OPTIC: Ponatinib in Participants With Resistant Chronic Phase Chronic Myeloid Leukemia (CP-CML) to Characterize the Efficacy and Safety of a Range of Doses

• Sponsor: Takeda (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02467270
• Collaborator: (none)
• Enrollment: 283
• Locations: 86
• Arms: 3
• Anticipated Duration (Months): 107.1
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to characterize the efficacy of ponatinib administered in 3 starting doses (45 mg, 30 mg, and 15 mg daily) in participants with CP-CML who are resistant to prior tyrosine-kinase inhibitor (TKI) therapy or have T315I mutation, as measured by <=1 % Breakpoint Cluster Region-Abelson Transcript Level using International Scale (BCR-ABL1IS) at 12 months.

Condition or Disease	Intervention/Treatment	Phase
Myeloid Leukemia, Chronic, Chronic Phase	Drug: Ponatinib	Phase 2

Detailed Description

The drug being tested in this study is ponatinib. This study will characterize the safety and efficacy of ponatinib over a range of 3 starting doses.

The study will enroll 276 participants in 3 cohorts and each cohort will have 92 participants. All the participants will be randomized to receive once-daily oral administration of 1 of 3 starting doses of ponatinib:

• Cohort A: 45 mg ponatinib tablet

• Cohort B: 30 mg ponatinib tablet

• Cohort C: 15 mg ponatinib tablet

The study is designed to consist of 2 periods: 24-cycle Main treatment period and optional treatment continuation period. Participants will be treated with their randomized dose of study drug in the Main Treatment Period until the occurrence of at least one of the following: absence of CHR by 3 months, absence of MCyR at 12 months, absence of <=1% BCR-ABL1IS at 12 months, loss of <=1% BCR-ABL1IS development of intolerance, or completion of all 24 cycles of treatment (whichever occurs first). Following completion of approximately 5 years or following early withdrawal, participants may enter into an optional treatment continuation period.

This multi-center trial will be conducted in the United States, United Kingdom, Republic of Korea, Spain, France, Taiwan, Australia, Canada, Italy, Chile, Japan, Germany, Argentina, Poland, Czech Republic, Denmark, Hong Kong, Portugal, Russia, Singapore, Switzerland, and Sweden. The overall time to participate in this study is approximately 96 months. Participants will make a final visit to the clinic approximately 30 days after the last dose of study treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 283 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label, Phase 2 Trial of Ponatinib in Patients With Resistant Chronic Phase Chronic Myeloid Leukemia to Characterize the Efficacy and Safety of a Range of Doses
• Actual Study Start Date: Jun 30, 2015
• Actual Primary Completion Date: Apr 14, 2020
• Anticipated Study Completion Date: Jun 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: Ponatinib 45 mg Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Drug: Ponatinib; Tablet, taken orally once daily.; Other Names: Iclusig AP24534
Experimental: Cohort B: Ponatinib 30 mg Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Drug: Ponatinib; Tablet, taken orally once daily.; Other Names: Iclusig AP24534
Experimental: Cohort C: Ponatinib 15 mg Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.	Drug: Ponatinib; Tablet, taken orally once daily.; Other Names: Iclusig AP24534

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Molecular Response (MR2: <=1% Breakpoint Cluster Region-Abelson Transcript Level) as Measured by the International Scale (BCR-ABL1IS) at Month 12 [12 months after the first dose of study treatment]

   MR2 is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL <=1% Breakpoint Cluster Region-Abelson Transcript Level as Measured by the International Scale (BCR-ABL1IS), equivalent to a 2-log reduction in transcript.

Secondary Outcome Measures

1. Percentage of Participants With Major Molecular Response (MMR/MR3) [12 months after the first dose of study treatment]

   MMR/MR3 is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).

2. Percentage of Participants With Major Cytogenetic Response (MCyR) [12 months after the first dose of study treatment]

   MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: 0% Ph + metaphases; PCyR: >0 to 35% Ph + metaphases.

3. Duration of Major Molecular Response (MMR/MR3) [Baseline up to approximately 8 years]

   Duration of MMR/MR3 is defined as the interval between the first assessment at which the criteria for <=0.1% MMR are met until the earliest date at which loss of <=0.1% MMR occurs, or the criteria for progression are met. Progression to accelerated phase (AP) is defined as: >= 15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets per liter (/L) in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to blast Phase (BP) is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

4. Percentage of Participants With Adjusted Incidence Rates for Treatment Emergent Arterial Occlusive Events (AOEs), Venous Thrombotic Events (VTEs), Adverse Events (AEs), and Serious AEs (SAEs) [From first dose up to 30 days after last dose of the study drug up to data cut-off date: 31 May 2020 (Up to approximately 5 years)]

   Percentage of participants with adjusted incidence rates who developed AOEs and VTEs were categorized according to arterial occlusive events and venous thrombotic events. AE is any untoward medical occurrence in participant administered medicinal investigational drug. Untoward medical occurrence does not necessarily have to have causal relationship with treatment. SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is congenital anomaly/birth defect/is medically important event that may not be immediately life-threatening/result in death or hospitalization, but may jeopardize participant/may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.

5. Percentage of Participants With Complete Cytogenetic Response (CCyR) [Month 12]

   Cytogenetic response is defined as the percentage of Ph+ metaphases in bone marrow (peripheral blood may not be used), with a review of a minimum of 20 metaphases. CCyR is defined as 0% Ph+ metaphases.

6. Percentage of Participants With Molecular Response 4 (MR4) and Molecular Response (MR4.5) [Up to approximately 8 years]

   MR4 is defined as <=0.01% BCR-ABL1IS. MR 4.5 is defined as <=0.0032% BCR-ALB1IS.

7. Percentage of Participants With Molecular Response 1 (MR1) [3 months after the first dose of study treatment]

   MR1 is defined as percentage of participants achieving a ratio of <=10% Breakpoint Cluster Region-abelson (BCR-ABL1) transcripts on the international scale. MR1 is molecular response with 1-log reduction in transcript.

8. Percentage of Participants With Complete Hematologic Response (CHR) [3 months after the first dose of study treatment]

   CHR is defined as achieving all of the following measurements: white blood cells (WBC) <= institutional upper limit of normal (ULN), platelets <450,000 per cubic millimeter (/mm^3), no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, and no extramedullary involvement (including no hepatomegaly or splenomegaly).

9. Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption [Up to data cut-off: 31 May 2020 (Approximately 5 years)]

   An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

10. Kaplan-Meier Estimate of Duration of Response (DOR) of <=1% BCR-ABL1 IS (MR2) at Months 12 and 24 [12 and 24 months after the first dose of study treatment]

    DOR (≤1% BCR-ABL1IS) is defined as interval between first assessment at which criteria for ≤1% BCR-ABL1IS are met until earliest date at which loss of ≤1% BCR-ABL1IS occurs, or criteria for progression accelerated phase (AP) or blast Phase (BP) of chronic myeloid leukemia (CML) are met. Loss of ≤1% BCR-ABL1IS is an increase to >1% of BCR-ABL1IS. Progression to AP: ≥15% and <30% blasts in peripheral blood or bone marrow or ≥20% basophils in peripheral blood or bone marrow or ≥30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets per liter in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP: ≥30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Kaplan-Meier method was used for analysis of percentage of participants who achieved DOR of 12 and 24 months.

11. Kaplan-Meier Estimate of Duration of Response (DOR) of Major Molecular Response (MMR/MR3) [12 and 24 months after the first dose of study treatment]

    Duration of MMR/MR3 is defined as interval between first assessment at which criteria for MMR are met until earliest date at which loss of MMR occurs, or criteria for progression (progression to AP or BP of CML) are met. Participants remaining in MMR will be censored at last date at which criteria for MMR are met. Loss of MMR is an increase to >0.1% of BCR-ABL1IS. Progression to AP: >= 15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts+promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Kaplan-Meier method was used for analysis of percentage of participants who achieved DOR of 12 and 24 months.

12. Duration of Response in Responders [Baseline up to data cut-off: 31 May 2020 (Approximately 5 years)]

    Duration of response in "responders" is defined as any participants who achieved ≤1% BCR-ABL1IS at any time during the study. Responders are defined as those participants who meet all of the following: are randomized and treated, respond at 12 months after the initiation of study treatment, and undergo baseline polymerase chain reaction (PCR) assessment.

13. Time to Response [Baseline up to data cut-off: 31 May 2020 (Approximately 5 years)]

    Time to response was defined as the time interval from the date of the first dose of the study drug until the initial observation of CR or PR for participants with confirmed CR/PR. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.

14. Percentage of Participants With Progression to Accelerated Phase (AP)-Chronic Myeloid Leukemia (CML) or Blast Phase (BP)-CML [From first dose date of study treatment up to data cut-off: 31 May 2020 (Approximately 5 years)]

    Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

15. Progression-free Survival (PFS) [Up to data cut-off: 31 May 2020 (Up to approximately 5 years)]

    PFS is defined as the interval between the first dose date of study treatment and the first date at which the criteria for progression are met (progression to the AP or BP of CML), or death due to any cause, censored at the last response assessment. Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

16. Overall Survival (OS) [Up to data cut-off: 31 May 2020 (Up to approximately 5 years)]

    OS is defined as the interval between the first does of study treatment and death due to any cause, censored at the last contact date when the participant was alive.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Have chronic phase-chronic myelogenous leukemia/chronic myeloid leukemia (CP-CML) and have received at least two prior tyrosine kinase inhibitor (TKI) therapies and have demonstrated resistance to treatment OR have documented history of presence of T315I mutation after receiving any number of prior TKI.

o] The diagnosis of chronic myeloid leukemia (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*10^{9/liter (L) platelets (>=100,000/mm}3). v No evidence of extramedullary disease except hepatosplenomegaly vi No prior diagnosis of AP-CML, and BP-CML o] Cytogenetic assessment at screening must demonstrate the BCR-ABL1 fusion by presence of the t(9;22) Philadelphia chromosome.

i Variant translocations are only allowed provided they meet inclusion criterion 1d.

o] Resistance to prior TKI therapy is defined as follows (participants must meet at least 1 criterion): i Three months after the initiation of prior TKI therapy: No cytogenetic response (>95% Ph+) or failure to achieve CHR or new mutation ii Six months after the initiation of prior TKI therapy: BCR-ABL1IS >10% and/or Ph+ >65% or new mutation iii Twelve months after the initiation of prior TKI therapy: BCR ABL1IS

10% and/or Ph+ >35% or new mutation iv At any time after the initiation of prior TKI therapy, the development of a new BCR-ABL1 kinase domain mutation(s) v At any time after the initiation of prior TKI therapy, the development of new clonal evolution vi At any time after the initiation of prior TKI therapy, the loss of CHR, or CCyR, or the confirmed loss of MMR in 2 consecutive tests, one of which has a BCR-ABL1IS transcript level of >=1% or new mutation o] >1% of BCR-ABL1IS as shown by real-time polymerase chain reaction

1. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

2. Have adequate renal function as defined by the following criterion:

o] Serum creatinine <=1.5*ULN for institution o] Estimated creatinine clearance >=30 milliliter per minute (mL/min) (Cockcroft-Gault formula)

1. Have adequate hepatic function as defined by the following criteria:

o] Total serum bilirubin <=1.5ULN, unless due to Gilbert's syndrome o] Alanine transaminase (ALT) <=2.5ULN, or <=5ULN if leukemic infiltration of the liver is present o] Aspartate transaminase (AST) <=2.5ULN, or <=5*ULN if leukemic infiltration of the liver is present

1. Have normal pancreatic status as defined by the following criterion:

o] Serum lipase and amylase <=1.5*ULN

1. Have normal QT interval corrected (Frederica) (QTcF) interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of <=450 milliseconds (ms) in males or <=470 ms in females.

2. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).

3. Agree to use a highly effective form of contraception with sexual partners from randomization through at least 4 months after the end of treatment (for female and male participants who are fertile).

4. Provide written informed consent.

5. Be willing and able to comply with scheduled visits and study procedures.

6. Have recovered from toxicities related to prior anticancer therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 grade <=1.

Exclusion Criteria:

1. Have used any approved TKIs or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is longer, prior to receiving study drug.

2. Received interferon, cytarabine, or immunotherapy within 14 days, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib, or have not recovered (>grade 1 by NCI CTCAE, version 4.0) from AEs (except alopecia), due to agents previously administered.

3. Have undergone autologous or allogeneic stem cell transplant <60 days prior to receiving the first dose of ponatinib; have any evidence of ongoing graft-versus-host disease (GVHD) or GVHD requiring immunosuppressive therapy.

4. Are being considered for hematopoietic stem cell transplant (HSCT) within 6-12 months of enrollment (note: ponatinib is not to be used as a bridge to HSCT in this trial).

5. Are taking medications with a known risk of Torsades de Pointes.

6. Have previously been treated with ponatinib.

7. Have active CNS disease as evidenced by cytology or pathology; in the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.

8. Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

o] Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or Transient Ischemic Attack (TIA) o] Any history of peripheral vascular infarction, including visceral infarction o] Any revascularization procedure, including the placement of a stent o] Congestive heart failure (CHF) (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal, per local institutional standards, within 6 months prior to enrollment o] History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia o] Venous thromboembolism, including deep venous thrombosis or pulmonary embolism, within 6 months prior to enrollment

1. Have uncontrolled hypertension (that is, >150 and >90 for systolic blood pressure (SBP) and diastolic blood pressure (DBP) respectively). Participants 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.

2. Have poorly controlled diabetes defined as HbA1c values of >7.5%. Participants with preexisting, well-controlled diabetes are not excluded.

3. Have a significant bleeding disorder unrelated to CML.

4. Have a history of alcohol abuse.

5. Have a history of either acute pancreatitis within 1 year of study enrollment or of chronic pancreatitis.

6. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.

7. Have a history of another malignancy, other than cervical cancer in situ or basal cell or squamous cell carcinoma of the skin; the exception is if participants have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy.

8. Are pregnant or lactating.

9. Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.

10. Have an active infection which requires intravenous antibiotics.

11. Have a known history of human immunodeficiency virus infection; testing is not required in the absence of prior documentation or known history.

12. Have any condition or illness that, in the opinion of the investigator, would compromise participant safety or interfere with the evaluation of the drug.

13. Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Winship Cancer Institute	Atlanta	Georgia	United States	30322
2	Indiana Blood & Marrow Transplantation	Indianapolis	Indiana	United States	46237
3	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
4	Michigan Medicine	Ann Arbor	Michigan	United States	48109
5	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
6	University of Minnesota Medical School	Minneapolis	Minnesota	United States	55455
7	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
8	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
9	Memorial Sloan-Kettering Cancer Center - New York	New York	New York	United States	10065
10	NewYork-Presbyterian Weill Cornell Medical Center	New York	New York	United States	10065
11	Duke University Medical Center	Durham	North Carolina	United States	27710
12	Cleveland Clinic Taussig Cancer Institute Main Campus	Cleveland	Ohio	United States	44195
13	Oregon Health and Science University	Portland	Oregon	United States	97239
14	Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
15	MD Anderson Cancer Center	Houston	Texas	United States	77030
16	University of Utah Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
17	Fundaleu	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1114AAN
18	Hospital General de Agudo Jose Maria Ramos Mejia	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1221ADC
19	Hospital Italiano La Plata	La Plata	Buenos Aires	Argentina	B1900AXI
20	Royal North Shore Hospital	Saint Leonards	New South Wales	Australia	2065
21	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
22	Princess Margaret Hospital - Toronto	Toronto	Ontario	Canada	M5G 2M9
23	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
24	Saskatchewan Cancer Agency	Regina	Saskatchewan	Canada	S4T 7T1
25	Hospital del Salvador	Providencia	Santiago	Chile	7500922
26	Centro de Investigaciones Clinicas Vina del Mar	Vina del Mar	Valparaiso	Chile	2540364
27	Ustav Hematologie a Krevni Transfuze Praha	Prague	Praha	Czechia	12820
28	Fakultni Nemocnice Olomouc	Olomouc		Czechia	772 00
29	Aarhus University Hospital	Aarhus C	\Aarhus	Denmark	DK-8000
30	Centre de Lutte Contre le Cancer - Institut Bergonie	Bordeaux	Aquitaine	France	33076
31	Centre Hospitalier Universitaire de Nancy Hopital de Brabois	Vandoeuvre les Nancy	Lorraine	France	54511
32	Institut Universitaire du Cancer de Toulouse Oncopole	Toulouse Cedex 9	Midi-pyrenees	France	31059
33	Centre Hospitalier Regional Universitaire de Lille	Lille cedex	NORD Pas-de-calais	France	59037
34	Center Hospitalier Universitaire d'Angers	Angers Cedex 9	PAYS DE LA Loire	France	49933
35	Centre Hospitalier Universitaire de Nantes Hotel Dieu	Nantes Cedex 1	PAYS DE LA Loire	France	44093
36	Centre Hospitalier Universitaire de Poitiers	Poitiers Cedex	Poitou-charentes	France	86021
37	Centre Hospitalier Universitaire de Nice Hopital l'Archet	Nice Cedex 3	Provence Alpes COTE D'azur	France	06202
38	Universitaetsklinikum Heidelberg	Mannheim	Baden-wuerttemberg	Germany	68169
39	Universitatsklinikum Ulm	Ulm	Baden-wuerttemberg	Germany	89081
40	Universitatsmedizin Rostock	Rostock	Mecklenburg-vorpommern	Germany	18057
41	Uniklinik RWTH Aachen	Aachen	Nordrhein-westfalen	Germany	52074
42	Universitaetsklinikum Essen	Essen	Nordrhein-westfalen	Germany	45147
43	Universitatsklinikum Jena	Jena	Thuringen	Germany	07747
44	Charite Universitatsmedizin Berlin	Berlin		Germany	13353
45	Universitatsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
46	Queen Mary Hospital	Hong Kong		Hong Kong	852
47	Azienda Ospedaliera San Gerardo di Monza	Monza	Monza E Brianza	Italy	20090
48	Azienda Ospedaliera Ospedali Riuniti Marche Nord	Pesaro	Pesaro E Urbino	Italy	61100
49	Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele	Catania		Italy	95124
50	Azienda Ospedaliera Universitaria San Martino	Genova		Italy	16132
51	Azienda Sanitaria Locale di Pescara Ospedale Civile Dello Spirito Santo	Pescara		Italy	65124
52	Sapienza Universita Di Roma	Roma		Italy	00161
53	AOUI - Ospedale Policlinico "Giambattista Rossi" di Borgo Roma	Verona		Italy	37134
54	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul		Korea, Republic of	6591
55	Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu	Wroclaw	Dolnoslaskie	Poland	50-367
56	Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi	Lodz	Lodzkie	Poland	93-510
57	Malopolskie Centrum Medyczne	Krakow	Malopolskie	Poland	30-510
58	Instytut Hematologii i Transfuzjologii	Warszawa	Mazowieckie	Poland	02-776
59	Uniwersyteckie Centrum Kliniczne	Gdansk	Pomorskie	Poland	80-952
60	Instituto Portugues de Oncologia de Lisboa Francisco Gentil	Lisboa		Portugal	1090-023
61	Centro Hospitalar Sao Joao	Porto		Portugal	4200-319
62	Rostov State Medical University	Rostov-na-Donu	Rostov	Russian Federation	344022
63	Chelyabinsk Regional Clinical Hospital	Chelyabinsk		Russian Federation	454076
64	Kemerovo Regional Clinical Hospital	Kemerovo		Russian Federation	650066
65	GBUZ Moscow Clinical Scientific Center DZM	Moscow		Russian Federation	111123
66	Russian Academy of Medical Science	Moscow		Russian Federation	125167
67	FGU Russian Scientific Research Institute of Hematology and Transfusiology	Saint Petersburg		Russian Federation	191024
68	Almazov Federal North-West Medical Research Centre of Department of Health of Russian Federation	Saint Petersburg		Russian Federation	197341
69	Samara State Medical University	Samara		Russian Federation	443099
70	Saratov State Medical University	Saratov		Russian Federation	355018
71	Singapore General Hospital	Singapore		Singapore	169856
72	Hospital Regional Universitario Carlos Haya	Malaga	Andalucia	Spain	29010
73	Hospital Universitario de Gran Canaria Doctor Nergrin	Las Palmas de Gran Canaria	LAS Palmas	Spain	35010
74	Hospital Clinic i Provincial de Barcelona	Barcelona		Spain	08036
75	Hospital Universitario de La Princesa	Madrid		Spain	28006
76	Hospital Universitario Ramon Y Cajal	Madrid		Spain	28034
77	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
78	Akademiska Sjukhuset	Uppsala		Sweden	751 85
79	University Hospital Zurich	Zurich		Switzerland	8091
80	National Taiwan University Hospital	Taipei		Taiwan	100
81	Royal Liverpool University Hospital NHS Trust	Liverpool	England	United Kingdom	L7 8XP
82	King's College Hospital NHS Foundation Trust	London	England	United Kingdom	SE5 9RS
83	Imperial College Healthcare NHS Trust	London	England	United Kingdom	W12 0NN
84	Nottingham City Hospital NHS Trust	Nottingham	England	United Kingdom	NG5 1PB
85	Churchill Hospital	Oxford	England	United Kingdom	OX3 7LE
86	Beatson West of Scotland Cancer Centre	Glasgow	Scotland	United Kingdom	G12 0YN

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director Clinical Science, Takeda

Study Documents (Full-Text)

• Study Protocol - Oct 5, 2020
• Statistical Analysis Plan - Dec 17, 2019

More Information

Additional Information:

• Iclusig® (ponatinib) US Prescribing Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02467270
• Other Study ID Numbers: AP24534-14-203; 2014-001617-12; 15/LO/1192; U1111-1238-0007
• First Posted: Jun 10, 2015
• Last Update Posted: Jan 13, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Chronic Phase Chronic Myeloid Leukemia; Molecular Response; CML; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; CP-CML
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Ponatinib

Study Results

Participant Flow

Recruitment Details

Participants took part in the study at 61 investigative sites in the Argentina, Austria, Chile, Denmark, France, United Kingdom, Hong Kong, Italy, Japan, Poland, Russia, Singapore, Korea, Republic of, Spain, Sweden, Taiwan, Province Of China, and United States from 30 June 2015 and up to data cut-off: 31 May 2020. The study is ongoing.

Pre-assignment Detail

Participants with diagnosis of chronic phase-chronic myelogenous leukemia (CP-CML) who received at least 2 prior tyrosine kinase inhibitor (TKI) therapies were enrolled in 1:1:1 ratio in 3 cohorts: ponatinib: 45 mg (Cohort A); 30 mg (Cohort B); or 15 mg (Cohort C). Participants who started at 45/30 mg received mandatory dose reduction of their daily dose to 15 mg upon achievement of ≤1% breakpoint cluster region-Abelson 1 transcript level as measured by International Scale (BCR-ABL1IS).

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Period Title: Overall Study
STARTED	94	95	94
Treated (Safety Population)	94	94	94
COMPLETED	0	0	0
NOT COMPLETED	94	95	94

Baseline Characteristics

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg	Total
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.	Total of all reporting groups
Overall Participants	94	94	94	282
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.7 (14.77)	48.5 (12.90)	48.8 (12.71)	48.3 (13.45)
Sex: Female, Male (Count of Participants)
Female	44 46.8%	56 59.6%	41 43.6%	141 50%
Male	50 53.2%	38 40.4%	53 56.4%	141 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	22 23.4%	26 27.7%	20 21.3%	68 24.1%
Not Hispanic or Latino	70 74.5%	67 71.3%	72 76.6%	209 74.1%
Unknown or Not Reported	2 2.1%	1 1.1%	2 2.1%	5 1.8%
Race/Ethnicity, Customized (Count of Participants)
Asian	16 17%	12 12.8%	15 16%	43 15.2%
Black or African American	1 1.1%	2 2.1%	3 3.2%	6 2.1%
White	73 77.7%	77 81.9%	72 76.6%	222 78.7%
Unknown	0 0%	1 1.1%	3 3.2%	4 1.4%
Other	2 2.1%	1 1.1%	0 0%	3 1.1%
Missing	2 2.1%	1 1.1%	1 1.1%	4 1.4%
Region of Enrollment (Count of Participants)
Argentina	15 16%	16 17%	7 7.4%	38 13.5%
Austria	0 0%	0 0%	2 2.1%	2 0.7%
Chile	7 7.4%	9 9.6%	9 9.6%	25 8.9%
Denmark	0 0%	0 0%	1 1.1%	1 0.4%
France	2 2.1%	1 1.1%	2 2.1%	5 1.8%
United Kingdom	1 1.1%	4 4.3%	7 7.4%	12 4.3%
Hong Kong	1 1.1%	3 3.2%	2 2.1%	6 2.1%
Italy	0 0%	3 3.2%	0 0%	3 1.1%
Japan	5 5.3%	2 2.1%	4 4.3%	11 3.9%
Poland	4 4.3%	6 6.4%	5 5.3%	15 5.3%
Russia	38 40.4%	31 33%	38 40.4%	107 37.9%
Singapore	4 4.3%	3 3.2%	2 2.1%	9 3.2%
Korea, Republic Of	0 0%	3 3.2%	2 2.1%	5 1.8%
Spain	2 2.1%	1 1.1%	2 2.1%	5 1.8%
Sweden	1 1.1%	2 2.1%	2 2.1%	5 1.8%
Taiwan, Province Of China	4 4.3%	1 1.1%	2 2.1%	7 2.5%
United States	10 10.6%	9 9.6%	7 7.4%	26 9.2%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	78.14 (20.841)	77.56 (18.375)	76.71 (17.434)	77.47 (18.879)
Height (meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meter]	1.68 (0.104)	1.68 (0.098)	1.68 (0.090)	1.68 (0.097)
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score (Count of Participants)
Score= 0	74 78.7%	73 77.7%	72 76.6%	219 77.7%
Score= 1	19 20.2%	20 21.3%	22 23.4%	61 21.6%
Score= 2	1 1.1%	1 1.1%	0 0%	2 0.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Molecular Response (MR2: <=1% Breakpoint Cluster Region-Abelson Transcript Level) as Measured by the International Scale (BCR-ABL1IS) at Month 12
Description	MR2 is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL <=1% Breakpoint Cluster Region-Abelson Transcript Level as Measured by the International Scale (BCR-ABL1IS), equivalent to a 2-log reduction in transcript.
Time Frame	12 months after the first dose of study treatment

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized and for whom BCR-ABL1IS could be measured (ie, participants who had the b2a2/b3a2 transcript type), regardless of whether they received the assigned study drug.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	93	93	91
Number (95% Confidence Interval) [percentage of participants]	44.1 46.9%	29.0 30.9%	23.1 24.6%

2. Secondary Outcome

Title	Percentage of Participants With Major Molecular Response (MMR/MR3)
Description	MMR/MR3 is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).
Time Frame	12 months after the first dose of study treatment

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized and for whom BCR-ABL1IS could be measured (ie, participants who had the b2a2/b3a2 transcript type), regardless of whether they received the assigned study drug.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	93	93	91
Number [percentage of participants]	17.2 18.3%	20.4 21.7%	16.5 17.6%

3. Secondary Outcome

Title	Percentage of Participants With Major Cytogenetic Response (MCyR)
Description	MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: 0% Ph + metaphases; PCyR: >0 to 35% Ph + metaphases.
Time Frame	12 months after the first dose of study treatment

Outcome Measure Data

Analysis Population Description

ITT Cytogenetic Population included all participants who were randomized and had a cytogenetic assessment at Baseline with ≥20 metaphases examined, regardless of whether they received the assigned study drug. Overall number analyzed are participants with data available for analysis.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	91	90	89
Number (95% Confidence Interval) [percentage of participants]	48.4 51.5%	27.8 29.6%	43.8 46.6%

4. Secondary Outcome

Title	Duration of Major Molecular Response (MMR/MR3)
Description	Duration of MMR/MR3 is defined as the interval between the first assessment at which the criteria for <=0.1% MMR are met until the earliest date at which loss of <=0.1% MMR occurs, or the criteria for progression are met. Progression to accelerated phase (AP) is defined as: >= 15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets per liter (/L) in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to blast Phase (BP) is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
Time Frame	Baseline up to approximately 8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Percentage of Participants With Adjusted Incidence Rates for Treatment Emergent Arterial Occlusive Events (AOEs), Venous Thrombotic Events (VTEs), Adverse Events (AEs), and Serious AEs (SAEs)
Description	Percentage of participants with adjusted incidence rates who developed AOEs and VTEs were categorized according to arterial occlusive events and venous thrombotic events. AE is any untoward medical occurrence in participant administered medicinal investigational drug. Untoward medical occurrence does not necessarily have to have causal relationship with treatment. SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is congenital anomaly/birth defect/is medically important event that may not be immediately life-threatening/result in death or hospitalization, but may jeopardize participant/may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.
Time Frame	From first dose up to 30 days after last dose of the study drug up to data cut-off date: 31 May 2020 (Up to approximately 5 years)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least 1 dose of study drug.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	94	94	94
AOEs	9.6 10.2%	5.3 5.6%	3.2 3.4%
VTEs	1.1 1.2%	0 0%	0 0%
AEs	100.0 106.4%	93.6 99.6%	94.7 100.7%
SAEs	34.0 36.2%	25.5 27.1%	33.0 35.1%

6. Secondary Outcome

Title	Percentage of Participants With Complete Cytogenetic Response (CCyR)
Description	Cytogenetic response is defined as the percentage of Ph+ metaphases in bone marrow (peripheral blood may not be used), with a review of a minimum of 20 metaphases. CCyR is defined as 0% Ph+ metaphases.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

ITT Cytogenetic Population included all participants who were randomized and had a cytogenetic assessment at Baseline with ≥20 metaphases examined, regardless of whether they received the assigned study drug. Overall number analyzed are participants with data available for analysis.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	91	90	89
Number [percentage of participants]	34.1 36.3%	17.8 18.9%	29.2 31.1%

7. Secondary Outcome

Title	Percentage of Participants With Molecular Response 4 (MR4) and Molecular Response (MR4.5)
Description	MR4 is defined as <=0.01% BCR-ABL1IS. MR 4.5 is defined as <=0.0032% BCR-ALB1IS.
Time Frame	Up to approximately 8 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Percentage of Participants With Molecular Response 1 (MR1)
Description	MR1 is defined as percentage of participants achieving a ratio of <=10% Breakpoint Cluster Region-abelson (BCR-ABL1) transcripts on the international scale. MR1 is molecular response with 1-log reduction in transcript.
Time Frame	3 months after the first dose of study treatment

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized and for whom BCR-ABL1IS could be measured (ie, participants who had the b2a2/b3a2 transcript type), regardless of whether they received the assigned study drug.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	93	93	91
Number [percentage of participants]	52.7 56.1%	44.1 46.9%	42.9 45.6%

9. Secondary Outcome

Title	Percentage of Participants With Complete Hematologic Response (CHR)
Description	CHR is defined as achieving all of the following measurements: white blood cells (WBC) <= institutional upper limit of normal (ULN), platelets <450,000 per cubic millimeter (/mm^3), no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, and no extramedullary involvement (including no hepatomegaly or splenomegaly).
Time Frame	3 months after the first dose of study treatment

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the analysis.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	94	95	94
Number (95% Confidence Interval) [percentage of participants]	87.2 92.8%	81.1 86.3%	81.9 87.1%

10. Secondary Outcome

Title	Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption
Description	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	Up to data cut-off: 31 May 2020 (Approximately 5 years)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received at least 1 dose of study drug.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	94	94	94
TEAEs Leading to Treatment Discontinuation	19.1 20.3%	16.0 17%	13.8 14.7%
TEAEs Leading to Dose Reduction	45.7 48.6%	35.1 37.3%	31.9 33.9%
TEAEs Leading to Dose Interruption	71.3 75.9%	61.7 65.6%	58.5 62.2%

11. Secondary Outcome

Title	Kaplan-Meier Estimate of Duration of Response (DOR) of <=1% BCR-ABL1 IS (MR2) at Months 12 and 24
Description	DOR (≤1% BCR-ABL1IS) is defined as interval between first assessment at which criteria for ≤1% BCR-ABL1IS are met until earliest date at which loss of ≤1% BCR-ABL1IS occurs, or criteria for progression accelerated phase (AP) or blast Phase (BP) of chronic myeloid leukemia (CML) are met. Loss of ≤1% BCR-ABL1IS is an increase to >1% of BCR-ABL1IS. Progression to AP: ≥15% and <30% blasts in peripheral blood or bone marrow or ≥20% basophils in peripheral blood or bone marrow or ≥30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets per liter in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP: ≥30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Kaplan-Meier method was used for analysis of percentage of participants who achieved DOR of 12 and 24 months.
Time Frame	12 and 24 months after the first dose of study treatment

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized and for whom BCR-ABL1IS could be measured (ie, participants who had the b2a2/b3a2 transcript type), regardless of whether they received the assigned study drug. Data is reported for responders.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	52	35	33
Month 12	79.13 84.2%	79.20 84.3%	90.10 95.9%
Month 24	73.17 77.8%	75.60 80.4%	90.10 95.9%

12. Secondary Outcome

Title	Kaplan-Meier Estimate of Duration of Response (DOR) of Major Molecular Response (MMR/MR3)
Description	Duration of MMR/MR3 is defined as interval between first assessment at which criteria for MMR are met until earliest date at which loss of MMR occurs, or criteria for progression (progression to AP or BP of CML) are met. Participants remaining in MMR will be censored at last date at which criteria for MMR are met. Loss of MMR is an increase to >0.1% of BCR-ABL1IS. Progression to AP: >= 15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts+promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Kaplan-Meier method was used for analysis of percentage of participants who achieved DOR of 12 and 24 months.
Time Frame	12 and 24 months after the first dose of study treatment

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized and for whom BCR-ABL1IS could be measured (ie, participants who had the b2a2/b3a2 transcript type), regardless of whether they received the assigned study drug. Data is reported for responders.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	32	24	21
Month 12	88.97 94.6%	93.33 99.3%	94.74 100.8%
Month 24	88.97 94.6%	84.00 89.4%	94.74 100.8%

13. Secondary Outcome

Title	Duration of Response in Responders
Description	Duration of response in "responders" is defined as any participants who achieved ≤1% BCR-ABL1IS at any time during the study. Responders are defined as those participants who meet all of the following: are randomized and treated, respond at 12 months after the initiation of study treatment, and undergo baseline polymerase chain reaction (PCR) assessment.
Time Frame	Baseline up to data cut-off: 31 May 2020 (Approximately 5 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized and for whom BCR-ABL1IS could be measured (ie, participants who had the b2a2/b3a2 transcript type), regardless of whether they received the assigned study drug. Data is reported for responders.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	52	35	33
Median (95% Confidence Interval) [months]	NA	NA	NA

14. Secondary Outcome

Title	Time to Response
Description	Time to response was defined as the time interval from the date of the first dose of the study drug until the initial observation of CR or PR for participants with confirmed CR/PR. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.
Time Frame	Baseline up to data cut-off: 31 May 2020 (Approximately 5 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who were randomized and for whom BCR-ABL1IS could be measured (ie, participants who had the b2a2/b3a2 transcript type), regardless of whether they received the assigned study drug. Data is reported for the responders.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	52	35	33
Median (95% Confidence Interval) [months]	6.00	3.04	6.04

15. Secondary Outcome

Title	Percentage of Participants With Progression to Accelerated Phase (AP)-Chronic Myeloid Leukemia (CML) or Blast Phase (BP)-CML
Description	Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
Time Frame	From first dose date of study treatment up to data cut-off: 31 May 2020 (Approximately 5 years)

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the analysis.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	94	95	94
Progressed to AP-CML	10.6 11.3%	9.5 10.1%	11.7 12.4%
Progressed to BP-CML	3.2 3.4%	1.1 1.2%	1.1 1.2%

16. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS is defined as the interval between the first dose date of study treatment and the first date at which the criteria for progression are met (progression to the AP or BP of CML), or death due to any cause, censored at the last response assessment. Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
Time Frame	Up to data cut-off: 31 May 2020 (Up to approximately 5 years)

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the analysis.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	94	95	94
Median (95% Confidence Interval) [months]	NA	NA	45.64

17. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the interval between the first does of study treatment and death due to any cause, censored at the last contact date when the participant was alive.
Time Frame	Up to data cut-off: 31 May 2020 (Up to approximately 5 years)

Outcome Measure Data

Analysis Population Description

All randomized participants were included in the analysis.

Arm/Group Title	Cohort A: Ponatinib 45 mg	Cohort B: Ponatinib 30 mg	Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Measure Participants	94	95	94
Median (95% Confidence Interval) [months]	NA	NA	NA

Adverse Events

Time Frame	From first dose up to 30 days after last dose of the study drug up to data cut-off: 31 May 2020 (Up to approximately 5 years)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. All cause-mortality was collected for all randomized participants. Serious and other adverse events was collected for participants from Safety Population who received at least 1 dose of study drug.
Arm/Group Title	Cohort A: Ponatinib 45 mg		Cohort B: Ponatinib 30 mg		Cohort C: Ponatinib 15 mg
Arm/Group Description	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.		Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.		Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
All Cause Mortality
	Cohort A: Ponatinib 45 mg		Cohort B: Ponatinib 30 mg		Cohort C: Ponatinib 15 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/94 (8.5%)		7/95 (7.4%)		8/94 (8.5%)
Serious Adverse Events
	Cohort A: Ponatinib 45 mg		Cohort B: Ponatinib 30 mg		Cohort C: Ponatinib 15 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/94 (34%)		24/94 (25.5%)		31/94 (33%)
Blood and lymphatic system disorders
Thrombocytopenia	5/94 (5.3%)		2/94 (2.1%)		5/94 (5.3%)
Neutropenia	2/94 (2.1%)		1/94 (1.1%)		3/94 (3.2%)
Anaemia	3/94 (3.2%)		0/94 (0%)		0/94 (0%)
Febrile neutropenia	1/94 (1.1%)		0/94 (0%)		2/94 (2.1%)
Pancytopenia	0/94 (0%)		1/94 (1.1%)		1/94 (1.1%)
Bone marrow failure	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Splenomegaly	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Cardiac disorders
Atrial fibrillation	2/94 (2.1%)		2/94 (2.1%)		1/94 (1.1%)
Acute coronary syndrome	1/94 (1.1%)		1/94 (1.1%)		0/94 (0%)
Acute myocardial infarction	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Atrial flutter	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Cardio-respiratory arrest	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Myocardial infarction	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Myocardial ischaemia	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Pericarditis	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Ventricular tachycardia	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Angina unstable	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Endocrine disorders
Thyroiditis	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Eye disorders
Age-related macular degeneration	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Gastrointestinal disorders
Abdominal pain	1/94 (1.1%)		0/94 (0%)		1/94 (1.1%)
Abdominal pain upper	2/94 (2.1%)		0/94 (0%)		0/94 (0%)
Pancreatitis	1/94 (1.1%)		1/94 (1.1%)		0/94 (0%)
Pancreatitis acute	1/94 (1.1%)		0/94 (0%)		1/94 (1.1%)
Coeliac artery stenosis	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Gastritis	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Haematemesis	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Small intestinal haemorrhage	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Vomiting	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Mesenteric vascular Insufficiency	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
General disorders
Pyrexia	4/94 (4.3%)		0/94 (0%)		1/94 (1.1%)
Sudden death	2/94 (2.1%)		0/94 (0%)		0/94 (0%)
Fatigue	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
General physical health deterioration	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Influenza like illness	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Hepatobiliary disorders
Acute hepatic failure	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Cholecystitis	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Cholecystitis acute	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Cholelithiasis	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Hepatic function abnormal	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Hepatotoxicity	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Infections and infestations
Pneumonia	0/94 (0%)		1/94 (1.1%)		3/94 (3.2%)
Cellulitis	0/94 (0%)		0/94 (0%)		2/94 (2.1%)
Sepsis	1/94 (1.1%)		1/94 (1.1%)		0/94 (0%)
Gastroenteritis viral	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Infection	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Influenza	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Localised infection	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Meningitis	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Neutropenic sepsis	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Respiratory tract infection	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Urinary tract infection	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Appendicitis	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
COVID-19 pneumonia	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Tooth abscess	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Injury, poisoning and procedural complications
Subdural haematoma	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Tibia fracture	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Investigations
Lipase increased	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Metabolism and nutrition disorders
Dehydration	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Tumour lysis syndrome	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Osteoarthritis	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Malignant melanoma	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Blast crisis in myelogenous leukaemia	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Nervous system disorders
Dizziness	0/94 (0%)		2/94 (2.1%)		0/94 (0%)
Ischaemic stroke	1/94 (1.1%)		1/94 (1.1%)		2/94 (2.1%)
Cerebral haematoma	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Facial nerve disorder	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Headache	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Seizure	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Cerebrovascular accident	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Renal and urinary disorders
Acute kidney injury	0/94 (0%)		1/94 (1.1%)		1/94 (1.1%)
Renal colic	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Reproductive system and breast disorders
Metrorrhagia	0/94 (0%)		1/94 (1.1%)		0/94 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/94 (1.1%)		1/94 (1.1%)		0/94 (0%)
Skin and subcutaneous tissue disorders
Erythema multiforme	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Rash erythematous	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Rash pruritic	0/94 (0%)		0/94 (0%)		1/94 (1.1%)
Vascular disorders
Hypertension	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Hypertensive crisis	1/94 (1.1%)		0/94 (0%)		0/94 (0%)
Other (Not Including Serious) Adverse Events
	Cohort A: Ponatinib 45 mg		Cohort B: Ponatinib 30 mg		Cohort C: Ponatinib 15 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	92/94 (97.9%)		85/94 (90.4%)		86/94 (91.5%)
Blood and lymphatic system disorders
Thrombocytopenia	40/94 (42.6%)		36/94 (38.3%)		35/94 (37.2%)
Neutropenia	28/94 (29.8%)		22/94 (23.4%)		23/94 (24.5%)
Anaemia	20/94 (21.3%)		17/94 (18.1%)		16/94 (17%)
Leukopenia	5/94 (5.3%)		4/94 (4.3%)		7/94 (7.4%)
Gastrointestinal disorders
Constipation	10/94 (10.6%)		11/94 (11.7%)		14/94 (14.9%)
Abdominal pain	9/94 (9.6%)		8/94 (8.5%)		7/94 (7.4%)
Abdominal pain upper	8/94 (8.5%)		10/94 (10.6%)		3/94 (3.2%)
Nausea	7/94 (7.4%)		8/94 (8.5%)		8/94 (8.5%)
Diarrhoea	4/94 (4.3%)		4/94 (4.3%)		9/94 (9.6%)
Vomiting	4/94 (4.3%)		8/94 (8.5%)		5/94 (5.3%)
Dyspepsia	3/94 (3.2%)		5/94 (5.3%)		3/94 (3.2%)
General disorders
Fatigue	7/94 (7.4%)		7/94 (7.4%)		4/94 (4.3%)
Pyrexia	14/94 (14.9%)		4/94 (4.3%)		9/94 (9.6%)
Asthenia	3/94 (3.2%)		5/94 (5.3%)		2/94 (2.1%)
Non-cardiac chest pain	1/94 (1.1%)		5/94 (5.3%)		2/94 (2.1%)
Infections and infestations
Folliculitis	5/94 (5.3%)		0/94 (0%)		1/94 (1.1%)
Upper respiratory tract infection	7/94 (7.4%)		4/94 (4.3%)		6/94 (6.4%)
Investigations
Lipase increased	19/94 (20.2%)		17/94 (18.1%)		12/94 (12.8%)
Platelet count decreased	11/94 (11.7%)		9/94 (9.6%)		10/94 (10.6%)
Alanine aminotransferase increased	21/94 (22.3%)		6/94 (6.4%)		16/94 (17%)
Aspartate aminotransferase increased	13/94 (13.8%)		3/94 (3.2%)		8/94 (8.5%)
Blood alkaline phosphatase increased	5/94 (5.3%)		3/94 (3.2%)		7/94 (7.4%)
Blood cholesterol increased	5/94 (5.3%)		4/94 (4.3%)		5/94 (5.3%)
Amylase increased	5/94 (5.3%)		3/94 (3.2%)		1/94 (1.1%)
Blood triglycerides increased	5/94 (5.3%)		1/94 (1.1%)		2/94 (2.1%)
Metabolism and nutrition disorders
Hypertriglyceridaemia	14/94 (14.9%)		9/94 (9.6%)		9/94 (9.6%)
Hypercholesterolaemia	5/94 (5.3%)		5/94 (5.3%)		7/94 (7.4%)
Hyperglycaemia	5/94 (5.3%)		10/94 (10.6%)		8/94 (8.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/94 (9.6%)		20/94 (21.3%)		13/94 (13.8%)
Myalgia	7/94 (7.4%)		6/94 (6.4%)		10/94 (10.6%)
Musculoskeletal pain	5/94 (5.3%)		8/94 (8.5%)		3/94 (3.2%)
Pain in extremity	8/94 (8.5%)		9/94 (9.6%)		7/94 (7.4%)
Back pain	7/94 (7.4%)		9/94 (9.6%)		5/94 (5.3%)
Nervous system disorders
Headache	16/94 (17%)		16/94 (17%)		18/94 (19.1%)
Dizziness	4/94 (4.3%)		6/94 (6.4%)		2/94 (2.1%)
Psychiatric disorders
Insomnia	5/94 (5.3%)		4/94 (4.3%)		3/94 (3.2%)
Respiratory, thoracic and mediastinal disorders
Cough	6/94 (6.4%)		2/94 (2.1%)		3/94 (3.2%)
Skin and subcutaneous tissue disorders
Rash	12/94 (12.8%)		9/94 (9.6%)		4/94 (4.3%)
Rash maculo-papular	6/94 (6.4%)		7/94 (7.4%)		4/94 (4.3%)
Dry skin	11/94 (11.7%)		5/94 (5.3%)		4/94 (4.3%)
Dermatitis	6/94 (6.4%)		3/94 (3.2%)		1/94 (1.1%)
Alopecia	3/94 (3.2%)		5/94 (5.3%)		5/94 (5.3%)
Hyperhidrosis	3/94 (3.2%)		2/94 (2.1%)		5/94 (5.3%)
Rash papular	3/94 (3.2%)		5/94 (5.3%)		1/94 (1.1%)
Vascular disorders
Hypertension	26/94 (27.7%)		32/94 (34%)		22/94 (23.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.