An Efficacy Study Comparing Ponatinib Versus Imatinib, Administered in Combination with Reduced-Intensity Chemotherapy, in Participants with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

INTERVENTION: Product Name: IMATINIB,Product Code: SUB25387,Pharmaceutical Form: FILM‐COATED TABLET,Other descriptive name: Imatinib,Strength: 100mg,Product Code: PRD10852522,Pharmaceutical Form: FILM‐COATED TABLET,Other descriptive name: ,Strength: Ponatinib 15mg,Current Sponsor code: Ponatinib (AP24534; Iclusig),Product Code: PRD10852523,Pharmaceutical Form: FILM‐COATED TABLET,Other descriptive name: ,Strength: Ponatinib 30mg,Current Sponsor code: Ponatinib (AP24534; Iclusig),Product Code: PRD10852516,Pharmaceutical Form: FILM‐COATED TABLET,Other descriptive name: ,Strength: Ponatinib 10mg,Current Sponsor code: Ponatinib (AP24534; Iclusig),Product Name: IMATINIB,Product Code: SUB25387,Pharmaceutical Form: FILM‐COATED TABLET,Other descriptive name: Imatinib,Strength: 400mg CONDITION: MedDRA version: 24.0Level: LLTClassification code: 10080018Term: Philadelphia positive acute lymphocytic leukemiaSystem Organ Class: 10029104 Newly Diagnosed Philadelphia Chromosome‐Positive Acute Lymphoblastic Leukemia (Ph+ ALL) ; MedDRA version: 24.0Level: LLTClassification code: 10080018Term: Philadelphia positive acute lymphocytic leukemiaSystem Organ Class: 10029104 Therapeutic area: Diseases [C] ‐ Hemic and Lymphatic Diseases [C15] PRIMARY OUTCOME: Main Objective:To compare the efficacy of ponatinib versus imatinib, administered as first‐line therapy in combination with reduced‐intensity chemotherapy, in patients with newly diagnosed Ph+ ALL, as measured by the MRD‐negative CR rate at the end of induction. Primary end point(s):Primary efficacy endpoint: MRD‐negative CR (BCR‐ABL/ABL1 =0.01% and meeting criteria for CR) Secondary Objective:To compare EFS between the 2 cohorts INCLUSION CRITERIA: Male or female patients aged 18 years or older.,Newly diagnosed Ph+ or BCR‐ABL1 positive ALL, as defined by the 2017 National Comprehensive Cancer Network guidelines.,Eastern Cooperative Oncology Group performance status of =2.,Clinical laboratory values as follows, within 30 days before randomization: a) Total serum bilirubin =1.5× the upper limit of normal (ULN), unless due to Gilbert's syndrome. b) Alanine aminotransferase (ALT) or aspartate aminotransferase =2.5× the ULN. c) Serum creatinine =1.5× the ULN and estimated creatinine clearance = 30 mL/minute (Cockcroft‐Gault formula). d) Serum lipase <1.5× the ULN.,Normal QT interval corrected per Fridericia method (QTcF) on screening electrocardiogram, defined as QTcF of =450 ms in males or = 470 ms in females.,Female patients who: a) Are postmenopausal for at least 1 year before the screening visit, OR b) Are surgically sterile, OR c) If they are of childbearing potential, agree to practice 1 highly effective meth SECONDARY OUTCOME: Secondary end point(s):CR is defined as meeting all of the following for at least 4 weeks (ie, 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/µl (or >1.0*10^9/L). 5. Platelets >100,000/µl (or >100*10^9/L). Secondary end point(s):CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC. Secondary end point(s):Duration of CR is defined as the interval between the first assessment at which the criteria for CR are met until the earliest date at which relapse from CR occurs. Secondary end point(s):Duration of MRD‐negative CR is defined as the 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. Secondary end point(s):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. Secondary end point(s):Exploratory end point: Biomarkers of disease sensitivity and resistance to ponatinib and imatinib and/or biomarkers affecting ponatinib efficacy or safety. Secondary end point(s):Molecule response is assessed by 3‐Log Reduction (MR3), Molecular Response 4‐Log Reduction (MR4) and Molecular Response 4.5‐Log Reduction (MR4.5). Secondary end point(s):MR4.5 is molecular response 4.5‐log reduction (=0.0032% BCRABL1/ABL1), or undetectable BCR‐ABL1 transcripts in cDNA with = 32,000 ABL1 transcripts. Secondary end point(s):On‐study participants with or without HSCT will be evaluated. OS is defined as the interval between randomization and death due to any cause, censored at the last contact date when the participant was alive. Secondary end point(s):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. Secondary end point(s):ORR is defined as CR + CRi. Secondary end point(s):OS is defined as interval between randomization and death due to any cause, censored at the last contact date when the participant was alive. Secondary end point(s):PIF is defined as participants who received treatment for chromosomepositive acute lymphoblastic leukemia (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. Secondary end point(s):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/or efficacy reasons.