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Ponatinib 30 mg, tablets, orally, once daily (QD), with vincristine 1.4 mg/m\^2 (max 2 mg) intravenous (IV), on Days 1 and 14 and dexamethasone 40 mg (\<60 years \[yrs\]) and 20 mg (≥60 yrs), orally, once on Days 1 to 4, Days 11 to 14 for up to 3 cycles (each cycle=28 days) in induction phase (reduced dose of ponatinib 15 mg upon achievement of MRD-negative CR at end of induction) followed by ponatinib last induction phase dose with cytarabine, 1000 mg/m\^2 as 2-hour IV infusion (\<60 yrs) and 250 mg/m\^2 (≥60 yrs) every 12 hours, IV on Days 1, 3, 5 of Cycles 2,4,6 and methotrexate, 1000 mg/m\^2 (\<60 yrs) and 250 mg/m\^2 (≥60 yrs), IV infusion, on Day 1 of cycles 1, 3, 5 in consolidation phase followed by ponatinib last consolidation phase dose with vincristine 1.4 mg/m\^2 (max 2 mg), IV, on Day 1 and prednisone 200 mg (\<60 yrs), 100 mg (≥60-69 yrs) and 50 mg(≥70 yrs) on Days 1 to 5 for up to 11 cycles in maintenance phase up to data cut-off date: 12 August 2022.

Imatinib 600 mg, tablets, orally, QD, with vincristine 1.4 mg/m\^2 (max 2 mg), IV, on Days 1 and 14 and dexamethasone 40 mg (\<60 yrs) and 20 mg (≥60 yrs), orally, once on Days 1 to 4 and Days 11 to 14 in each 28-day cycle for up to 3 cycles in the induction phase followed by imatinib 600 mg, tablets, orally, QD, with cytarabine, 1000 mg/m\^2 every 12 hours as a 2-hour-IV infusion (\<60 yrs) and 250 mg/m\^2 every 12 hours (≥60 yrs), IV on Days 1, 3, and 5 of each 28-day even cycles (Cycles 2, 4, and 6), and methotrexate, 1000 mg/m\^2 (\<60 yrs) and 250 mg/m\^2 (≥60 yrs), IV infusion, on Day 1 of each 28-day odd cycles (Cycle 1, 3, and 5) in consolidation phase followed by imatinib 600 mg, tablets, orally, QD, along with vincristine 1.4 mg/m\^2 (max 2 mg), IV, on Day 1 and prednisone 200 mg (\<60 yrs), 100 mg (≥60-69 yrs) and 50 mg (≥70 yrs) on Days 1 through 5 in each 28-day cycle up to 11 cycles in maintenance phase up to data cut-off date: 12 August 2022.

Imatinib

Study Director

In this study, adults with newly-diagnosed Philadelphia Chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) will receive first-line therapy of ponatinib or imatinib.

The main aim of this study is to compare the number of participants on each treatment that show no signs of disease.

Participants will take tablets of either ponatinib or imatinib at the same time each day combined with reduced-intensity chemotherapy for up to 20 months. Then, they will continue with single-agent therapy (ponatinib or imatinib) until they meet the discontinuation criteria from the study.

The drug being tested in this study is called ponatinib. Ponatinib is being tested to treat people who have newly diagnosed Ph+ ALL. This study will look at the efficacy of ponatinib in participants in addition to standard care.

The study will enroll approximately 230 participants. Participants will be randomized in a 2:1 ratio to receive oral ponatinib or imatinib (Cohort A and Cohort B, respectively) daily throughout the study.

All participants will be asked to take ponatinib or imatinib at the same time each day with reduced-intensity chemotherapy in induction phase (Cycles 1 to 3), consolidation phase (Cycles 4 to 9) and maintenance phase (Cycles 10 to 20). At the end of the 20 cycles, participants will remain on ponatinib or imatinib (administered as a single agent). The dose of ponatinib in consolidation and maintenance phase will start with the last dose given in the previous phase. The dose can be modified based on MRD-negative CR results.

This multi-center trial will be conducted in Argentina, Australia, Austria, Belarus, Brazil, Bulgaria, Canada, Chile, France, Mexico, Greece, Italy, Japan, Korea, Republic Of, Poland, Romania, Russia, Spain, Taiwan, Province Of China, Turkey, Finland and the United States. Participants including those who achieve a clinical response, may receive study drug until they are deceased, have failed to achieve the primary endpoint, have experienced relapse from CR or have progressive disease, have an unacceptable toxicity, have withdrawn consent, have proceeded to HSCT, or until the sponsor terminates the study, whichever occurs first. After disease progression, all participants will be contacted every 3 months for survival follow-up. Participants will be followed until completion of the study or until the participant's death has been reported.

It is an open-label trial, therefore investigators and participants are unblinded.

A Study of Ponatinib Versus Imatinib in Adults With Acute Lymphoblastic Leukemia

A Phase 3, Randomized, Open-label, Multicenter Study Comparing Ponatinib Versus Imatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

MRD-negative CR was achieved when a participant met the criteria for both MRD negativity and CR. MRD-negativity: ≤0.01 % breakpoint cluster region-Abelson (BCR-ABL1/ABL1), or undetectable BCR-ABL1 transcripts in complementary deoxyribonucleic acid (cDNA) with ≥ 10,000 ABL1 transcripts. CR: meeting all the following for at least 4 weeks (that is no recurrence):1. No circulating blasts and less than (\<) 5% blasts in the bone marrow (BM). 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (central nervous system \[CNS\] involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. Absolute neutrophil count (ANC) \> 1000 per microliter (/mcL) (or \>1.0\*10\^9/L). 5. Platelets \>100,000/mcL (or \>100\*10\^9/L).

EFS is defined as the dates of randomization until death due to any cause or failure to achieve CR by end of induction or relapse from CR. CR: meeting all the following for at least 4 weeks (that is no recurrence):1. No circulating blasts and less than (\<) 5% blasts in the bone marrow (BM). 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (central nervous system \[CNS\] involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. Absolute neutrophil count (ANC) greater than (\>) 1000 per micro liter (/mcL) (or \>1.0\*10\^9/L). 5. Platelets \>100,000/mcL (or \>100\*10\^9/L).Relapse from CR: reappearance of blasts in the blood or BM (\>=5%) or in any extramedullary site after a CR.

CR is defined as meeting all the following for at least 4 weeks (that is, no recurrence): 1. No circulating blasts and \<5% blasts in the BM. 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (CNS involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. ANC \>1000/mcL (or \>1.0\*10\^9/L). 5. Platelets \>100,000/mcL (or \>100\*10\^9/L). CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC.

Molecule response is assessed by 3-Log Reduction (MR3), Molecular Response 4-Log Reduction (MR4) and Molecular Response 4.5-Log Reduction (MR4.5). MR3 is defined as molecular response 3-log reduction (\<=0.1% BCR-ABL1/ABL1), or undetectable BCR-ABL1 transcripts in cDNA with \>=1000 ABL1 transcripts. MR4 is defined as molecular response 4-log reduction (\<=0.01% BCR-ABL1/ABL1), or undetectable BCR-ABL1 transcripts in cDNA with \>=10,000 ABL1 transcripts. MR4.5 is defined as Molecular response 4.5-log reduction (\<=0.0032% BCR-ABL1/ABL1), or undetectable BCR-ABL1 transcripts in cDNA with \>=32,000 ABL1 transcripts.

PIF is defined as participants who received treatment for ALL but never achieved CR or CRi by the end of induction. PIF is not limited by the number of unsuccessful treatments; this disease status only applies to recipients who have never been in CR or CRi. CR is defined as meeting all the following for at least 4 weeks (that is no recurrence): 1. No circulating blasts and \<5% blasts in the BM. 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (CNS involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. ANC \>1000/mcL (or \>1.0\*10\^9/L). 5. Platelets \>100,000/mcL (or \>100\*10\^9/L). CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC.

ORR is defined as CR + CRi by end of induction. CR is defined as meeting all the following for at least 4 weeks (that is no recurrence): 1. No circulating blasts and \<5% blasts in the BM. 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (CNS involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. ANC \>1000/mcL (or \>1.0\*10\^9/L). 5. Platelets \>100,000/mcL (or \>100\*10\^9/L). CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC.

MRD is defined as the percentage of participants achieving CR who are MRD-negative at multiple intervals after end of induction. MRD negativity: \<=0.01% BCR-ABL1/ABL1, or undetectable BCR-ABL1 transcripts in cDNA with \>=10,000 ABL1 transcripts. Relapse from CR: Reappearance of blasts in the blood or BM (\>=5%) or in any extramedullary site after a CR.

Duration of MRD-negative CR is defined as interval between the first assessment at which the criteria for MRD-negative CR are met until the earliest date at which loss of MRD negativity or relapse from CR occurs. MRD negativity (MR4): \<=0.01% BCR-ABL1/ABL1, or undetectable BCR-ABL1 transcripts in cDNA with \>=10,000 ABL1 transcripts. CR is defined as meeting all the following for at least 4 weeks (that is, no recurrence): 1. No circulating blasts and \<5% blasts in the BM. 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (CNS involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. ANC \>1000/mcL (or \>1.0\*10\^9/L). 5. Platelets \>100,000/mcL (or \>100\*10\^9/L). Relapse from CR: Reappearance of blasts in the blood or BM (\>=5%) or in any extramedullary site after a CR.

Duration of CR is defined as interval between the first assessment at which the criteria for CR are met until the earliest date at which relapse from CR occurs. CR is defined as meeting all the following for at least 4 weeks (that is no recurrence): 1. No circulating blasts and \<5% blasts in the BM. 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (CNS involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. ANC \>1000/mcL (or \>1.0\*10\^9/L). 5. Platelets \>100,000/mcL (or \>100\*10\^9/L). Relapse from CR: Reappearance of blasts in the blood or BM (\>=5%) or in any extramedullary site after a CR.

Time to treatment failure is defined as time to end of study randomized treatment (except for hematopoietic stem cell transplantation \[HSCT\] without loss of MRD-negative CR) due to safety and efficacy reasons. MRD-negative CR is achieved when a participant meets the criteria for both MRD negativity and CR. MRD-negativity: \<=0.01% BCR-ABL1/ABL1, or undetectable BCR-ABL1 transcripts in cDNA with \>=10,000 ABL1 transcripts. CR: meeting all the following for at least 4 weeks (that is no recurrence):1. No circulating blasts and \<5% blasts in the BM. 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (CNS involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. ANC \>1000/mcL (or \>1.0\*10\^9/L). 5. Platelets \>100,000/mcL (or \>100\*10\^9/L).

Duration of MR4.5 is defined as interval between the first assessment at which the criteria for MR4.5 are met until the earliest date at which loss of MR4.5 occurs. MR4.5 is molecular response 4.5-log reduction (\<=0.0032% BCR-ABL1/ABL1), or undetectable BCR-ABL1 transcripts in cDNA with \>=32,000 ABL1 transcripts.

On-study participants with or without HSCT will be evaluated. OS is defined as interval between randomization and death due to any cause, censored at the last contact date when the participant was alive.

On-study participants with or without HSCT will be evaluated. Relapse from CR is defined as reappearance of blasts in the blood or BM (\>=5%) or in any extramedullary site after a CR.

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

Takeda

Safety population was defined as all participants who were randomized to the ponatinib or imatinib arm and received at least 1 dose of any study drug.

Ponatinib 30 mg, tablets, orally, once daily (QD), with vincristine 1.4 mg/m\^2 (max 2 mg) intravenous (IV), on Days 1 and 14 and dexamethasone 40 mg (\<60 years \[yrs\]) and 20 mg (≥60 yrs), orally, once on Days 1 to 4, Days 11 to 14 for up to 3 cycles (each cycle=28 days) in induction phase (IP) (reduced dose of ponatinib 15 mg upon achievement of MRD-negative CR at end of induction) followed by ponatinib last induction phase dose with cytarabine, 1000 mg/m\^2 as 2-hour IV infusion (\<60 yrs) and 250 mg/m\^2 (≥60 yrs) every 12 hours, IV on Days 1, 3, 5 of Cycles 2,4,6 and methotrexate, 1000 mg/m\^2 (\<60 yrs) and 250 mg/m\^2 (≥60 yrs), IV infusion, on Day 1 of cycles 1, 3, 5 in consolidation phase (CP) followed by ponatinib last consolidation phase dose with vincristine 1.4 mg/m\^2 (max 2 mg), IV, on Day 1 and prednisone 200 mg (\<60 yrs), 100 mg (≥60-69 yrs) and 50 mg(≥70 yrs) on Days 1 to 5 for up to 11 cycles in maintenance phase (MP) up to data cut-off date: 12 August 2022.

Cohort A: Ponatinib 30 mg

Cohort B: Imatinib 600 mg

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Hispanic or Latino

Non-Hispanic and Latino

Not reported

Unknown

Race/Ethnicity, Customized

Australia

China

Korea, South

Taiwan

Austria

France

Greece

Italy

Poland

Russia

Spain

Turkey

Canada

Mexico

United States

Argentina

Brazil

Region of Enrollment

Number analyzed are the number of participants available for height at baseline.

Height

Number analyzed are the number of participants available for weight at baseline.

Weight

Number analyzed are the number of participants available for BSA at baseline.

Body Surface Area (BSA)

ITT analysis set was defined as all participants who were randomized.

Medical

ITT population with p190/p210 variant was defined as all participants in the ITT population who were identified by the central laboratory as having baseline breakpoint cluster region-Abelson1 (BCR-ABL1) dominant variants of p190 or p210.

Spots Global Cancer Trial Database for philadelphia chromosome positive acute lymphoblastic leukemia (ph+all)