Trial Outcomes & Findings for Ponatinib in Participants With Resistant Chronic Phase Chronic Myeloid Leukemia (CP-CML) to Characterize the Efficacy and Safety of a Range of Doses (NCT NCT02467270)

Last Updated: 2025-05-01

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

283 participants

Primary outcome timeframe

12 months after the first dose of study treatment

Results posted on

2025-05-01

Participant Flow

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.

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).

Participant milestones

Participant milestones
Measure	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.	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.	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.
Overall Study STARTED	94	95	94
Overall Study Treated (Safety Population)	94	94	94
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	94	95	94

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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.
Overall Study Participants Never Treated	0	1	0
Overall Study Ongoing	50	41	43
Overall Study Adverse Event	16	15	14
Overall Study Progressive Disease	7	7	4
Overall Study Death	2	0	2
Overall Study Lack of Efficacy	12	18	23
Overall Study Non-compliance With Study Drug	0	2	1
Overall Study Lost to Follow-up	2	1	0
Overall Study Pregnancy	0	1	0
Overall Study Physician Decision	0	4	1
Overall Study Withdrawal by Subject	4	3	5
Overall Study Reason not Specified	1	2	1

Baseline Characteristics

Number analyzed is the number of participants with data available for height at Baseline.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort A: Ponatinib 45 mg n=94 Participants 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.	Cohort B: Ponatinib 30 mg n=94 Participants 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.	Cohort C: Ponatinib 15 mg n=94 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.	Total n=282 Participants Total of all reporting groups
Age, Continuous	47.7 years STANDARD_DEVIATION 14.77 • n=94 Participants	48.5 years STANDARD_DEVIATION 12.90 • n=94 Participants	48.8 years STANDARD_DEVIATION 12.71 • n=94 Participants	48.3 years STANDARD_DEVIATION 13.45 • n=282 Participants
Sex: Female, Male Female	44 Participants n=94 Participants	56 Participants n=94 Participants	41 Participants n=94 Participants	141 Participants n=282 Participants
Sex: Female, Male Male	50 Participants n=94 Participants	38 Participants n=94 Participants	53 Participants n=94 Participants	141 Participants n=282 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	22 Participants n=94 Participants	26 Participants n=94 Participants	20 Participants n=94 Participants	68 Participants n=282 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	70 Participants n=94 Participants	67 Participants n=94 Participants	72 Participants n=94 Participants	209 Participants n=282 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=94 Participants	1 Participants n=94 Participants	2 Participants n=94 Participants	5 Participants n=282 Participants
Race/Ethnicity, Customized Race · Asian	16 Participants n=94 Participants	12 Participants n=94 Participants	15 Participants n=94 Participants	43 Participants n=282 Participants
Race/Ethnicity, Customized Race · Black or African American	1 Participants n=94 Participants	2 Participants n=94 Participants	3 Participants n=94 Participants	6 Participants n=282 Participants
Race/Ethnicity, Customized Race · White	73 Participants n=94 Participants	77 Participants n=94 Participants	72 Participants n=94 Participants	222 Participants n=282 Participants
Race/Ethnicity, Customized Race · Unknown	0 Participants n=94 Participants	1 Participants n=94 Participants	3 Participants n=94 Participants	4 Participants n=282 Participants
Race/Ethnicity, Customized Race · Other	2 Participants n=94 Participants	1 Participants n=94 Participants	0 Participants n=94 Participants	3 Participants n=282 Participants
Race/Ethnicity, Customized Race · Missing	2 Participants n=94 Participants	1 Participants n=94 Participants	1 Participants n=94 Participants	4 Participants n=282 Participants
Region of Enrollment Argentina	15 Participants n=94 Participants	16 Participants n=94 Participants	7 Participants n=94 Participants	38 Participants n=282 Participants
Region of Enrollment Austria	0 Participants n=94 Participants	0 Participants n=94 Participants	2 Participants n=94 Participants	2 Participants n=282 Participants
Region of Enrollment Chile	7 Participants n=94 Participants	9 Participants n=94 Participants	9 Participants n=94 Participants	25 Participants n=282 Participants
Region of Enrollment Denmark	0 Participants n=94 Participants	0 Participants n=94 Participants	1 Participants n=94 Participants	1 Participants n=282 Participants
Region of Enrollment France	2 Participants n=94 Participants	1 Participants n=94 Participants	2 Participants n=94 Participants	5 Participants n=282 Participants
Region of Enrollment United Kingdom	1 Participants n=94 Participants	4 Participants n=94 Participants	7 Participants n=94 Participants	12 Participants n=282 Participants
Region of Enrollment Hong Kong	1 Participants n=94 Participants	3 Participants n=94 Participants	2 Participants n=94 Participants	6 Participants n=282 Participants
Region of Enrollment Italy	0 Participants n=94 Participants	3 Participants n=94 Participants	0 Participants n=94 Participants	3 Participants n=282 Participants
Region of Enrollment Japan	5 Participants n=94 Participants	2 Participants n=94 Participants	4 Participants n=94 Participants	11 Participants n=282 Participants
Region of Enrollment Poland	4 Participants n=94 Participants	6 Participants n=94 Participants	5 Participants n=94 Participants	15 Participants n=282 Participants
Region of Enrollment Russia	38 Participants n=94 Participants	31 Participants n=94 Participants	38 Participants n=94 Participants	107 Participants n=282 Participants
Region of Enrollment Singapore	4 Participants n=94 Participants	3 Participants n=94 Participants	2 Participants n=94 Participants	9 Participants n=282 Participants
Region of Enrollment Korea, Republic Of	0 Participants n=94 Participants	3 Participants n=94 Participants	2 Participants n=94 Participants	5 Participants n=282 Participants
Region of Enrollment Spain	2 Participants n=94 Participants	1 Participants n=94 Participants	2 Participants n=94 Participants	5 Participants n=282 Participants
Region of Enrollment Sweden	1 Participants n=94 Participants	2 Participants n=94 Participants	2 Participants n=94 Participants	5 Participants n=282 Participants
Region of Enrollment Taiwan, Province Of China	4 Participants n=94 Participants	1 Participants n=94 Participants	2 Participants n=94 Participants	7 Participants n=282 Participants
Region of Enrollment United States	10 Participants n=94 Participants	9 Participants n=94 Participants	7 Participants n=94 Participants	26 Participants n=282 Participants
Weight	78.14 kg STANDARD_DEVIATION 20.841 • n=94 Participants	77.56 kg STANDARD_DEVIATION 18.375 • n=94 Participants	76.71 kg STANDARD_DEVIATION 17.434 • n=94 Participants	77.47 kg STANDARD_DEVIATION 18.879 • n=282 Participants
Height	1.68 meter STANDARD_DEVIATION 0.104 • n=94 Participants • Number analyzed is the number of participants with data available for height at Baseline.	1.68 meter STANDARD_DEVIATION 0.098 • n=91 Participants • Number analyzed is the number of participants with data available for height at Baseline.	1.68 meter STANDARD_DEVIATION 0.090 • n=92 Participants • Number analyzed is the number of participants with data available for height at Baseline.	1.68 meter STANDARD_DEVIATION 0.097 • n=277 Participants • Number analyzed is the number of participants with data available for height at Baseline.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score Score= 0	74 Participants n=94 Participants	73 Participants n=94 Participants	72 Participants n=94 Participants	219 Participants n=282 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score Score= 1	19 Participants n=94 Participants	20 Participants n=94 Participants	22 Participants n=94 Participants	61 Participants n=282 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score Score= 2	1 Participants n=94 Participants	1 Participants n=94 Participants	0 Participants n=94 Participants	2 Participants n=282 Participants

PRIMARY outcome

Timeframe: 12 months after the first dose of study treatment

Population: 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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=93 Participants 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.	Cohort B: Ponatinib 30 mg n=93 Participants 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.	Cohort C: Ponatinib 15 mg n=91 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
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	44.1 percentage of participants Interval 33.8 to 54.8	29.0 percentage of participants Interval 20.1 to 39.4	23.1 percentage of participants Interval 14.9 to 33.1

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=93 Participants 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.	Cohort B: Ponatinib 30 mg n=93 Participants 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.	Cohort C: Ponatinib 15 mg n=91 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Percentage of Participants With Major Molecular Response (MMR/MR3)	17.2 percentage of participants	20.4 percentage of participants	16.5 percentage of participants

SECONDARY outcome

Timeframe: 12 months after the first dose of study treatment

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=91 Participants 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.	Cohort B: Ponatinib 30 mg n=90 Participants 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.	Cohort C: Ponatinib 15 mg n=89 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Percentage of Participants With Major Cytogenetic Response (MCyR)	48.4 percentage of participants Interval 37.7 to 59.1	27.8 percentage of participants Interval 18.9 to 38.2	43.8 percentage of participants Interval 33.3 to 54.7

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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)

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

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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=94 Participants 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.	Cohort B: Ponatinib 30 mg n=94 Participants 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.	Cohort C: Ponatinib 15 mg n=94 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
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) AEs	100.0 percentage of participants	93.6 percentage of participants	94.7 percentage of participants
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) VTEs	1.1 percentage of participants	0 percentage of participants	0 percentage of participants
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) AOEs	9.6 percentage of participants	5.3 percentage of participants	3.2 percentage of participants
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) SAEs	34.0 percentage of participants	25.5 percentage of participants	33.0 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=91 Participants 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.	Cohort B: Ponatinib 30 mg n=90 Participants 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.	Cohort C: Ponatinib 15 mg n=89 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Percentage of Participants With Complete Cytogenetic Response (CCyR)	34.1 percentage of participants	17.8 percentage of participants	29.2 percentage of participants

SECONDARY outcome

Timeframe: Up to approximately 8 years

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=93 Participants 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.	Cohort B: Ponatinib 30 mg n=93 Participants 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.	Cohort C: Ponatinib 15 mg n=91 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Percentage of Participants With Molecular Response 1 (MR1)	52.7 percentage of participants	44.1 percentage of participants	42.9 percentage of participants

SECONDARY outcome

Timeframe: 3 months after the first dose of study treatment

Population: All randomized participants were included in the analysis.

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).

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=94 Participants 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.	Cohort B: Ponatinib 30 mg n=95 Participants 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.	Cohort C: Ponatinib 15 mg n=94 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Percentage of Participants With Complete Hematologic Response (CHR)	87.2 percentage of participants Interval 78.8 to 93.2	81.1 percentage of participants Interval 71.7 to 88.4	81.9 percentage of participants Interval 72.6 to 89.1

SECONDARY outcome

Timeframe: Up to data cut-off: 31 May 2020 (Approximately 5 years)

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

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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=94 Participants 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.	Cohort B: Ponatinib 30 mg n=94 Participants 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.	Cohort C: Ponatinib 15 mg n=94 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption TEAEs Leading to Treatment Discontinuation	19.1 percentage of participants	16.0 percentage of participants	13.8 percentage of participants
Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption TEAEs Leading to Dose Reduction	45.7 percentage of participants	35.1 percentage of participants	31.9 percentage of participants
Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption TEAEs Leading to Dose Interruption	71.3 percentage of participants	61.7 percentage of participants	58.5 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=52 Participants 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.	Cohort B: Ponatinib 30 mg n=35 Participants 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.	Cohort C: Ponatinib 15 mg n=33 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Kaplan-Meier Estimate of Duration of Response (DOR) of <=1% BCR-ABL1 IS (MR2) at Months 12 and 24 Month 12	79.13 percentage of participants Interval 64.5 to 88.3	79.20 percentage of participants Interval 61.2 to 89.5	90.10 percentage of participants Interval 72.4 to 96.7
Kaplan-Meier Estimate of Duration of Response (DOR) of <=1% BCR-ABL1 IS (MR2) at Months 12 and 24 Month 24	73.17 percentage of participants Interval 57.0 to 84.1	75.60 percentage of participants Interval 56.9 to 87.0	90.10 percentage of participants Interval 72.4 to 96.7

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=32 Participants 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.	Cohort B: Ponatinib 30 mg n=24 Participants 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.	Cohort C: Ponatinib 15 mg n=21 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Kaplan-Meier Estimate of Duration of Response (DOR) of Major Molecular Response (MMR/MR3) Month 12	88.97 percentage of participants Interval 69.5 to 96.3	93.33 percentage of participants Interval 61.3 to 99.0	94.74 percentage of participants Interval 68.1 to 99.2
Kaplan-Meier Estimate of Duration of Response (DOR) of Major Molecular Response (MMR/MR3) Month 24	88.97 percentage of participants Interval 69.5 to 96.3	84.00 percentage of participants Interval 48.7 to 95.9	94.74 percentage of participants Interval 68.1 to 99.2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=52 Participants 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.	Cohort B: Ponatinib 30 mg n=35 Participants 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.	Cohort C: Ponatinib 15 mg n=33 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Duration of Response in Responders	NA months Interval 26.9 to Median and upper limit of 95% confidence interval (CI) was not estimable as participants were censored.	NA months Interval 27.3 to Median and upper limit of 95% CI was not estimable as participants were censored.	NA months Median, upper limit and lower limit of 95% CI was not estimable as participants were censored.

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=52 Participants 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.	Cohort B: Ponatinib 30 mg n=35 Participants 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.	Cohort C: Ponatinib 15 mg n=33 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Time to Response	6.00 months Interval 3.1 to 6.0	3.04 months Interval 3.0 to 6.0	6.04 months Interval 3.0 to 9.1

SECONDARY outcome

Timeframe: From first dose date of study treatment up to data cut-off: 31 May 2020 (Approximately 5 years)

Population: All randomized participants were included in the analysis.

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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=94 Participants 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.	Cohort B: Ponatinib 30 mg n=95 Participants 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.	Cohort C: Ponatinib 15 mg n=94 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Percentage of Participants With Progression to Accelerated Phase (AP)-Chronic Myeloid Leukemia (CML) or Blast Phase (BP)-CML Progressed to AP-CML	10.6 percentage of participants	9.5 percentage of participants	11.7 percentage of participants
Percentage of Participants With Progression to Accelerated Phase (AP)-Chronic Myeloid Leukemia (CML) or Blast Phase (BP)-CML Progressed to BP-CML	3.2 percentage of participants	1.1 percentage of participants	1.1 percentage of participants

SECONDARY outcome

Timeframe: Up to data cut-off: 31 May 2020 (Up to approximately 5 years)

Population: All randomized participants were included in the analysis.

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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=94 Participants 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.	Cohort B: Ponatinib 30 mg n=95 Participants 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.	Cohort C: Ponatinib 15 mg n=94 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Progression-free Survival (PFS)	NA months Median, Lower limit and Upper limit of 95% confidence interval was not estimable due to low number of participants with event.	NA months Interval 35.6 to Median and Upper limit of 95% confidence interval was not estimable due to low number of participants with event.	45.64 months Interval 38.7 to Upper limit of 95% confidence interval was not estimable due to low number of participants with event.

SECONDARY outcome

Timeframe: Up to data cut-off: 31 May 2020 (Up to approximately 5 years)

Population: All randomized participants were included in the analysis.

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.

Outcome measures

Outcome measures
Measure	Cohort A: Ponatinib 45 mg n=94 Participants 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.	Cohort B: Ponatinib 30 mg n=95 Participants 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.	Cohort C: Ponatinib 15 mg n=94 Participants Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.
Overall Survival (OS)	NA months Median, Lower limit and Upper limit of 95% confidence interval was not estimable due to low number of participants with event.	NA months Median, Lower limit and Upper limit of 95% confidence interval was not estimable due to low number of participants with event.	NA months Median, Lower limit and Upper limit of 95% confidence interval was not estimable due to low number of participants with event.

Adverse Events

Cohort A: Ponatinib 45 mg

Serious events: 32 serious events

Other events: 92 other events

Deaths: 8 deaths

Cohort B: Ponatinib 30 mg

Serious events: 24 serious events

Other events: 85 other events

Deaths: 7 deaths

Cohort C: Ponatinib 15 mg

Serious events: 31 serious events

Other events: 86 other events

Deaths: 8 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER