Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ALL)
Conditions
Keywords
Ponatinib, Imatinib mesylate, Bcr-Abl Tyrosine Kinase, Bcr-abl fusion proteins, Iclusig, Gleevec
Brief summary
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.
Detailed description
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the primary endpoint, have experienced relapse from CR or have progressive disease, have an unacceptable toxicity, have withdrawn consent, have proceeded to HSCT, or until the sponsor terminates the study, whichever occurs first.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.
Interventions
DRUGPonatinib
Ponatinib Tablets.
DRUGImatinib
Imatinib Tablets.
DRUGVincristine
Vincristine IV injection.
DRUGDexamethasone
Dexamethasone Tablets.
DRUGCytarabine
Cytarabine IV infusion.
DRUGMethotrexate
Methotrexate IV infusion.
DRUGPrednisone
Prednisone Tablets.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
It is an open-label trial, therefore investigators and participants are unblinded.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Newly diagnosed Philadelphia chromosome-positive (Ph+) or BCR-ABL1-positive ALL, as defined by the 2017 national comprehensive cancer network (NCCN) guidelines. 2. Eastern Cooperative Oncology Group (ECOG) performance status of \<=2.
Exclusion criteria
1. With a history or current diagnosis of chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML). 2. Prior/current treatment with any systemic anticancer therapy (including but not limited to any tyrosine kinase inhibitor \[TKI\]) and/or radiotherapy for ALL, with the exception of an optional prephase therapy or chemotherapy induction (no more than 1 cycle), which should be discussed with the sponsor's medical monitor/designee. 3. Currently taking drugs that are known to have a risk of causing prolonged corrected QT (QTc) or torsades de pointes (TdP) (unless these can be changed to acceptable alternatives or discontinued). 4. Taking any medications or herbal supplements that are known to be strong inhibitors or strong inducers of cytochrome P450 (CYP)3A4 within at least 14 days before the first dose of study drug. 5. Uncontrolled active serious infection that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. 6. Major surgery within 28 days before randomization (minor surgical procedures such as catheter placement or BM biopsy are not exclusionary criteria). 7. Known human immunodeficiency virus (HIV) seropositivity, known active hepatitis B or C infection. 8. History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis. 9. Uncontrolled hypertriglyceridemia (triglycerides \>450 milligram per deciliter \[mg/dL\]). 10. Diagnosed and treated for another malignancy within 5 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. 11. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis. 12. Clinical manifestations of CNS or extramedullary involvement with ALL other than lymphadenopathy or hepatosplenomegaly. 13. Autoimmune disease with potential CNS involvement. 14. Known significant neuropathy of Grade \>=2 severity. 15. Clinically significant, uncontrolled, or active cardiovascular, cerebrovascular, or peripheral vascular disease, or history of or active venous thrombotic/embolic event (VTE) disease. 16. Have a significant bleeding disorder unrelated to ALL.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Minimal Residual Disease (MRD)-Negative Complete Remission (CR) at The End of Induction Phase | From Cycle 1 through Cycle 3 (approximately 3 months) (Cycle length = 28 days) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With CR and Incomplete Complete Remission (CRi) | End of Cycle 1 (approximately 1 month), Cycle 2 (approximately 2 months), Cycle 3 (approximately 3 months), and Cycle 9 (approximately 9 months) (Cycle length= 28 days) | 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. |
| Percentage of Participants With Molecular Response | End of Cycle 1 (approximately 1 month), Cycle 2 (approximately 2 months), Cycle 3 (approximately 3 months), and Cycle 9 (approximately 9 months) (Cycle length= 28 days) | 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. |
| Percentage of Participants With Primary Induction Failure (PIF) | Up to 3 months | 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. |
| Percentage of Participants With Overall Response Rate (ORR) | Up to 3 months | 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. |
| Percentage of MRD-Negative CR | Up to approximately 3 to 6 years | 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 | Up to approximately 3 to 6 years | 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. |
| Event-free Survival (EFS) | Baseline up to approximately 3 to 6 years | 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. |
| Time to Treatment Failure | Up to approximately 6 years | 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 | Up to approximately 3 to 6 years | 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. |
| Percentage of On-Study Participants With Overall Survival (OS) | Up to approximately 3 to 6 years | 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. |
| Percentage of On-Study Participants With Relapse From CR | Up to approximately 3 to 6 years | 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. |
| Overall Survival (OS) | Up to approximately 3 to 6 years | 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. |
| Duration of CR | Up to approximately 3 to 6 years | 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. |
Countries
Argentina, Australia, Austria, Brazil, Bulgaria, Canada, China, Finland, France, Greece, Italy, Japan, Mexico, Poland, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
Participants took part in the study at 77 investigative sites in Australia, China, Korea, Taiwan, Austria, France, Greece, Italy, Poland, Russia, Spain, Turkey, United States, Canada, Mexico, Argentina and Brazil from 04 October 2018 to 31 July 2027. This study is ongoing. The data is reported for primary outcome measures up to 12 August 2022.
Pre-assignment details
Participants with a diagnosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) were enrolled in a 2:1 ratio to receive ponatinib or imatinib.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Ponatinib 30 mg 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. | 164 |
| Cohort B: Imatinib 600 mg 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. | 81 |
| Total | 245 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| IP (Cycles 1-3) (Cycle Length=28 Days) | Death | 21 | 13 |
| IP (Cycles 1-3) (Cycle Length=28 Days) | Lost to Follow-up | 0 | 1 |
| IP (Cycles 1-3) (Cycle Length=28 Days) | Participants Ongoing on Study | 135 | 63 |
| IP (Cycles 1-3) (Cycle Length=28 Days) | Reason not Specified | 2 | 0 |
| IP (Cycles 1-3) (Cycle Length=28 Days) | Withdrawal by Subject | 6 | 4 |
Baseline characteristics
| Characteristic | Total | Cohort B: Imatinib 600 mg | Cohort A: Ponatinib 30 mg |
|---|---|---|---|
| Age, Continuous | 51.0 years STANDARD_DEVIATION 15.59 | 50.6 years STANDARD_DEVIATION 14.6 | 51.2 years STANDARD_DEVIATION 16.09 |
| Body Surface Area (BSA) | 1.85 meters squared (m^2) STANDARD_DEVIATION 0.258 | 1.86 meters squared (m^2) STANDARD_DEVIATION 0.255 | 1.84 meters squared (m^2) STANDARD_DEVIATION 0.261 |
| Height | 167.25 centimeters (cm) STANDARD_DEVIATION 9.662 | 167.27 centimeters (cm) STANDARD_DEVIATION 9.029 | 167.24 centimeters (cm) STANDARD_DEVIATION 9.98 |
| Race/Ethnicity, Customized Hispanic or Latino | 59 Participants | 20 Participants | 39 Participants |
| Race/Ethnicity, Customized Non-Hispanic and Latino | 161 Participants | 56 Participants | 105 Participants |
| Race/Ethnicity, Customized Not reported | 19 Participants | 4 Participants | 15 Participants |
| Race/Ethnicity, Customized Unknown | 6 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 31 Participants | 11 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 30 Participants | 2 Participants | 28 Participants |
| Race (NIH/OMB) White | 166 Participants | 62 Participants | 104 Participants |
| Region of Enrollment Argentina | 3 Participants | 0 Participants | 3 Participants |
| Region of Enrollment Australia | 6 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Austria | 6 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Brazil | 28 Participants | 10 Participants | 18 Participants |
| Region of Enrollment Canada | 13 Participants | 5 Participants | 8 Participants |
| Region of Enrollment China | 22 Participants | 8 Participants | 14 Participants |
| Region of Enrollment France | 10 Participants | 1 Participants | 9 Participants |
| Region of Enrollment Greece | 5 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Italy | 38 Participants | 10 Participants | 28 Participants |
| Region of Enrollment Korea, South | 3 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Mexico | 3 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Poland | 7 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Russia | 11 Participants | 6 Participants | 5 Participants |
| Region of Enrollment Spain | 25 Participants | 9 Participants | 16 Participants |
| Region of Enrollment Taiwan | 3 Participants | 0 Participants | 3 Participants |
| Region of Enrollment Turkey | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 60 Participants | 20 Participants | 40 Participants |
| Sex: Female, Male Female | 133 Participants | 43 Participants | 90 Participants |
| Sex: Female, Male Male | 112 Participants | 38 Participants | 74 Participants |
| Weight | 74.86 kilograms (kg) STANDARD_DEVIATION 18.626 | 76.23 kilograms (kg) STANDARD_DEVIATION 18.565 | 74.17 kilograms (kg) STANDARD_DEVIATION 18.675 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 21 / 163 | 13 / 81 |
| other Total, other adverse events | 159 / 163 | 80 / 81 |
| serious Total, serious adverse events | 97 / 163 | 45 / 81 |
Outcome results
Primary
Number of Participants With Minimal Residual Disease (MRD)-Negative Complete Remission (CR) at The End of Induction Phase
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).
Time frame: From Cycle 1 through Cycle 3 (approximately 3 months) (Cycle length = 28 days)
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Ponatinib 30 mg | Number of Participants With Minimal Residual Disease (MRD)-Negative Complete Remission (CR) at The End of Induction Phase | 53 Participants |
| Cohort B: Imatinib 600 mg | Number of Participants With Minimal Residual Disease (MRD)-Negative Complete Remission (CR) at The End of Induction Phase | 13 Participants |
p-value: =0.002195% CI: [0.06, 0.29]Chi-squared
Secondary
Duration of 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 frame: Up to approximately 3 to 6 years
Secondary
Duration of MR4.5
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.
Time frame: Up to approximately 3 to 6 years
Secondary
Duration of MRD-Negative 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.
Time frame: Up to approximately 3 to 6 years
Secondary
Event-free Survival (EFS)
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.
Time frame: Baseline up to approximately 3 to 6 years
Secondary
Overall Survival (OS)
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.
Time frame: Up to approximately 3 to 6 years
Secondary
Percentage of MRD-Negative CR
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.
Time frame: Up to approximately 3 to 6 years
Secondary
Percentage of On-Study Participants With Overall Survival (OS)
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.
Time frame: Up to approximately 3 to 6 years
Secondary
Percentage of On-Study Participants With Relapse From CR
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.
Time frame: Up to approximately 3 to 6 years
Secondary
Percentage of Participants With CR and Incomplete Complete Remission (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.
Time frame: End of Cycle 1 (approximately 1 month), Cycle 2 (approximately 2 months), Cycle 3 (approximately 3 months), and Cycle 9 (approximately 9 months) (Cycle length= 28 days)
Secondary
Percentage of Participants With Molecular Response
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.
Time frame: End of Cycle 1 (approximately 1 month), Cycle 2 (approximately 2 months), Cycle 3 (approximately 3 months), and Cycle 9 (approximately 9 months) (Cycle length= 28 days)
Secondary
Percentage of Participants With Overall Response Rate (ORR)
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.
Time frame: Up to 3 months
Secondary
Percentage of Participants With Primary Induction Failure (PIF)
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.
Time frame: Up to 3 months
Secondary
Time to Treatment Failure
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).
Time frame: Up to approximately 6 years