do not include medicines that prolong the 
QT interval or that are strong inhibitors of CYP3A4.
If a cause for QT prolongation is identified and corrected and QTcF returns 
to <450 ms and to within 20 msec of screening within 2 weeks, 400 mg 
BID may be resumed and a repeat ECG must be performed 7 days 
following the dose adjustment.
If QTcF is between 450 msec and 480 msec after 2 weeks, reduce to dose 
of nilotinib to 400 mg QD and a repeat ECG must be performed 7 days 
following the dose reduction.
If no cause is identified and QTcF returns to <450 ms within 2 weeks, 
400 mg BID may be restarted and a repeat ECG must be performed 7 days 
following the dose adjustment. 
If upon re-exposure, QTcF exceeds 480 ms, discontinue nilotinib and a 
repeat ECG must be performed 7 days following discontinuation.
LVEF
Grade 2
Monitor by ECHO
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at current dose level 
Recurrenceb at 400 mg BID:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Grade 3 
Monitor by ECHO
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD:
Discontinue nilotinib
Grade 4
Discontinue nilotinib
Hematologic Toxicity
Drug-Related ANC/platelets
≥Grade 3
First occurrencea at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at current dose level if recovery occurs within 14 days
If recovery takes more than 14 days or recurs at 400 mg BID:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrenceb at 400 mg QD: discontinue nilotinib
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Toxicity
Modification
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BID = twice daily; CT = 
computed tomography; LVEF = left ventricular ejection fraction; QD = once daily; QTc = rate-corrected QT interval; ULN = 
upper limit of normal.
a
“Occurrence” means the first time an AE is encountered by a patient at a given dose level. 
b
“Recurrence” means the second time an AE is encountered by a patient at a given dose level. 
14.4.2.2
Dose Modifications for Arterial Occlusive Events and Venous Thrombotic/Embolic 
Events
If a serious arterial occlusive or venous thrombotic/embolic adverse reaction occurs, treatment 
should be interrupted. Neither ponatinib nor nilotinib should be readministered to patients with 
AOEs or VTEs unless the potential benefit outweighs the risk of recurrent AOEs or VTEs.
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. 
14.4.2.2.1 Arterial Occlusive Events
In patients suspected of developing any arterial occlusive event, ponatinib or nilotinib should be 
immediately interrupted. 
Patients should be discontinued from ponatinib or nilotinib in the event of MI, unstable angina, 
cerebrovascular accident, TIA, or revascularization procedures. 
For all other arterial occlusive events, dose modification guidelines are outlined in Table 9 for 
ponatinib and Table 10 for nilotinib.
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Table 9
Dose Modifications for Arterial Occlusive Events for Patients on Ponatinib
Arterial Occlusion: Cardiovascular and Cerebrovascular Eventsa
Grade 1 
Consider interruption or dose reduction of ponatinib until the event resolves, then resume at 
current dose.
Grade 2
First occurrenceb at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level. 
Recurrencec at 30 mg: Discontinue ponatinib
Recurrencec at 15 mg: Discontinue ponatinib
Recurrencec at 10 mg: Discontinue ponatinib
Grade 3 and 4
Discontinue ponatinib.
Other Arterial Occlusions including Peripheral Vascular Events
Grade 1 
Consider interruption or dose reduction of ponatinib until the event resolves, then resume at 
current dose.
Grade 2 
First occurrenceb at any dose level:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level 
Recurrencec at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrencec at 15 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Recurrencec at 10 mg:
Discontinue ponatinib
Grade 3
Occurrenceb at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 15 mg 
Occurrenceb at 15 mg: 
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Occurrenceb at 10 mg: 
Discontinue ponatinib
Any recurrencec at any dose level, discontinue ponatinib
Grade 4
Discontinue ponatinib
a
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. 
b
“Occurrence” means the first time an AE is encountered by a patient at a given dose level. 
c
“Recurrence” means the second time any AOE, not necessarily recurrence of the same AOE, is encountered by a patient at 
any dose level. 
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Table 10 Dose Modifications for Arterial Thrombotic or Occlusive Events in Patients on 
Nilotinib
Arterial Occlusion: Cardiovascular and Cerebrovascular Eventsa
Grade 1 
Consider interruption or dose reduction of nilotinib until the event resolves.
Grade 2
First occurrenceb at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at current dose level 
Recurrencec at 400 mg BID:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrencec at 400 mg QD:
Discontinue nilotinib
Grade 3 and 4
Discontinue nilotinib
Other Arterial Occlusions including Peripheral Vascular Events
Grade 1 
Consider interruption or dose reduction of nilotinib until the event resolves.
Grade 2 
First occurrenceb at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at current dose level 
Recurrencec at 400 mg BID:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrencec at 400 mg QD:
Discontinue nilotinib
Grade 3
First occurrenceb at 400 mg BID:
Hold until event is ≤grade 1, or has returned to baseline 
Resume at 400 mg QD
Recurrencec at 400 mg QD:
Discontinue nilotinib
Grade 4
Discontinue nilotinib
a
Patients should be discontinued from nilotinib in the event of myocardial infarction (MI), unstable angina, cerebrovascular 
accident or transient ischemic attack (TIA), or revascularization procedures. 
b
“Occurrence” means the first time an AE is encountered by a patient at a given dose level. 
c
“Recurrence” means the second time any AOE, not necessarily recurrence of the same AOE, is encountered by a patient at 
any dose level. 
14.4.2.2.2 Venous Thromboembolic Events
Venous thromboembolic events are associated with ponatinib therapy. 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 in patients taking ponatinib, dose modification 
guidelines are outlined in Table 11.
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Table 11 Dose Modifications for Venous Thromboembolic Events for Patients on 
Ponatinib
Venous Thromboembolic Events
Grade 1 
Consider interruption or dose reduction of ponatinib until the event resolves.
Grade 2 
First occurrencea at any dose level: 
Hold until event is ≤ grade 1, or has returned to baseline
Resume at current dose level
Recurrenceb at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 15 mg 
Recurrenceb at 15 mg:
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg
Recurrenceb at 10 mg:
Discontinue ponatinib
Grade 3
Occurrencea at 30 mg:
Hold until event is ≤ grade 1, or has returned to baseline 
Resume at 15 mg 
Occurrencea at 15 mg: 
Hold until event is ≤ grade 1, or has returned to baseline
Resume at 10 mg 
Occurrencea at 10 mg: 
Discontinue ponatinib
Grade 4
Discontinue ponatinib
a
“Occurrence” means the first time an AE is encountered by a patient at a given dose level. 
b
“Recurrence” means the second time any VTE, not necessarily recurrence of the same VTE, is encountered by a patient at 
any dose level. 
14.4.2.3
Dose Re-Escalation after Resolution of Adverse Drug Reactions
The dose of ponatinib or nilotinib can be re-escalated from the reduced dose level to the 
previously administered dose level if either of the following criteria are met:
●
All ≥grade 2 nonhematologic toxicities have recovered to ≤grade 1 for at least 
1 month
●
All ≥grade 3 hematologic and nonhematologic toxicities have recovered to ≤grade 2
and are manageable with supportive therapy
Patients may receive step-wise ponatinib dose escalations (eg, 10 mg QD to 15 mg QD to 30 mg 
QD) or nilotinib dose escalation 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 AOE or VTE are not eligible for dose re-
escalation after resolution of their symptoms.
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14.5
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 last dose of study drug or an investigator/patient decision 
to discontinue, whichever occurs later) are to be reported on the appropriate eCRF for each 
patient.
14.6
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)
14.7
Prohibited Treatment(s)/Therapy
The following concurrent medications and treatments are prohibited: 
●
Other anticancer therapies, including other TKIs
●
Other investigational drugs or devices
●
Medications with a known risk of Torsades de Pointes or that prolong the QTcF 
interval (Appendix A)
●
Strong CYP3A4 inhibitors (see Appendix B)
●
Strong CYP3A4 inducers (see Appendix B)
●
Herbal preparations or related over-the-counter preparations containing herbal 
ingredients
●
Stem cell transplantation
Elective surgery requiring inpatient care should be postponed until study completion if possible.
14.8
Potential Drug Interactions
14.8.1
Potential Interactions with Ponatinib
In vitro studies demonstrate that human CYP3A4 is involved in the metabolism of ponatinib. 
Based on in vitro studies, drug-drug interactions due to either CYP inhibition or induction by 
ponatinib are highly unlikely in clinical studies using the recommended daily doses of 15 and 
30 mg. A drug interaction study in healthy subjects was performed with a strong CYP3A4 
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inhibitor (ketoconazole). Co-administration of ponatinib and ketoconazole was found to increase
ponatinib Cmax and AUC by 47% and 78%, respectively. 
Some medications associated with QT prolongation also interact with CYP3A4; medications that 
are associated with the prolongation of the QT interval may interact with ponatinib either directly 
or through a common interaction with CYP3A4. As discussed in Section 11.2 Exclusion Criteria, 
and Section 14.7 Prohibited Treatment(s)/Therapy, the use of medications that prolong the QTcF 
interval or strong inhibitors or inducers of CYP3A4 is prohibited.
14.8.2
Potential Interactions with Nilotinib
Nilotinib is metabolized by CYP3A4 and is a substrate for P-gp. Therefore, absorption and 
subsequent elimination of systemically absorbed nilotinib may be influenced by substances that 
affect CYP3A4 and/or P-gp. When administered with ketoconazole, a strong CYP3A4 inhibitor, 
nilotinib exposure increased 3-fold. When co-administered with rifampicin, a strong CYP3A4 
inducer, the Cmax and AUC of nilotinib decreased by 64% and 80%, respectively. Additional 
studies have shown insignificant changes in nilotinib concentrations when administered with 
esomeprazole, an antacid, and a H2 blocker (famotidine given 10 hours before and 2 hours after 
dose of nilotinib).
14.9
Treatment Supply
14.9.1
Formulation, Packaging, and Labeling
14.9.1.1
Ponatinib
Ponatinib investigational drug product is supplied as tablets. Each tablet contains nominally
10 mg, 15 mg or 30 mg of ponatinib active ingredient. Other ingredients are typical 
pharmaceutical excipients which consist of: lactose monohydrate, microcrystalline cellulose, 
sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and film-coating. Film 
coating is comprised of: 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 or 60 count in white HDPE bottles with foil induction seal and 
cap 
30 mg tablets: 30 count in white HDPE bottles with foil induction seal and cap
Bottle labels will bear the appropriate label text as required by governing regulatory agencies. At 
a minimum, such text will include product name, product strength, number of tablets, and lot 
number.
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14.9.1.2
Nilotinib
Commercially available nilotinib, which will be used in this study and will be supplied by the 
sponsor, is in capsule form. Each capsule contains 200 mg of nilotinib as hydrochloride 
monohydrate. Other ingredients are lactose monohydrate, crospovidone, poloxamer 188, 
colloidal anhydrous silica, magnesium stearate, gelatin, titanium dioxide, yellow iron oxide, 
shellac, and red iron oxide. Capsules are packaged as follows:
200 mg capsules: 28-count blister packs or bottles, depending on local supply form
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 capsules, and lot 
number.
14.9.2
Treatment Storage, Dispensing, and Accountability
The recommended storage condition for ponatinib and nilotinib is ≤30°C.
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, 
dosage strength, the number of tablets or capsules dispensed (with the corresponding lot 
number), and the initials of the person dispensing the drug. These logs are to be maintained by 
the study pharmacist in the pharmacy throughout the duration of the study and will be 
periodically verified by a representative of the sponsor. The investigator is responsible for 
ensuring that the patient diary card(s) and study drug provided to the patient and returned from 
the patient are accounted for and noted in source documentation.
14.9.2.1
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 study and at termination, patients must return all unused study drug supplies and the 
return of these unused study drug supplies must be recorded. Returned supplies must not be re-
dispensed.
No other utilization of ponatinib or nilotinib 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.
14.9.2.2
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 study, 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
Adverse Events
15.1.1
Adverse Event 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 preexisting condition that is temporally associated with the use of 
the study drug (eg, occurs after the first dose of study drug), is also defined as an AE.
Adverse events include:
●
Abnormal test findings
●
Changes in physical exam findings
●
Other untoward medical events, regardless of their relationship to the study drug, such 
as injury, events that require surgery, accidents, or apparently unrelated illnesses
●
Hypersensitivity
Additionally, AEs may include signs or symptoms resulting from:
●
Drug overdose
●
Drug withdrawal
●
Drug abuse
●
Drug misuse
●
Drug interactions
●
Drug dependency
●
Exposure during breastfeeding
●
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 Adverse Events 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 an SAE (see 
Section 15.2.1) requiring immediate notification to ARIAD Pharmaceuticals, Inc (ARIAD) or its 
designated representative.
15.1.4
Reporting Period
All AEs (serious, non-serious, and 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 AEs (serious, non-serious and AESIs) 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
Adverse Event Severity
The severity of AEs will be assessed according to the NCI CTCAE, v.4.0 (see Appendix C and 
the Study Reference Manual). If the AE is not defined in the CTCAE, the investigator will 
determine the severity of the event 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
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
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●
The AE is more likely explained by study drug than by another cause
Definitely Related (drug related)
●
There is evidence of exposure to study drug
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
Study Drug Action Taken
The investigator will classify the study drug action taken with regard to the AE. The action taken 
should be classified according to the following categories:
●
Dose Not Changed: Study drug dose not changed in response to an AE. 
●
Dose Reduced: Study drug dose reduced in response to an AE.
●
Drug Interrupted: Study drug administration interrupted in response to an AE. 
●
Drug Withdrawn: Study drug administration permanently discontinued in response 
to an AE. 
●
Not Applicable: Action taken regarding study drug administration does not apply.
"Not applicable" should be used in circumstances such as when the investigational 
treatment had been completed before the AE began, and there was therefore no 
opportunity to decide whether to continue, interrupt, or withdraw treatment.
15.1.8
Adverse Event Outcome
An AE should be followed until the investigator has determined and provided the final outcome. 
The outcome should be classified according to the following categories:
●
Recovered/Resolved: Resolution of an AE with no residual signs or symptoms.
●
Recovered/Resolved With Sequelae: Resolution of an AE with residual signs or 
symptoms.
●
Not Recovered/Not Resolved (Continuing): Either incomplete improvement or no 
improvement of an AE, such that it remains ongoing.
●
Fatal: Outcome of an AE is death. "Fatal" should be used when death is at least 
possibly related to the AE.
●
Unknown: Outcome of an AE is not known (eg, a subject was lost to follow-up).
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15.1.9
Expectedness
The expectedness of an SAE is assessed by the sponsor in the overall classification of SAEs for 
regulatory reportability. The current Investigator’s Brochure will be used as the reference for 
determination of expectedness and risk assessment for ponatinib. The current SmPC for Tasigna
(nilotinib) (Nilotinib SmPC, 2016) will be used as the reference for determination of 
expectedness for nilotinib.
15.2
Serious Adverse Events and Adverse Events of Special Interest
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 Event Definition
The investigator or the sponsor may determine the seriousness of an AE based on the following.
An AE is considered an SAE if at least one of the following conditions applies:
●
Death: An AE that results in death is any patient death within 30 days of the last dose 
of study drug administration. The cause of death or AE that resulted in a fatal outcome 
is the SAE.
●
Life-threatening: An AE that places the patient, in the view of the investigator or the 
sponsor, at immediate risk of death from the event as it occurred (ie, this does not 
include an event that, had it occurred in a more severe form, might have caused death).
●
Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions: 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 (ie, 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.
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15.2.1.2
Progression of the malignancy under study
Worsening of signs and symptoms of the malignancy under study (including signs and symptoms 
of progression) 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.
15.2.1.3
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 is 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)
Hospitalization or prolongation of hospitalization in the absence of a precipitating AE is not in 
itself an SAE. Examples include:
●
Social admission (eg, patient has no place to sleep)
●
Protocol-specified admission during a clinical study (eg, for a procedure required by 
the study protocol)
●
Optional admission not associated with a precipitating AE (eg, for elective surgery 
that was planned prior to study enrollment [appropriate documentation is required for 
these cases])
15.2.2
Adverse Events of Special Interest
Arterial occlusive and venous thrombotic/embolic events have been identified as AESIs for 
ponatinib and will be evaluated for nilotinib as well in this study. These include arterial and 
venous thrombotic and occlusive adverse events that meet the criteria for SAEs, defined above in 
Section 15.2.1, as well as those AEs that do not meet the SAE criteria. These events have also 
been observed for nilotinib.
AESIs require ongoing monitoring by investigators and rapid identification and communication 
by the investigator to the sponsor. All AESIs, regardless of seriousness, must be reported to the 
sponsor within 24 hours by completion of the AE eCRF. The sponsor has determined that the 
events listed below are AESIs (see Section 15.2.3 for reporting responsibilities).
●
Myocardial infarction (MI): The Third Universal Definition of Myocardial Infarction 
(Thygesen et al, 2012) is used to define MI (see below)
●
Angina (newly diagnosed or worsening of existing or unstable angina)
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●
Coronary artery disease (CAD) (newly diagnosed or worsening of existing CAD) or 
symptoms that may reflect cardiovascular disease (Thygesen et al, 2012)
●
Cerebrovascular ischemic disease including ischemic or hemorrhagic stroke, vascular 
stenosis, TIA, cerebrovascular occlusive disease documented on diagnostic 
neuroimaging, or symptoms that may reflect cerebrovascular disease (Easton et al, 
2009)
●
New onset or worsening of peripheral artery occlusive disease (eg, of the renal artery, 
mesenteric artery, or femoral artery) or symptoms that may reflect peripheral vascular 
disease 
●
Retinal vascular thrombosis, both venous and arterial
●
Venous thromboembolism that could result in significant compromise of organ 
function or other significant consequences (eg, pulmonary embolism, portal vein 
thrombosis, or renal vein thrombosis), or symptoms that may reflect venous 
thrombosis
15.2.3
Reporting SAEs and AESI
The investigator or investigator’s designee must notify ARIAD Pharmacovigilance and Risk 
Management or its designated representative immediately (within 24 hours) after becoming 
aware of an SAE or AESI (either serious or nonserious). This timeframe also applies to 
additional new information (follow-up) on previously reported SAEs or AESIs.
15.2.4
Information to be Provided by the Investigator for an SAE or AESI
The sponsor requires all of the following information about the patient and the event:
●
Investigator identification
●
Patient identification code (eg, sex, age, date of birth)
●
Information on study drug (eg, study drug name, assigned cohort, start/stop date, dose 
and frequency of study drug administered, most recent administered dose)
●
Description of event
In addition to the above information, the sponsor will require the investigator’s assessment of the 
following:
●
Severity of the SAE or AESI
●
Relationship of the SAE or AESI to the study drug
●
Outcome of the SAE or AESI
15.2.5
Follow-up Information on an SAE or AESI
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 or AESIs, 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 
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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 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 or AESIs
Routine follow-up should be conducted through and including 30 days after the last 
administration of assigned study treatment in the study or the investigator/patient decision to 
discontinue treatment, whichever occurs later, in all patients in order to monitor for the 
occurrence of SAEs or AESIs. If an SAE or AESI continues after the 30-day evaluation period, 
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.
15.3
Expedited Reporting of SUSARs
ARIAD, as study sponsor, is responsible for reporting suspected, unexpected and 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, 
ARIAD, 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.
15.4
Other Safety Issues
15.4.1
Pregnancy, Contraception and Breastfeeding
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 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
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
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 participant)
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 of 
childbearing potential should be advised to take a pregnancy test if their period is late, and to 
inform their investigator of the result promptly.
If a patient is confirmed pregnant during the study, 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 the Pregnancy Form. Initial information 
regarding a pregnancy must be immediately forwarded to ARIAD Pharmacovigilance and Risk 
Management 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 study. Consent to report information regarding these pregnancy outcomes should be 
obtained from the female partner.
It is not known whether ponatinib passes into the breast milk. Female patients should not 
breastfeed babies during ponatinib treatment. 
15.4.2
Overdose
An overdose is defined as the accidental or intentional ingestion or infusion of any dose of study 
treatment that exceeds the dose described in the protocol. All overdoses should be recorded on 
the Overdose Form and forwarded to ARIAD Pharmacovigilance and Risk Management, or its 
designated representative, within 24 hours. An overdose should be reported even if it does not 
result in an AE. If an overdose results in an AE, the AE should be reported on the AE eCRF. The 
dose administered should be documented on the Study Drug Administration eCRF.
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 or nilotinib.
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In the phase 2 portion, eligible CP-CMP patients will receive ponatinib 15 mg QD. Upon 
achievement of MMR, patients will have their daily dose of ponatinib reduced to 10 mg. In the 
phase 3 portion, eligible CP-CML patients will be randomized to one of 3 cohorts (Cohort A: 
30 mg ponatinib QD, Cohort B: 15 mg ponatinib QD, Cohort C: 400 mg nilotinib BID) in a 1:2:1 
fashion. Upon achievement of MMR, patients assigned to ponatinib 30 mg will have their daily 
dose of ponatinib reduced to 15 mg, and patients assigned to ponatinib 15 mg will have their 
daily dose of ponatinib reduced to 10 mg. In the phase 3 portion, patients will be stratified by age 
at baseline (≥60 years versus <60 years) and best response to prior imatinib therapy (CCyR or 
≤1% BCR-ABL1IS or better yes/no).
16.2
Analysis Populations
Intention to Treat (ITT) Population: The ITT population includes all patients who are treated
in (phase 2) or randomized to (phase 3) the study. Patients will be analyzed according to the 
treatment to which they were assigned. Patients who are subsequently determined to be assigned 
to an incorrect stratum will be analyzed according to the stratum to which they were assigned at 
randomization.
Full Analysis Set (FAS): The Full Analysis Set includes all patients in the ITT population as 
defined above who have b2a2/b3a2 BCR-ABL1 transcript types at study entry (patients for 
whom a BCR-ABL1IS ratio can be determined).
Treated Population: The treated population for each cohort includes all patients who have 
received at least 1 dose of study drug. The primary analyses of safety will be based on the treated 
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 anti-cancer therapy concurrent with study drug, and administration of 
incorrect dose (eg, 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 in Phase 2 and Each Cohort in Phase 3
●
Major molecular response by 12 months for each cohort
Key Secondary Endpoints to be Estimated (Phase 2) and Formally Tested Statistically
(Phase 3)
Molecular Key Secondary Efficacy Endpoints
●
MR3/MMR at 24 months
●
MR4 at 24 months
●
MR4.5 at 24 months
●
MR1 (≤10% BCR-ABL1IS) at 3 months 
Cytogenetic Key Secondary Efficacy Endpoints
●
MCyR by 12 months
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16.4.2
Phase 3
Based on accumulating data from the 15 mg cohort in phase 2, the phase 3 design (including 
number of ponatinib cohorts) and/or sample size may be amended prior to enrollment of patients 
into the phase 3 portion of the study.
The primary endpoint for this study will be MMR rate by 12 months. The primary analysis of the 
primary endpoint of MMR will be performed using a 2-sided alpha = 0.024 for each comparison.
A sample size of 150 patients in each Cohort A and C (ponatinib 30 mg and nilotinib, 
respectively) will distinguish a favorable MMR rate of 45% for ponatinib from a null or an 
uninteresting MMR rate of 25% for nilotinib with a nominal 90% power to detect an 
improvement in MMR of 20%. 
The sample size of 300 patients in Cohort B and 150 patients in Cohort C will distinguish a 
favorable MMR rate of 40% for ponatinib from a null or an uninteresting MMR rate of 25% for 
nilotinib with approximately 80% power to detect an improvement in MMR of 15%. 
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, will be provided in the SAP.
16.5.1.1
Molecular Response Definitions
Major molecular response (MMR) is defined as a ≤0.1% ratio of BCR-ABL1 to ABL1
transcripts on the international scale (BCR-ABL1IS), measured by real-time quantitative PCR.
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.
Molecular response: ≤1% BCR-ABL1IS, MR4, and MR4.5 are defined as ≤1%, ≤0.01%, and 
≤0.0032% BCR-ABL1IS, respectively. In the case of undetectable BCR-ABL1 transcript levels, a 
minimum of 10,000 and 32,000 ABL1 copies must be present in order to be classified as MR4 
and MR4.5, respectively.
Time to MMR is defined as the interval between the date of first dose (phase 2) or
randomization date (phase 3) and the first date at which the criteria for MMR are met.
Duration of ≤1% BCR-ABL1IS/MMR/MR4/MR4.5 is defined as the interval between the first 
assessment at which the criteria for ≤1% BCR-ABL1IS/MMR/MR4/MR4.5 are met until the 
earliest date at which loss of ≤1% BCR-ABL1IS/MMR/MR4/MR4.5 occurs (see below), or the 
criteria for progression (see Section 16.5.1.4) are met. Patients remaining in/at ≤1% BCR-
ABL1IS/MMR/MR4/MR4.5 will be censored at the last date at which the criteria for ≤1% BCR-
ABL1IS/MMR/MR4/MR4.5 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 progression to AP- or BP-CML, or death due to CML. 
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Loss of ≤1% BCR-ABL1IS is defined as 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 
progression to AP- or BP-CML, 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 progression to AP- or BP-CML, 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 progression to AP- or BP-CML, or death due to CML.
16.5.1.2
Cytogenetic Response Definitions
Rate of major cytogenetic response (MCyR) by 12 months is the proportion of patients 
achieving CCyR or PCyR at any time within 12 months after randomization.
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 

Complete cytogenetic response (CCyR): 0% Ph+ metaphases

Partial cytogenetic response (PCyR): >0% to 35% Ph+ metaphases
Rate of complete cytogenetic response (CCyR) by 12 months is the proportion of patients 
achieving CCyR at any time within 12 months after first dose date (phase 2) or randomization
(phase 3). Additionally, CCyR at 12 months will be calculated using only cytogenetic criteria.
Additional analyses will be performed that will consider patients who achieve ≤1% BCR-
ABL1IS to have achieved CCyR.
Time to MCyR is defined as the interval from first dose date (phase 2) or randomization (phase 
3) until the criteria for MCyR are first met.
Duration of MCyR is defined as the interval between the first assessment at which the criteria 
for MCyR are met until the earliest date at which loss of MCyR occurs, or the criteria for 
progression (Section 16.5.1.4) are met. Patients remaining in response will be censored at their 
latest assessment (either cytogenetic or molecular).
Loss of MCyR is defined as a single BM assessment with Ph+ metaphases >35% after 
achievement of MCyR (CCyR or PCyR or ≤1% BCR-ABL1IS)
Loss of CCyR is defined as either an increase in the Ph+ metaphases in BM to >0% in a single 
BM assessment, defined in Section 16.5.1.1.
Loss of PCyR is defined as an increase in the Ph+ metaphases in BM from >0% to 35% to >35% 
in a single BM assessment.
16.5.1.3
Hematologic Response Definitions
Complete hematologic response (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.
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CHR is defined as achieving all of the following measurements:
●
White blood cells (WBC) ≤institutional ULN
●
Platelets <450 x 109/L
●
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 x 109/L
●
Platelet count that rises to ≥600 x 109/L
●
Progressing splenomegaly 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
Progression-free survival (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 AP- or 
BP-CML), or death due to any cause, censored at the last response assessment.
Progression to AP-CML 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 x 109 platelets/L in peripheral blood unrelated to therapy
or
●
Cytogenetic, genetic evidence of clonal evolution
and
●
No extramedullary disease
Progression to BP-CML is defined as:
●
≥30% blasts in peripheral blood or bone marrow
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or
●
Extramedullary disease other than hepatosplenomegaly
Overall survival (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 to be alive.
16.5.2
Primary Endpoint Analysis
For the phase 2 portion, the primary analysis of the primary endpoint will be performed using an 
exact binomial confidence interval for the MMR rate by 12 months on the ITT population. A 
sample size of 75 patients will distinguish a favorable MMR by 12 month rate of 40% from a 
null or an uninteresting MMR rate of 25%, with a nominal 80% power and a 2-sided type I error 
rate of 0.05 (equivalent to a 2-sided 0.025). Using the 25% boundary for MMR, 27 or more 
MMR responders will be needed for a lower limit of the 2-sided exact 95% CI for the MMR rate 
to exceed 25%.
For the phase 3 portion, the primary analysis of the primary endpoint will be performed using a 
stratified Cochran Mantel-Haenszel (CMH) test. The phase 3 portion will be stratified by age at 
baseline (≥60 versus <60 years) and best response to prior imatinib therapy (CCyR or 
≤1% BCR-ABL1IS or better, yes/no) to compare the MMR rate by 12 months between patients 
receiving either dose level of ponatinib (initial dose: 30 mg once daily [QD] or 15 mg once daily 
[QD]) and patients receiving nilotinib (initial dose: 400 mg BID) and will follow a testing 
procedure to ensure an overall 2-sided Type I error rate of <0.05 (see Section 16.11).
The primary analysis for phase 3 will be based on the Full Analysis Set (all patients randomized 
to a treatment group for whom a BCR-ABL1IS ratio can be determined at baseline). A sensitivity 
analysis of the primary endpoint will be performed on the ITT population, with patients not 
evaluable treated as nonresponders.
16.5.2.1
Data Handling Rules for the Primary Analyses of the Primary Endpoint
The following patients will be analyzed as responders in the primary analysis:
●
Patients who meet the criteria for MMR by 12 months after randomization
All other patients will be analyzed as non-responders in the primary analysis, including treated
(phase 2) or randomized (phase 3) patients without follow-up (and any patients who meet the 
criteria for MMR at study entry).
16.5.3
Secondary Efficacy Endpoint Analyses
16.5.3.1
Key Secondary Efficacy Endpoints
For the phase 2 portion, key secondary endpoints will be performed on the ITT population.
Sensitivity analyses of molecular key secondary endpoints may be performed on the Full 
Analysis Set. Note that at some analysis time points not all key secondary endpoints will be 
mature (eg, molecular key secondary endpoints will not be mature at interim analysis or 12 
month analysis – see Section 16.5.3.3 for the statistical handling of these key secondary 
endpoints). In addition to the final analyses of key secondary endpoints, an interim analysis will 
be performed after 50 patients reach 6 months of treatment (see Section 16.11.1).
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For the phase 3 portion, formal statistical analyses will be performed on the following molecular 
key secondary endpoints (MR3/MMR at 24 months; MR4 at 24 months; MR4.5 at 24 months, 
MR1 at 3 months) and key secondary cytogenetic endpoints (CCyR at 12 months; MCyR by 
12 months). Comparisons of molecular key secondary endpoints and cytogenetic key secondary 
endpoints will be performed separately. Analyses of molecular key secondary endpoints will be 
performed on the Full Analysis Set. Analyses of cytogenetic key secondary endpoints will be 
performed on the ITT population. For each dose comparison (within a given set of key secondary 
endpoints) that is significant in the primary analysis, formal statistical comparisons of key 
secondary endpoints will be performed using a closed testing procedure according to the ranking 
below and will take place only if comparisons of all other secondary efficacy endpoints with a 
smaller rank are significant at the 2-sided 0.025 level (molecular endpoints and cytogenetic 
endpoints will be tested separately, thus the significance level has been halved). Note that at 
some analysis time points not all key secondary endpoints will be mature (eg, molecular key 
secondary endpoints will not be mature at interim analysis or 12 month analysis – see 
Section 16.5.3.3 for the statistical handling of these key secondary endpoints). Each sequence of 
key efficacy endpoints will be tested separately for each treatment comparison (Cohort A versus 
Cohort C, Cohort B versus Cohort C), within the sets of molecular and cytogenetic endpoints, 
respectively.
Molecular Key Secondary Efficacy Endpoints to be Formally Tested Statistically in Phase 3
●
MR3/MMR at 24 months
●
MR4 at 24 months
●
MR4.5 at 24 months
●
MR1 (≤10% BCR-ABL1IS) at 3 months 
Cytogenetic Key Secondary Efficacy Endpoints to be Formally Tested Statistically in 
Phase 3
●
CCyR at 12 months
●
MCyR by 12 months
The additional key secondary efficacy endpoints to be tested are listed below. These will not be 
subject to formal statistical testing.
●
Molecular response rates: ≤1% BCR-ABL1IS, MR3/MMR, at 3-month intervals, and
MR4, MR4.5 at 3-month intervals other than 24 months
●
CCyR by 12 months
●
Time to response
●
Duration of response:
i.
≤1% BCR-ABL1IS and MMR at 12, 18, and 24 months 
ii.
MCyR at 12 and 24 months
iii.
Duration of response in responders
iv.
Duration of therapy
●
Progression-free survival 
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●
Overall survival 
16.5.3.2
Analysis Methods for Secondary Efficacy Endpoints
For the phase 2 portion, the analysis of the secondary efficacy endpoints of molecular response 
rates, cytogenetic response rates, CHR rate and rate of progression to AP or BP CML will be 
performed using an exact binomial confidence interval on the ITT population. For the phase 3 
portion, the analysis of the secondary efficacy endpoints of molecular response rates, cytogenetic 
response rates, CHR rate and rate of progression to AP- or BP-CML will be performed using a 
stratified CMH test. For both phases, PFS and OS will be analyzed using the Kaplan-Meier 
method. Descriptive statistics will be provided for duration of response in responders and 
duration of therapy.
For the phase 3 portion, analyses of molecular response rates will be performed on the Full 
Analysis Set. All other analyses will be performed on the ITT population.
16.5.3.3
Data Handling Rules for Secondary Efficacy Endpoint Analyses
For the secondary endpoints of cytogenetic responses, at any given cytogenetic assessment after 
baseline, if fewer than 20 metaphases are examined, the rules in Table 12 will apply to the 
determination of MCyR:
Table 12 Determination of MCyR by Cytogenic Assessment
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
Ph+ = Philadelphia chromosome positive; PCyR = partial cytogenetic response
Determination of CCyR by cytogenetic assessment will require at least 20 metaphases examined.
For the analyses of secondary endpoints of MCyR, CCyR, ≤1% BCR-ABL1IS, MR4.5, MR4, 
and CHR, if patients do not have a baseline assessment or post-baseline response assessment, the 
patients will be considered as non-responders. Patients who meet the criteria for response at 
baseline will also be analyzed 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 Statistical Analysis Plan [SAP]). Subgroups may 
include:
●
Age (<60, ≥60 years)
●
Gender
●
Race
●
Geographic region 
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●
T315I mutation history (Yes, No)
●
Best response to prior imatinib therapy (CCyR, ≤1% BCR-ABL1IS or better)
●
Other disease-related prognostic factors
16.6
Safety Analysis (Phase 2 and Phase 3)
All patients receiving at least one 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 treatment-
emergent adverse events (TEAEs) and all AEs will be listed.
16.6.1
Analysis of Arterial Occlusive and Venous Thrombotic/Embolic Events 
Number and percentages of patients who develop arterial occlusive and venous 
thrombotic/embolic events will be summarized for the single arm in phase 2 and each cohort in 
phase 3. The arterial occlusive and venous thrombotic/embolic events will be categorized as 
follows:
●
Arterial occlusive events
i.
Cardiovascular occlusive events 
ii.
Cerebrovascular occlusive events
iii.
Peripheral vascular occlusive events
●
Venous thromboembolic events
Details for classification of specific events as arterial occlusive and venous thrombotic/embolic 
events are given in Section 14.4.1.1.
The primary analysis of arterial occlusive events and venous thromboembolic events will be an 
exposure-adjusted incidence rate, as follow-up may differ among the cohorts. The exposure-
adjusted incidence rate is calculated as number of patients with the AE divided by total treatment 
exposure time. Further description of methods of calculating exposure time will be documented 
in the statistical analysis plan.
The following additional descriptive analyses will be performed to characterize arterial occlusive 
and venous thrombotic/embolic events:
●
Time to onset: calculated as date of first arterial occlusive or venous 
thrombotic/embolic adverse event – first dose date + 1
●
Dose at onset: dose of ponatinib or nilotinib taken immediately prior to onset of first 
arterial occlusive or venous thrombotic/embolic event.
Detailed data handling rules will be specified in the SAP for incomplete or missing onset dates.
Baseline risk factors for the occurrence of arterial occlusive or venous thrombotic/embolic events 
will be evaluated for all patients, and will include:
●
History of arterial occlusive disease 
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●
History of other cardiovascular disease
●
History of venous thromboembolism
●
Hypertension
●
History of diabetes/hyperglycemia
●
History of smoking
●
Obesity
●
History of hyperlipidemia
●
Age
●
Gender
●
Other risk factors 
16.6.2
Analysis of Categories of Adverse Events
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 the single arm in phase 2 and each cohort in phase 
3. 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 treatment-emergent AEs 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 shift in laboratory parameters from 
baseline to worst post-baseline value in terms of CTCAE 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.
16.6.4
Analysis of Treatment Discontinuation Rate due to AEs, Dose Reductions, and 
Dose Interruptions
For the single arm in phase 2 and each dose cohort in phase 3, 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 to 
characterize length of dose interruptions and reductions.
16.7
Exposure-Response Analysis 
Analyses of the relationship between ponatinib exposure and efficacy (MMR, MCyR, and 
≤1% BCR-ABL1IS) and safety measures (including at a minimum AOEs and VTEs and events 
occurring in at least 30 patients), will be undertaken. Logistic regression models and Cox 
regression models will be used for the binary outcomes, with exposure as a time varying 
covariates. Further detail will be summarized in the SAP.
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s of Use
the Applicable Terms f Use


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for comparisons of Cohorts A and B to Cohort C, with a dose considered significant if the 
2-sided p-value is <0.024. 
Impact on Study Conduct and Secondary Endpoints (Phase 3)
The phase 3 design may be modified based on accumulating data from the 15 mg cohort in 
phase 2 before enrolling new patients.
It is expected that the study will be fully enrolled prior to the conduct of the interim analysis and 
the interim analysis will not affect enrollment or continuity of therapy. In the event that the study 
crosses the efficacy boundary at the interim analysis, we would expect to continue patients on 
their randomized treatment arm to allow for continued assessment of other time points and the 
secondary efficacy endpoints. The key secondary efficacy endpoints will not be mature at the 
time of the interim analysis (see Section 16.5.3.1). For each dose comparison that is significant 
in the primary analysis, these endpoints will be considered significant if they reach a nominal 
significance level of 0.001 two-sided, otherwise they will be tested at 0.025 two-sided when 
mature for the molecular and cytogenetic sets of key secondary endpoints, respectively, in the 
order defined in the closed testing procedure described in Section 16.5.3.3. Additionally, at the 
time the primary analysis becomes significant, conditional power will be calculated for the 
secondary endpoints that have not yet matured. The main conditional power calculations will 
assume the observed effect continues, and sensitivity analyses will also be conducted using the 
boundaries of 80% and 95% confidence intervals on the observed effect. Because these 
confidence intervals will likely be wide, it would be expected that the conditional power might 
vary widely. 
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 personnel or its designee and the 
investigator will review the protocol, the Investigator's Brochure, the electronic Case Report 
Forms (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 visiting the site and by contacting the site by telephone.
During the visits, 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
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●
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 (sponsor, IRB/EC, or
other investigators) who accepts the responsibility. The sponsor must be notified in writing and 
must agree to the change in advance. An updated FDA Form 1572 will be filed with the sponsor 
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)
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 (ie, list the investigator’s name, the protocol number and title, the date of 
the protocol and informed consent document, and the date of approval of the protocol and the 
informed consent document). Any advertisements used to recruit patients should also be 
reviewed by the IRB/EC. The sponsor will not ship clinical supplies until a signed approval letter 
from the IRB/EC has been received and a 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.
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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 gives to the investigator, and all information 
generated in connection with the study, shall be kept confidential and shall not be disclosed to a 
third party without the prior written consent of the sponsor or published prior to the sponsor’s 
review in accordance with the terms of the Clinical Trial Agreement.
18.4
Study Committees
18.4.1
Data Monitoring Committee
An independent Data Monitoring Committee (DMC), consisting of 3 to 5 members not 
associated with the conduct of the study, will be established for this study. The DMC 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 will make 
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. An independent committee may be installed to assess cardiovascular events and 
other related safety concerns as appropriate.
18.4.2
Study Steering Committee
A study 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 study steering committee will include clinicians expert in 
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the clinical care and investigation of the targeted patient population, and will also include 
sponsor representatives. In addition to general study oversight, it 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 study 
steering committee may make recommendations for the sponsor’s consideration based on 
periodic review.
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
Study 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, 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). Study 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
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●
Protocol violations
●
Inaccurate or incomplete data
●
Unsafe or unethical practices
●
Questionable safety of the study drug
●
Suspected lack of efficacy of the study drug
●
Administrative decision
In the event of the termination of the Study, by either the sponsor or an investigator:
●
The investigator will return all study drugs, eCRFs, and related study materials to the 
sponsor
●
A written statement describing why the study was terminated prematurely will be 
provided by either the sponsor or the investigator
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 non-approval 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 study. 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 studies of drugs (including biological products) and medical devices subject to 
FDA regulations for any disease or condition. The International Committee of Medical Journal 
Editors requires study registration as a condition for publication of research results generated by 
a clinical study (http://www.icmje.org [Accessed: 21 March 2015]).
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 
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(“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 ARIAD’s proprietary interests, the 
institution will submit to ARIAD 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 ARIAD. If 
ARIAD 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 ARIAD receives the Proposed Disclosure to permit ARIAD to file patent 
applications. If ARIAD believes that any Proposed Disclosure contains Confidential Information, 
ARIAD 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, ARIAD 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 ARIAD 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
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American Diabetes Association, Position Statement 2013
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Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the 
management of chronic myeloid leukemia: 2013. Blood. 2013; 122(6): 872-84.
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York, NY, USA. Available at: 
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n_med_001613.jsp&mid=WC0b01ac058001d124. [Accessed: 25 March 2015].
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 
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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 
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Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinib-resistant or -
intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia. 2012;26(5):959-
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Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or imatinib-intolerant 
patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase 
II study. Leukemia. 2013;27(1):107-112; doi:10.1038/leu.2012.181.
Gleevec® (imatinib) tablets for oral use. Prescribing Information. Novartis Pharmaceuticals 
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http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021588s035lbl.pdf. [Accessed: 
24 March 2015].
Glivec® (imatinib) hard capsules. Summary of Product Characteristics. MAH: Novartis 
Europharm Limited, Camberley, UK. February 2015. Available at: 
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_Product_Information/human/000406/WC500022207.pdf and 
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http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000406/huma
n_med_000808.jsp&mid=WC0b01ac058001d124. [Accessed: 24 March 2015].
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predictive for long-term progression-free and overall survival in chronic myeloid leukemia 
(CML). Leukemia 2012;26:2096-2102.
Henk HJ, Woloj M, Shapiro M, et al. Real-world analysis of tyrosine kinase inhibitor treatment 
patterns among patients with chronic myeloid leukemia in the United States. Clin Ther. 
2015;37(1):124-33. doi: 10.1016/j.clinthera.2014.10.019. Epub 2014 Nov 22. 
Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL mutations on response to 
nilotinib in patients with chronic myeloid leukemia in chronic phase. JCO; 2009:27(25):4204-10.
Iclusig® (ponatinib) tablets for oral use. Prescribing Information. ARIAD Pharmaceuticals, Inc. 
Cambridge, MA, USA. 2016 Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203469s022lbl.pdf. [Accessed: 18
January 2017].
Iclusig® (ponatinib) film-coated tablets. Summary of Product Characteristics. MAH: ARIAD
Pharmaceuticals Ltd., Surrey, UK. 2016. Available at: 
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_Product_Information/human/002695/WC500145646.pdf [Accessed: 18 January 2017].
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. 
Kantarjian H, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients whith chronic myeloid 
leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. 
Blood. 2011; 117(4):1141-45.
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.. Presented at the 54th Annual Meeting of the American Society of Hematology. Atlanta, 
GA. December 8-11, 2012. Abstract 2495.
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.
Muller MC, Baccarani M, Deininger MW, et al. Achieving early landmark response is predictive 
of outcomes in heavily pretreated parients with chronic phase chronic myeloid leukemia 
(CP-CML) treated with ponatinib. Presented at the 56th Annual Meeting of the American 
Society of Hematology. San Francisco, USA. Decemeber 6-0, 2014. Abstract 518.
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Protocol Version 3.0
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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.
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. 
Sprycel® (dastinib) tablets for oral use. Prescribing Information. Bristol-Myers Squibb Company, 
Pinceton, NJ, USA. 2015. Available at: 
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24 March 2015].
Sprycel® (dastinib) film-coated tablets. Summary of Product Characteristics. MAH: Bristol-
Myers Squib Pharma EEIG, Uxbridge, UK. February 2015. [Accessed: 24 March 2015].
Tasigna® (nilotinib) capsules. Prescribing Information. Novartis Pharmaceuticals Corporation, 
East Hanover, NJ, USA. June 2010. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022068s004s005lbl.pdf. [Accessed: 
18 January 2017].
Tasigna® (nilotinib) hard capsules. Summary of Product Characteristics. MAH: Novartis 
Europharm Limited, Camberley, UK. 2016. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000798/WC500034394.pdf. [Accessed: 18 January 2017].
Thygesen K, Alpert JS, Jaffe AS. Third Universal Definition of Myocardial Infarction. 
Circulation. 2012;126:2020-2035.
Valent P, Hadzijusufovic E, Schernthaner GH,et al. Vascular safety issues in CML patients 
treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125(6):901-6. 
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23
APPENDICES
APPENDIX A
Drugs with a Risk of Torsade de Pointes
Four categories of QT-prolonging drugs that may be used as a guide for this protocol can be 
accessed at http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/ [Accessed: 
21March 2014]. 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 Torsade de Pointes are the only category of QT-prolonging drugs 
that are prohibited in this study.
Note: The website is only to be used as a guideline and is not comprehensive. It is the 
investigator’s responsibility to ensure that any drugs under consideration have not been newly 
identified as causing Torsade de Pointes.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


ARIAD Pharmaceuticals, Inc.
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EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 108 of 109
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 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx [Accessed 21 March 2015]. 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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


ARIAD Pharmaceuticals, Inc.
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EudraCT Number: 2015-001318-92
Protocol Version 3.0
10 March 2017
Page 109 of 109
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 v.4.0) can be found on the following website:
http://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).
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 2/3 Open-label Study to Evaluate Safety and Efficacy of Ponatinib, Followed by a 
Randomized Study of Ponatinib Versus Nilotinib in Patients with Chronic Myeloid Leukemia in 
Chronic Phase (CP-CML) Resistant to Imatinib
NCT Number: NCT02627677
SAP Approve Date: 31 July 2016
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information or 
company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


ARIAD Pharmaceuticals, Inc.
(a wholly-owned subsidiary of Takeda Pharmaceutical 
Ltd. Co.)
AP24534-15-303
Statistical Analysis Plan (SAP)
Version 2.0 23 July 2020
Page 1
STATISTICAL ANALYSIS PLAN (SAP)
FOR
AP24534-15-303
PROTOCOL TITLE: A Randomized, Open-Label Study of Ponatinib Versus Nilotinib in Patients 
with Chronic Myeloid Leukemia in Chronic Phase Following Resistance to Imatinib
PROTOCOL NUMBER:
AP24534-15-303
IDENTIFIER:
ClinicalTrials.gov:
NCT02627677
EudraCT Number:
2015-001318-92
SPONSOR:
ARIAD Pharmaceuticals, Inc.
(a wholly-owned subsidiary of Takeda Pharmaceutical Ltd. Co.)
40 Landsdowne Street
Cambridge, MA 02139
Telephone: (617) 679-7000
ORIGINAL ISSUE DATE:
Version 1.0 31 July 2016
REVISION/AMENDMENT HISTORY:
Protocol Version
SAP Version
SAP Date
Original Protocol Version 1.0
Protocol Version 2.0
Original SAP Version 1.0
31 July 2016
Protocol Version 2.0
SAP Version 2.0
23 July 2020
n-Commercial Use Only and Subject to the Applicable Terms of Use
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AP24534-15-303
Statistical Analysis Plan (SAP)
Version 2.0 23 July 2020
Page 2
TABLE OF CONTENTS
List of Abbreviations...................................................................................................................4
1
Introduction.....................................................................................................................6
2
Study Objectives and Endpoints ......................................................................................6
2.1
Study Objectives............................................................................................................6
2.1.1
Primary Objective....................................................................................................6
2.1.2
Key Secondary Objectives .......................................................................................6
2.1.3
Other Secondary Objectives.....................................................................................6
2.1.4
Exploratory Objectives.............................................................................................7
2.2
Study Endpoints.............................................................................................................7
2.2.1
Primary Endpoint.....................................................................................................7
2.2.2
Key Secondary Endpoints........................................................................................7
2.2.3
Other Secondary Endpoints......................................................................................7
2.2.4
Exploratory Endpoints .............................................................................................8
3
Study Design...................................................................................................................8
3.1
Study Design .................................................................................................................8
3.1.1
Schedule of Events...................................................................................................8
3.2
Blinding.........................................................................................................................9
3.3
Randomization...............................................................................................................9
3.4
Study Treatment.............................................................................................................9
3.4.1
Ponatinib Treatment for Patients in Cohorts A and B ...............................................9
3.4.1.1
Mandatory Dose Reduction for Response Scheme in Ponatinib Cohorts A 
and B.................................................................................................................9
3.4.1.2
Loss of Response after Dose Reduction for MMR or MCyR in Cohorts A 
and B...............................................................................................................11
3.4.2
Nilotinib Treatment for Patients in Cohort C..........................................................11
3.5
Determination of Sample Size......................................................................................12
4
Statistical Analyses and Methods...................................................................................12
4.1
General Considerations................................................................................................12
4.2
Analysis Populations....................................................................................................13
4.3
Patient Disposition.......................................................................................................13
4.4
Major Protocol Deviations ...........................................................................................13
4.5
Demographics and Baseline Characteristics .................................................................13
4.6
Concomitant Medications ............................................................................................14
4.7
Efficacy Analyses ........................................................................................................14
4.7.1
Efficacy Assessments.............................................................................................14
4.7.2
Definitions of Efficacy Endpoints ..........................................................................14
4.7.2.1
Molecular Response Definitions ......................................................................14
4.7.2.2
Cytogenetic Response Definitions....................................................................15
4.7.2.3
Hematologic Response Definitions ..................................................................16
4.7.2.4
Event-Related Definitions................................................................................16
4.7.2.5
Time Windows for Analyses of Molecular and Cytogenetic Response .............17
4.7.3
Primary Endpoint Analysis ....................................................................................18
4.7.3.1
Data Handling Rules for the Primary Analyses of the Primary Endpoint..........18
4.7.4
Secondary Efficacy Endpoint Analyses..................................................................18
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Statistical Analysis Plan (SAP)
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4.7.4.1
Key Secondary Efficacy Endpoints..................................................................18
4.7.4.2
Analysis Methods for Other Secondary Efficacy Endpoints .............................19
4.7.4.3
Data Handling Rules for Secondary Efficacy Endpoint Analyses.....................20
4.7.4.4
Subgroup Analyses of the Primary Endpoint and Secondary Efficacy
Endpoints ........................................................................................................20
4.8
Safety Analysis............................................................................................................20
4.8.1
Analysis of Vascular Occlusive Events ..................................................................21
4.8.2
Analysis of Categories of Adverse Events..............................................................21
4.8.3
TEAEs, Treatment-Related AEs and SAEs ............................................................22
4.8.4
Analyses of Treatment Discontinuation Rate, Dose Reductions, and Dose 
Interruptions due to AEs ........................................................................................22
4.8.5
Study Drug Exposure.............................................................................................22
4.8.6
Laboratory Tests....................................................................................................23
4.8.7
Vital Signs and Blood Pressures.............................................................................23
4.8.8
12-Lead Electrocardiogram (ECG).........................................................................23
4.8.9
Echocardiogram (ECHO).......................................................................................23
4.8.10 ECOG Performance Status.....................................................................................23
4.9
Exposure-Response Analysis .......................................................................................23
4.10 Quality of Life / Health Outcomes Analysis.................................................................23
4.10.1 EQ-5D-5L..............................................................................................................24
4.10.2 FACT-Leu .............................................................................................................24
4.11 Interim Analysis...........................................................................................................24
5
References.....................................................................................................................24
6
Appendix.......................................................................................................................25
bject to the Applicable Terms of Use
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ARIAD Pharmaceuticals, Inc.
(a wholly-owned subsidiary of Takeda Pharmaceutical 
Ltd. Co.)
AP24534-15-303
Statistical Analysis Plan (SAP)
Version 2.0 23 July 2020
Page 4
LIST OF ABBREVIATIONS
Abbreviation
Term
AE(s)
AESI(s)
AOE(s)
AP
ARIAD
AUC
adverse event(s)
adverse event(s) of special interest
arterial occlusive event(s)
accelerated phase
ARIAD Pharmaceuticals, Inc.
area under the curve
BCR-ABL
BCR-ABLIS
Breakpoint Cluster Region-Abelson
BCR-ABL transcript level as measured by the International Scale
BM
BMI
BP
CBC
CCyR
CHR
CI(s)
CM(s)
bone marrow
body mass index
blast phase
complete blood count
complete cytogenetic response
complete hematologic response
confidence interval(s)
concomitant medication(s)
CMH
Cochran Mantel-Haenszel
CML
chronic myelogenous leukemia/chronic myeloid leukemia
Cmax
maximum plasma concentration
CP
chronic phase
CSR
clinical study report
CTCAE
EAIR
Common Terminology Criteria for Adverse Events
exposure-adjusted incidence rate
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
FACT-Leu
Functional Assessment of Cancer Therapy – Leukemia
FAS
Full Analysis Set
HR-QoL
health-related quality of life
IS
international scale
ITT
Intent-to-Treat
LVEF
left ventricular ejection fraction
MCyR
major cytogenetic response
MedDRA
Medical Dictionary for Regulatory Activities 
MMR
major molecular response
MR1
molecular response with 1-log reduction
MR2
molecular response with 2-log reduction
MR3/MMR
molecular response with 3-log reduction
MR4
molecular response with 4-log reduction
MR4.5
molecular response with 4.5-log reduction
NCI
National Cancer Institute (of the United States)
OS
overall survival
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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ARIAD Pharmaceuticals, Inc.
(a wholly-owned subsidiary of Takeda Pharmaceutical 
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AP24534-15-303
Statistical Analysis Plan (SAP)
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Page 5
Abbreviation
Term
PCR
polymerase chain reaction
PCyR
partial cytogenetic response 
PFS
progression-free survival
Ph+
Philadelphia chromosome positive
PK
pharmacokinetic(s)
PP
Per-Protocol
PRO
patient-reported outcome
QD
once daily
QoL
quality of life
QTcF
QT interval corrected (Fridericia)
SAE(s)
serious adverse event(s)
SAP
statistical analysis plan
SD
standard deviation
SMQ
Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query
TEAE(s)
treatment-emergent adverse event(s)
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
VAS
visual analog scale
VOE(s)
vascular occlusive event(s)
VTE(s)
venous thromboembolic event(s)
WHO
World Health Organization
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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AP24534-15-303
Statistical Analysis Plan (SAP)
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Page 6
1
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the design characteristics and statistical analysis methods 
for the study. It specifies the statistical approaches and data handling conventions for key analyses that 
include the analysis for the primary endpoint and the analyses for secondary endpoints, based on the 
Protocol Version 2.0.
The study accrual is terminated prematurely based on the consideration of landscape change in 
availability of 2nd line nilotinib treated patients. At the time of accrual termination, a total of 44 patients 
have been enrolled into the study and randomized to receive the study drugs. Based on this change in 
situation, the efficacy analyses will no longer be sufficiently powered per the study design. Therefore, 
efficacy data will be summarized descriptively, and no formal statistical tests will be conducted as 
originally planned in the protocol.
Instead of a full clinical study report (CSR), an abbreviated CSR will be submitted, as decided by the 
study team. Since an abbreviated CSR will include all safety information as included in a full report,
whereas efficacy information will be concise and not as comprehensive as in a full CSR, the analysis 
will be planned accordingly in this document.
2
STUDY OBJECTIVES AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objective

To demonstrate the efficacy of ponatinib administered at 2 starting doses (30 and 15 mg QD) 
compared to nilotinib administered at 400 mg BID in patients with chronic phase chronic myeloid 
leukemia (CP-CML) who are resistant to imatinib, as measured by major molecular response
(MMR) by 12 months.
2.1.2
Key Secondary Objectives

To characterize, according to each arm and ponatinib starting dose, the rates of vascular occlusive 
events (VOEs), adverse events (AEs), and serious adverse events (SAEs).

To characterize, according to each arm and ponatinib starting dose, the rate of cytogenetic 
responses and molecular responses other than MMR.

To further characterize efficacy according to each arm and ponatinib starting dose, including time to 
response, duration of cytogenetic and molecular response, duration of therapy, progression free 
survival (PFS), overall survival (OS), and impact of dose escalation after loss of response 
(ponatinib cohorts only).
2.1.3
Other Secondary Objectives

To characterize, according to each arm and ponatinib starting dose, the rate of discontinuation, 
dose reductions, and interruptions.

To characterize, according to each arm and ponatinib starting dose, the rate of hematologic 
responses.
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2.1.4
Exploratory Objectives
2.2
Study Endpoints
2.2.1
Primary Endpoint

MMR by 12 months for each cohort
2.2.2
Key Secondary Endpoints

Cytogenetic response rates:
a.
Major cytogenetic response (MCyR) by 12 months
b.
Complete cytogenetic response (CCyR) by 12 months

Molecular response rates: MR2 (≤1% BCR-ABLIS), MR3/MMR (≤0.1% BCR-ABLIS), MR4
(≤0.01% BCR-ABLIS), MR4.5 (≤0.0032% BCR-ABLIS) at 3-month intervals until end-of-
treatment and MR1 (≤10% BCR-ABLIS) at 3 months

Safety
a.
Rate of arterial occlusive events (AOEs) and VOEs in each cohort
b.
Rate of AEs in each cohort
c.
Rate of SAEs in each cohort

Time to response

Duration of response:
a.
MR2 and MMR at 3, 6, 9, and 12 months, and then at 3-month intervals until completion 
of treatment
b.
MCyR at 12 and 24 months, by cytogenetic analysis
c.
Duration of response in responders
d.
Duration of therapy

PFS

OS
2.2.3
Other Secondary Endpoints

Hematologic response rates: complete hematologic response (CHR)
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
Tolerability:
a.
Rate of discontinuation due to AEs in each cohort
b.
Rate of dose reductions due to toxicity (prior to response) in each cohort
c.
Rate of dose interruptions in each cohort 

Rate of progression to accelerated phase (AP) or blast phase (BP) CML
2.2.4
Exploratory Endpoints
3
STUDY DESIGN
3.1
Study Design
This is a multi-center, randomized study to demonstrate the efficacy and safety of two starting doses of 
ponatinib as compared to nilotinib. Eligible patients must have CP-CML, be resistant to first-line 
imatinib treatment and not received any other tyrosine kinase inhibitor (TKI) therapy.
Patients will be randomized to receive once daily oral administration of either 30 mg ponatinib QD 
(Cohort A), or 15 mg ponatinib QD (Cohort B), or 400 mg nilotinib BID (Cohort C). They will be 
randomized in a ratio of 1:2:1, respectively. The primary endpoint of MMR by 12 months is defined 
according to standard criteria as ≤0.1% BCR-ABL/ABLIS. Upon achievement of MMR, patients in 
Cohort A will have their daily dose of ponatinib reduced to 15 mg and patients in Cohort B will have 
their daily dose of ponatinib reduced to 10 mg. The dose of nilotinib for patients in Cohort C will not 
be adjusted based on response.
Treatment will continue until lack of response at 12 months is established, intolerance develops or 
response is lost. In the ponatinib arms, Cohorts A and B, patients who achieve and then lose response 
after dose reduction for MMR may have their dose escalated to their initial dose and remain on study.
In the nilotinib arm, Cohort C, patients who lose response will discontinue study treatment.
The study will assess hematologic response, cytogenetic response, and molecular response, as well as 
additional measures of efficacy including time to responses, and duration of responses by starting dose 
and after dose reduction. PFS and OS data will also be collected and analyzed. 
Adverse event (AE) rates and the rates of VOEs, in particular, will be measured. Assessments will be 
according to standard international criteria. The duration of patient participation will be 60 months for 
all patients, unless they withdraw prior to that based on the withdrawal criteria defined within the 
protocol.
3.1.1
Schedule of Events
Table 3 in the protocol lists the screening and study procedures to be done through Cycle 12. Table 4 in 
the protocol lists the procedures to be done 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. 
CCI
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Page 9
Cycle visit samples or activities should occur within 3 days of the scheduled study day unless otherwise 
noted in the Schedule of Events (Section 12.1 of the protocol).
3.2
Blinding 
This study is an open-label study; patients, investigators, and the sponsor will know the identity of each 
patient’s study treatment.
3.3
Randomization 
Patients will be randomized in a 1:2:1 ratio to receive either ponatinib in one of two starting doses or 
nilotinib:

Cohort A: 30 mg ponatinib QD with reduction to 15 mg at 3, 6, 9, or 12 months upon 
achievement of MMR.

Cohort B: 15 mg ponatinib QD with reduction to 10 mg at 3, 6, 9, or 12 months upon 
achievement of MMR.

Cohort C: 400 mg nilotinib BID.
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 best 
response to prior imatinib therapy (CCyR or MR2 or better, yes/no). Randomization procedures should 
be performed following confirmation of eligibility and prior to the initiation of assigned treatment.
3.4
Study Treatment
The starting dose of study drug will be 30 mg ponatinib QD (Cohort A), 15 mg ponatinib QD 
(Cohort B), or 400 mg nilotinib BID (Cohort C), taken orally. Study drug will be self-administered by 
the patient on a daily schedule. Patients in Cohort A will have their daily dose of ponatinib reduced to 
15 mg and patients in Cohort B will have their daily dose of ponatinib reduced to 10 mg if MMR has 
been achieved.
Study treatment will be administered only to eligible randomized patients at qualified centers.
3.4.1
Ponatinib Treatment for Patients in Cohorts A and B
The starting dose of study drug will be 30 mg ponatinib QD (Cohort A), 15 mg ponatinib QD (Cohort 
B). Each 28-day dosing period is referred to as 1 cycle. Patients will be assessed for MMR and MCyR 
as described below, and doses will be modified according to response. Doses may also be modified to 
manage AEs.
3.4.1.1
Mandatory Dose Reduction for Response Scheme in Ponatinib Cohorts A and B
Patients will be assessed for molecular and cytogenetic response at 3-month intervals. Patients in the 
ponatinib cohorts will have their doses reduced upon attainment of MMR or MCyR, as defined in
Sections 4.7.2.1 and 4.7.2.2. No dose reduction for response will be implemented for patients in the 
nilotinib cohort. The dose reduction scheme is described in the Table below.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Response Criteria
Time Point
Value
Cohort
Action
MMR (≤0.1%)
3 months and every
subsequent 3 months
MMR
A
Reduce dose to 15 mg
B
Reduce dose to 10 mg
C
No change in dose
MCyR by BM 
cytogenetics
12 months
MCyR
A
Reduce dose to 15 mg
B
Reduce dose to 10 mg
C
No change in dose
Not in MCyR
A, B or C
Discontinue from study
MMR is defined as a ≤0.1% ratio of BCR-ABL to ABL transcripts on the IS (BCR-ABLIS), measured 
by real-time quantitative polymerase chain reaction (PCR).
MCyR is defined according to standard criteria as ≤35% Ph+-containing metaphases (typically <7/20 
involved metaphases), that is, as either a PCyR or a CCyR. Increasingly, patient monitoring is being 
performed by quantitation of BCR-ABL transcript from a standard according to the international scale 
(IS). Using such monitoring, ≤1% BCR-ABL/ABLIS (also denoted as MR2) is taken to be equivalent to 
CCyR.
Patients will undergo a baseline BM aspirate and cytogenetics to establish the diagnosis and eligibility.
They will then undergo molecular monitoring at 3-month intervals for the assessment of response. In 
the ponatinib arms (Cohorts A and B), the assessment will also inform the decision regarding dose 
reduction. They will undergo a BM aspirate with cytogenetics after 12 cycles, which will be used to 
assess cytogenetic response at 12 months and to inform the decision regarding dose reduction, at end of 
treatment as specified in the Schedule of Events (Table 4 in the protocol), and other time points
depending on response.
Note: patients may undergo dose reduction for adverse events prior to the achievement of MMR. This 
should not affect the assessment of response and the mandated dose reduction in patients enrolled in the 
ponatinib cohorts upon its attainment.
The schedule of patient assessment for mandatory response-related dose reduction in Cohorts A 
and B is as follows:
At 3 months, patients in Cohorts A and B will have their dose reduced to 15 mg and 10 mg,
respectively, if they are in MMR. If not, they will continue at their current dose until the 6-month
assessment.
At 6 months, patients in Cohorts A and B will have their dose reduced to 15 mg and 10 mg,
respectively if they are in MMR. If not, they will continue at their current dose until the 9-month
assessment.
At 9 months, patients in Cohorts A and B will have their dose reduced to 15 mg and 10 mg,
respectively, if they are in MMR. If not, they will continue at their current dose until the 12-month 
assessment.
At 12 months, all patients will undergo a BM aspirate and cytogenetics. Patients in Cohorts A and B 
will have their dose reduced to 15 mg and 10 mg, respectively, if they are in MMR or in MCyR, and 
will continue therapy. If not in MCyR, they will discontinue therapy.
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3.4.1.2
Loss of Response after Dose Reduction for MMR or MCyR in Cohorts A and B
Patients being treated with ponatinib who achieve MMR at any time point, undergo dose reduction, and 
then lose MMR, as determined by real-time quantitative PCR assessment (Section 4.7.2.1), are 
candidates for dose re-escalation to their starting dose, in the absence of AEs requiring dose 
modification. Patients who achieve MCyR, but not MMR, at 12 months also will undergo dose 
reduction. These patients who subsequently lose MCyR are also candidates for dose escalation at the 
discretion of the physician.
Patients will be monitored with a cytogenetic assessment at 12 months and molecular response
assessments every 3 months according to the Schedule of Events (Table 3 and Table 4 in the protocol).
Any patient who has a greater than 1-log increase in transcript level should also have a BM cytogenetic 
assessment performed unless the patient remains in MR2. If the cytogenetic assessment indicates loss 
of MCyR, dose escalation may be considered. If the cytogenetic assessment does not demonstrate loss 
of MCyR, continued monitoring is indicated.
Patients may be dose re-escalated as follows:
Patients may only undergo dose re-escalation if they do not have ongoing AEs necessitating treatment 
at 10 mg or 15 mg as per Section 14.4.2 of the protocol (Dose Modifications for Adverse Drug
Reactions).
For patients in Cohort A, re-escalate to the starting dose of 30 mg. For patients in Cohort B, escalate to 
the starting dose of 15 mg.
If patients regain MCyR after dose escalation, continue their therapy at the escalated dose and monitor 
according to the Schedule of Events.
If patients do not regain MCyR after 6 months of therapy at the escalated dose, they must be
discontinued from the study.
The dose re-escalation scheme is described in the table below.
Current Response Criteria
Time Point
Cohort
Action
Loss of MCyR by
cytogenetics
12 months or later
A
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B
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If
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MCyR then re-escalate to 30mga; if 
no loss of MCyR, continue to 
monitor according to SOE
B
Perform BM cytogenetics; if loss of
MCyR then re-escalate to 15 mga; if 
no loss of MCyR, continue to 
monitor according to SOE
a
unless dose-reduction was due to AEs
3.4.2
Nilotinib Treatment for Patients in Cohort C
The starting dose of study drug will be 400 mg nilotinib BID (Cohort C). Each 28-day dosing period is 
referred to as 1 cycle. Patients will be assessed for MMR and MCyR as described above, but in contrast 
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(a wholly-owned subsidiary of Takeda Pharmaceutical 
Ltd. Co.)
AP24534-15-303
Statistical Analysis Plan (SAP)
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Page 12
to the ponatinib arms, doses will not be modified according to achievement of response. Doses may be 
modified to manage AEs.
3.5
Determination of Sample Size
The primary endpoint for this study will be MMR rate by 12 months. The primary analysis of the 
primary endpoint of MMR will be performed using a 2-sided alpha = 0.024 for each comparison.
A sample size of 150 patients in each Cohort A and C (ponatinib 30 mg and nilotinib, respectively) will 
distinguish a favorable MMR rate of 45% for ponatinib from a null or an uninteresting MMR rate of 
25% for nilotinib with a nominal 90% power to detect an improvement in MMR of 20%. 
The sample size of 300 patients in Cohort B and 150 patients in Cohort C will distinguish a favorable 
MMR rate of 40% for ponatinib from a null or an uninteresting MMR rate of 25% for nilotinib with 
approximately 80% power to detect an improvement in MMR of 15%.
Per the original study design, the overall total sample size will be 600 patients with 150 patients in the 
ponatinib 30 mg starting dose cohort (Cohort A), 300 patients in the ponatinib 15 mg starting dose 
cohort (Cohort B), and 150 patients in the nilotinib cohort (Cohort C).
The study accrual is terminated prematurely based on the consideration of landscape change in 
availability of 2nd line nilotinib treated patients. At the time of accrual termination, a total of 44 patients 
have been enrolled into the study and randomized to receive the study drugs.
4
STATISTICAL ANALYSES AND METHODS
4.1
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 or nilotinib.
Eligible CP-CML patients will be randomized to one of 3 cohorts (Cohort A: 30 mg ponatinib QD, 
Cohort B: 15 mg ponatinib QD, Cohort C: 400 mg nilotinib BID) in a 1:2:1 fashion. Upon achievement 
of MMR, patients assigned to ponatinib 30 mg will have their daily dose of ponatinib reduced to 15 mg, 
and patients assigned to ponatinib 15 mg will have their daily dose of ponatinib reduced to 10 mg.
Patients will be stratified by age at baseline (≥60 years versus <60 years) and best response to prior 
imatinib therapy (CCyR or MR2 or better yes/no).
Categorical data will be summarized by the number and percentage of patients in each category.
Continuous variables will be summarized by descriptive statistics (ie, n, mean, standard deviation [SD], 
median, minimum, and maximum). Two-sided confidence interval (CI) will be provided where 
appropriate.
Baseline value is defined as the last valid value on or before the first dose date of study treatment, 
unless otherwise specified. Missing/partial dates for initial diagnosis date, prior cancer therapy, AE, 
and concomitant medication (CM) will be imputed using a conservative approach. The imputation 
methods are available upon request.
Due to earlier termination of study accrual, no statistical inference will be made, and no formal 
statistical tests will be conducted as originally planned in the protocol. The final analysis is planned to 
be performed for abbreviated CSR.
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4.2
Analysis Populations
Intention-to-Treat (ITT) Population: The ITT population includes all patients who are randomized to 
the study. Patients will be analyzed according to the treatment to which they were assigned. Patients 
who are subsequently determined to be assigned to an incorrect stratum will be analyzed according to 
the stratum to which they were assigned at randomization.
Full Analysis Set (FAS): The FAS includes all patients in the ITT population as defined above who 
have b2a2/b3a2 BCR-ABL transcript types at study entry (patients for whom a BCR-ABLIS ratio can be 
determined).
Safety Population: The safety population for each cohort includes all patients who have received at 
least 1 dose of study drug. The primary analyses of safety will be based on the safety population where 
data will be analyzed according to the treatment to which patient is actually assigned.
Per-Protocol (PP) Population: The PP 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 anti-cancer 
therapy concurrent with study drug, and administration of incorrect dose (eg, dose that was not the one 
to which the patient was randomized). Major protocol violations will be finalized and documented prior 
to database lock. The PP analyses may only be performed if the difference in number of patients 
between ITT population and PP population is at least 5 in each cohort.
4.3
Patient Disposition
The following data for patient disposition will be summarized:

Numbers of patients in ITT population, FAS, safety population, and PP population

Numbers of patients still on study treatment

Numbers of patients discontinued from treatment

Primary reason for treatment discontinuation

Follow-up status

Duration of follow-up
4.4
Major Protocol Deviations
Major protocol deviations that could be expected to impact analysis of the primary endpoint, such as: 
failure to satisfy one or more eligibility criteria, administration of incorrect dose (eg, starting dose that 
was not the one to which the patient was randomized), no baseline or post-baseline cytogenetic or 
molecular response assessment, administration of prohibited anti-leukemia therapy concurrent with
study drug, will be identified prior to database lock and will be listed and summarized.
4.5
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized separately for each cohort and will 
include at a minimum: 

Age, gender, race, ethnicity, geographic region, weight, height, body mass index (BMI), and 
ECOG score
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Page 14

Time from initial diagnosis of CP-CML to first dose date (years)

Medical history including history of hypertension, diabetes, and hyperlipidermia

Prior TKI therapy and anti-cancer regimen

Resistance or intolerance to prior TKIs

Mutation status at baseline

Cytogenetic, hematologic, and molecular statuses at baseline
4.6
Concomitant Medications
Prior and concomitant medications will be coded using the World Health Organization (WHO) drug 
dictionary. Medications not in the WHO dictionary will be summarized as ‘Not Coded’ for analysis. 
Concomitant medications (CMs) defined as all medications used on or after the first dose of study
treatment will be summarized. Medications belonging to categories of interest such as aspirin and 
anticoagulants will be identified and summarized. 
4.7
Efficacy Analyses
Due to earlier termination of study accrual, the efficacy analyses (including primary analysis for 
primary endpoint, MMR rate by 12 months) will no longer be sufficiently powered per the original
study design. Therefore, efficacy data will be summarized descriptively, and no formal statistical tests
will be conducted as originally planned in the protocol.
4.7.1
Efficacy Assessments
Efficacy assessments comprise at least:

BCR-ABL transcript assessment to determine molecular response

Bone marrow aspirates for assessment of cytogenetic response

Complete blood count for assessment of hematologic response

PFS and Survival follow-up
4.7.2
Definitions of Efficacy Endpoints
The primary and secondary efficacy endpoints are listed in Section 2.2. This section defines the 
endpoints themselves and the associated conditions defining loss of those endpoints.
4.7.2.1
Molecular Response Definitions
Major molecular response (MMR) is defined as a ≤0.1% ratio of BCR-ABL to ABL transcripts on the
international scale (BCR-ABLIS), measured by real-time quantitative PCR.
MR1 at 3 months is the proportion of patients achieving a ratio of ≤10% BCR-ABL to ABL
transcripts on the international scale at 3 months.
Molecular response: MR2, MR4, and MR4.5 are defined as ≤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 order to be classified as MR4 and MR4.5, 
respectively.
Time to MMR is defined as the interval between the randomization date and the first date at which the 
criteria for MMR are met.
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Duration of MR2/MMR/MR4/MR4.5 is defined as the interval between the first assessment at which 
the criteria for MR2/MMR/MR4/MR4.5 are met until the earliest date at which loss of 
MR2/MMR/MR4/MR4.5 occurs (see below), or the criteria for progression (see Section 4.7.2.4) are 
met. Patients remaining in MR2/MMR/MR4/MR4.5 will be censored at the last date at which the 
criteria for MR2/MMR/MR4/MR4.5 are met.
Loss of MMR is defined as an increase to >0.1% of BCR-ABLIS. This result must be confirmed at the 
subsequent visit, unless it is associated with confirmed loss of CHR, or loss of CCyR, or progression to 
AP- or BP-CML, or death due to CML.
Loss of MR2 is defined as an increase to >1% of BCR-ABLIS. This result must be confirmed at the 
subsequent visit, unless it is associated with confirmed loss of CHR, or loss of CCyR, or progression to 
AP- or BP-CML, or death due to CML.
Loss of MR4 is defined as an increase to >0.01% of BCR-ABLIS. This result must be confirmed at the 
subsequent visit, unless it is associated with confirmed loss of CHR, or loss of CCyR, or progression to 
AP- or BP-CML, or death due to CML.
Loss of MR4.5 is defined as an increase to >0.0032% of BCR-ABLIS. This result must be confirmed at 
the subsequent visit, unless it is associated with confirmed loss of CHR, or loss of CCyR, or
progression to AP- or BP-CML, or death due to CML.
4.7.2.2
Cytogenetic Response Definitions
Rate of major cytogenetic response (MCyR) by 12 months is the proportion of patients achieving 
CCyR or PCyR at any time within 12 months after randomization.
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

Complete cytogenetic response (CCyR): 0% Ph+ metaphases

Partial cytogenetic response (PCyR): >0% to 35% Ph+ metaphases
Rate of complete cytogenetic response (CCyR) by 12 months is the proportion of patients achieving 
CCyR at any time within 12 months after randomization. Additionally, CCyR at 12 months will be 
calculated using only cytogenetic criteria. Additional analyses may be performed that will consider 
patients who achieve MR2 to have achieved CCyR.
Time to MCyR is defined as the interval from randomization until the criteria for MCyR are first met.
Duration of MCyR is defined as the interval between the first assessment at which the criteria for 
MCyR are met until the earliest date at which loss of MCyR occurs, or the criteria for progression 
(Section 4.7.2.4) are met. Patients remaining in response will be censored at their latest assessment 
(either cytogenetic or molecular).
Loss of MCyR is defined as a single BM assessment with Ph+ metaphases >35% after achievement of 
MCyR (CCyR or PCyR or MR2).
Loss of CCyR is defined as an increase in the Ph+ metaphases in BM to >0% in a single BM 
assessment.
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Loss of PCyR is defined as an increase in the Ph+ metaphases in BM from >0% to 35% to >35% in a 
single BM assessment.
4.7.2.3
Hematologic Response Definitions
Complete hematologic response (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 upper limit of normal (ULN)

Platelets <450 x 109/L

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 4.7.2.4] or CML-related death):

WBC count that rises to >20 x 109/L

Platelet count that rises to ≥600 x 109/L

Progressing splenomegaly 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
4.7.2.4
Event-Related Definitions
Progression-free survival (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 AP- or BP-
CML), or death due to any cause, censored at the last response assessment.
Progression to AP-CML 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
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●
Cytogenetic, genetic evidence of clonal evolution
and
●
No extramedullary disease
Progression to BP-CML is defined as:
●
≥30% blasts in peripheral blood or bone marrow
or
●
Extramedullary disease other than hepatosplenomegaly
PFS will also be analyzed according to the criteria in O’Brien et al, 2003:
1. Death
3. Development of AP or BP
4. Loss of CHR (in the absence of cytogenetic response)
    Confirmed by development in complete blood counts (CBCs) at least 4 weeks apart
5. Loss of MCyR by BM cytogenetic assessment
6. Increasing WBC in patient without CHR defined by:
    Doubling of WBC to >20K on 2 occasions at least 4 weeks apart (after the first 4 weeks of
    therapy)
Overall Survival (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 to be alive.
4.7.2.5
Time Windows for Analyses of Molecular and Cytogenetic Response
Table 1
Time Windows for Analyses of Molecular Response1
Planned Assessment2
Time window
Baseline
As specified in Section 4.1
Month 3 (Day 84)
Day 42 – Day 126
Month 6 (Day 168)
Day 127 – Day 210
Month 9 (Day 252)
Day 211 – Day 294
Month 12 (Day 336)
Day 295 – Day 378
1Molecular response assessed at Month 1, 2, 3 and every 3 months thereafter.
2Planned Assessments beyond Month 12 will be determined in a similar fashion.
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Table 2
Time Windows for Analyses of Cytogenetic Response
Planned Assessment
Time window
Baseline
As specified in Section 4.1
Month 12 (Day 336)
Day 253 – Day 420
4.7.3
Primary Endpoint Analysis
Per the original plan in the protocol, the primary analysis of the primary endpoint (ie, MMR rate by 12 
months) will be performed using a stratified Cochran Mantel-Haenszel (CMH) test. The study will be 
stratified by age at baseline (≥60 versus <60 years) and best response to prior imatinib therapy (CCyR 
or MR2 or better, yes/no) to compare the MMR rate by 12 months between patients receiving either 
dose level of ponatinib (initial dose: 30 mg once daily [QD] or 15 mg once daily [QD]) and patients 
receiving nilotinib (initial dose: 400 mg BID) and will follow a testing procedure to ensure an overall 
2-sided Type I error rate of <0.05 (see Section 16.11 of the protocol).
As a result of earlier termination of study accrual, the primary analysis of the primary endpoint (ie, 
MMR rate by 12 months) will only be performed descriptively with point estimate and its 95% CI by 
each cohort for MMR rate by 12 months, and no formal statistical tests (eg, CMH test) will be 
conducted as originally planned in the protocol.
The primary analysis will be based on the Full Analysis Set (all patients randomized to a treatment 
group for whom a BCR-ABLIS ratio can be determined at baseline). A sensitivity analysis of the 
primary endpoint will be performed on the ITT population, with patients not evaluable treated as non-
responders.
4.7.3.1
Data Handling Rules for the Primary Analyses of the Primary Endpoint
The following patients will be analyzed as responders in the primary analysis:

Patients who meet the criteria for MMR by 12 months after randomization
All other patients will be analyzed as non-responders in the primary analysis, including randomized 
patients without follow-up (and any patients who meet the criteria for MMR at study entry).
4.7.4
Secondary Efficacy Endpoint Analyses
As a result of earlier termination of study accrual, the secondary efficacy endpoint analyses will only be 
performed descriptively with point estimates and 95% confidence intervals (CIs) by each cohort, and 
no formal statistical tests (eg, CMH test) will be conducted as originally planned in the protocol.
4.7.4.1
Key Secondary Efficacy Endpoints
Descriptive statistics summary with point estimates and 95% CIs will be performed on the following 
molecular key secondary endpoints (MR3/MMR at 24 months; MR4 at 24 months; MR4.5 at 24 
months, MR1 at 3 months) and key secondary cytogenetic endpoints (CCyR at 12 months; MCyR by 
12 months), by each cohort.
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Analyses of molecular key secondary endpoints will be performed on the Full Analysis Set. Analyses 
of cytogenetic key secondary endpoints will be performed on the ITT population.  
Note that at some analysis time points not all key secondary endpoints will be mature (eg, molecular 
key secondary endpoints will not be mature at interim analysis or 12-month analysis – see 
Section 4.7.4.3 for the statistical handling of these key secondary endpoints).
The additional key secondary efficacy endpoints to be descriptively summarized in the same fashion
are listed below.

Molecular response rates: MR2, MR3/MMR, at 3-month intervals, and MR4, MR4.5 at 3-month 
intervals other than 24 months

CCyR by 12 months

Time to response

Duration of response:
1. MR2 and MMR at 12, 18, and 24 months
2. MCyR at 12 and 24 months
3. Duration of response in responders
4. Duration of therapy

PFS

OS
PFS and OS will be estimated using the Kaplan-Meier method, the median time to event and its 95% CI 
will be provided. Descriptive statistics (eg, mean, median, minimum and maximum, etc.) will be 
provided for time to response, duration of response in responders and duration of therapy.
4.7.4.2
Analysis Methods for Other Secondary Efficacy Endpoints
The analysis of other secondary efficacy endpoints of molecular response rates, cytogenetic response 
rates, CHR rate and rate of progression to AP- or BP-CML will be performed descriptively with point 
estimates and 95% CIs by each cohort.
Analyses of molecular response rates will be performed on the Full Analysis Set. All other analyses 
will be performed on the ITT population.
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4.7.4.3
Data Handling Rules for Secondary Efficacy Endpoint Analyses
For the secondary endpoints of cytogenetic responses, at any given cytogenetic assessment after 
baseline, if fewer than 20 metaphases are examined, the rules in Table 3 will apply to the determination 
of MCyR:
Table 3
Determination of MCyR by Cytogenic Assessment
Number of metaphases 
examined
≤12
13
14
15
16
17
18
19
Number of Ph+ cells
Any number
0
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≤13%
≤19%
≤24%
≤28%
≤32%
Response
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PCyR
PCyR
PCyR
PCyR
PCyR
PCyR
PCyR
Ph+ = Philadelphia chromosome positive; PCyR = partial cytogenetic response
Determination of CCyR by cytogenetic assessment will require at least 20 metaphases examined. For 
the analyses of secondary endpoints of MCyR, CCyR, MR2, MR4.5, MR4, and CHR, if patients do not 
have a baseline assessment or post-baseline response assessment, the patients will be considered as 
non-responders. Patients who meet the criteria for response at baseline will also be analyzed as non-
responders.
4.7.4.4
Subgroup Analyses of the Primary Endpoint and Secondary Efficacy Endpoints
The subgroup analyses for the primary endpoint and secondary efficacy endpoints may be performed 
by baseline potential prognostic factors when warranted based on numbers of patients in subgroups. 
Subgroups may include:

Age (<60, ≥60 years)

Gender

Race

Geographic region

T315I mutation history (Yes, No)

Best response to prior imatinib therapy (CCyR, MR2 or better)

Other disease-related prognostic factors
As a result of earlier termination of study accrual, the subgroup analyses for the primary endpoint and 
secondary efficacy endpoints may not be performed when not warranted based on numbers of patients 
in subgroups.
4.8
Safety Analysis
Safety analyses will be performed based on the safety 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 treatment-emergent adverse events 
(TEAEs) and all AEs will be listed.
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4.8.1
Analysis of Vascular Occlusive Events
Number and percentages of patients who develop VOEs will be summarized for each cohort. VOEs 
will be categorized as follows:

Arterial occlusive events (AOEs)
o
Cardiovascular occlusive events
o
Cerebrovascular occlusive events
o
Peripheral vascular occlusive events

Venous thromboembolic events (VTEs)
Details for classification of specific events as VOEs are given in Section 14.4.1.1 of the protocol.
The primary analysis of AOEs and VTEs will be an exposure-adjusted incidence rate, as follow-up may
differ among the cohorts. 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 VOEs:

Time to onset: calculated as date of first VOE – first dose date + 1

Dose at onset: dose of ponatinib or nilotinib taken immediately prior to onset of first VOE.
Baseline risk factors for the occurrence of VOEs will be evaluated for all patients, and will include:

History of arterial occlusive disease

History of other cardiovascular disease

History of venous thromboembolism

Hypertension

History of diabetes/hyperglycemia

History of smoking

Obesity

History of hyperlipidemia

Age

Gender

Other risk factors
4.8.2
Analysis of Categories of Adverse Events
Categories of AEs will be prospectively defined using Standardized Medical Dictionary for Regulatory
Activities (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 
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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characterized by time to onset, dose at onset, and duration as described above. Categories of AEs will 
include but will not be limited to:

Cardiac failure

Arrhythmias including QT prolongation

Pancreatitis and Amylase or Lipase elevations

Hepatotoxicity

Myelosuppression

Hemorrhage

Fluid retention

Hypertension 
4.8.3
TEAEs, Treatment-Related AEs and SAEs
For all TEAEs, treatment-related AEs and SAEs, crude rates as well as the frequency of occurrence by
overall toxicity, categorized by toxicity grades (severity) will be summarized for each cohort.
4.8.4
Analyses of Treatment Discontinuation Rate, Dose Reductions, and Dose Interruptions
due to AEs
Tolerability will be summarized by:

Rate of treatment discontinuation due to AEs in each dose cohort

Dose reductions in each dose cohort. Dose reduction is defined as any dose reduction due to 
AE, excluding the mandatory dose reduction described in Section 14.2.1 of the protocol.

Dose interruptions in each dose cohort. Dose interruption is defined as at least 3 consecutive 
days gap with no dose taken due to AEs.
Number of days at each dose level on the starting dose and on reduced dose(s) will be summarized in 
order to characterize length of dose interruptions and reductions due to AEs. Number of patients with 
dose interruption without resuming dosing after the interruption will be provided.
Time to first dose interruption due to AEs and time to first dose reduction due to AE will also be 
summarized to characterize length of dose interruptions and reductions.
4.8.5
Study Drug Exposure
Parameters pertaining to study drug exposure (ie, duration of exposure, number of days dosed, dose 
intensity, total cumulative dose) will be summarized separately for each cohort. Duration of treatment 
exposure is defined as the time interval from the first dose to the last dose of study treatment (last dose 
date – first dose date +1). Dose intensity in mg/day is calculated as total cumulative dose in mg divided 
by duration of treatment exposure in day.
In addition, the following data will be summarized:

Number of patients in cohorts A and B who have dose reduction to 15 mg after achieving ≤1% 
BCR-ABLIS

Number of patients who re-escalate dose after loss of ≤1% BCR-ABLIS
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4.8.6
Laboratory Tests
The absolute change from baseline will be summarized at each of the laboratory timepoints, using 
descriptive statistics (ie, n, mean, SD, median, minimum and maximum) for each cohort.
Shifts in laboratory parameters from baseline to the best post-baseline value (ie, minimum severity
grade) and worst post-baseline value (ie, maximum severity grade) in term of National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be summarized up 
to 30 days after the last dose date.
Listings of laboratory test results will be generated.
4.8.7
Vital Signs and Blood Pressures
The actual values of vital sign parameters (ie, systolic blood pressure, diastolic blood pressure, pulse
rate, respiratory rate, temperature, height, and weight) will be summarized at all planned timepoints for
each cohort using descriptive statistics (ie, n, mean, SD, median, minimum and maximum). Change of 
vital signs from baseline values will also be summarized at all planned timepoints.
Shift from baseline in blood pressure over time will be summarized.
Vital sign values will also be presented in a by-patient listing.
4.8.8
12-Lead Electrocardiogram (ECG)
The absolute values and absolute change from baseline of electrocardiogram (ECG) parameters 
including heart ventricular rate, QT duration, and QT interval corrected (Fridericia) (QTcF) interval 
will be summarized at each timepoint using descriptive statistics (ie, n, mean, SD, median, minimum 
and maximum). Maximum QTcF changes from baseline will also be summarized similarly.
In addition, a categorical analysis of QTcF intervals will be performed for each time point. The number 
and percentage of patients in each QTcF interval (eg, < 450 msec, ≥ 450 - < 480 msec, ≥ 480 -
< 500 msec, and ≥ 500 msec) will be summarized at each time point. Categories of changes from 
baseline (eg, ≥ 30 - < 60 msec and ≥ 60 msec) will be summarized as well.
4.8.9
Echocardiogram (ECHO)
Left ventricular ejection fraction (LVEF) at baseline and LVEF shift from baseline to the minimum 
post-baseline value will be summarized up to 30 days after the last dose date.
4.8.10
ECOG Performance Status
ECOG performance status over time will be summarized by each cohort.
4.9
Exposure-Response Analysis
No exposure-response analysis will be performed due to earlier termination of study accrual.
4.10
Quality of Life / Health Outcomes Analysis
QoL and health outcomes measures are being collected using the EQ-5D-5L and FACT-Leu 
instruments. Patient-reported outcome (PRO) assessments using the EQ-5D-5L and FACT-Leu will be 
da: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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analyzed using patients with PRO measurements at baseline and at least one post baseline measurement 
in the ITT population.
The scores of these EQ-5D-5L and FACT-Leu PRO questionnaires will be summarized using 
descriptive statistics (eg, mean and median) for each cohort by time point, overall, and for each 
dimension/domain.
4.10.1
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 (ie, 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 (VAS), where the same 
dimensions are rated along a 100-point visual ruler with 100 being best health.
The scores of these questionnaires rating HR-QoL for 5 dimensions and VAS will be summarized using 
descriptive statistics (ie, n, mean, SD, median, minimum and maximum) for each cohort.
The frequencies for each level of response for 5 dimensions will be summarized using categorical data 
analysis.
4.10.2
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
(ie, physical well-being, social/family well-being, emotional well-being, and functional well-being). A 
fifth category titled “Additional Concerns” contains general questions.
The scores of these questionnaires for 4 QoL domains and the fifth category titled “Additional
Concerns” as well as LEU Subscale score, FACT-Leukemia TOI, Fact-G Total Score, FACT-Leukemia 
Total Score will be summarized using descriptive statistics (ie, n, mean, SD, median, minimum and 
maximum) for each cohort. Fact-G Total Score and FACT-Leukemia Total Score may be presented by
graphs.
4.11
Interim Analysis
No efficacy interim analysis will be carried due to earlier termination of study accrual.
5
REFERENCES
Guidance for Industry Submission of Abbreviated Reports and Synopses in Support of Marketing 
Applications, U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER), August 1999
O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared 
with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. 
N Engl J Med. 2003 Mar 13 ;348(11) :994-1004.
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ARIAD Pharmaceuticals, Inc.
(a wholly-owned subsidiary of Takeda Pharmaceutical 
Ltd. Co.)
AP24534-15-303
Statistical Analysis Plan (SAP)
Version 2.0 23 July 2020
Page 25
6
APPENDIX
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