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)
A Study of Ponatinib Versus Imatinib in Adults With Acute Lymphoblastic Leukemia
Yanai Tomoko
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka
+81-6-6204-2111
smb.Japanclinicalstudydisclosure@takeda.com
Contact for Clinical Trial Information
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka
+81-6-6204-2111
smb.Japanclinicalstudydisclosure@takeda.com
Not Recruiting
Oct. 04, 2018
Oct. 04, 2018
245
Interventional
randomized controlled trial
open(masking not used)
active control
parallel assignment
treatment purpose
1. Newly diagnosed Philadelphia chromosome-positive (Ph+) or breakpoint cluster region-Abelson (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.
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 central nervous system (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.
18age old over
No limit
Both
Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Cohort A and Patients from Japan sites: Ponatinib 30 milligram (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 (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.
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 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.
1. Number of Participants with Minimal Residual Disease (MRD)-Negative Complete Remission (CR) at The End of Induction Phase
Time Frame: From Cycle 1 through Cycle 3 (approximately 3 months) (Cycle length is equal to [=] 28 days)
MRD-negative CR was achieved when a participant meets the criteria for both MRD negativity and CR. MRD-negativity: less than or equal to (<=) 0.01 percent (%)BCR-ABL1/ABL1, or undetectable BCR-ABL1 transcripts in complementary deoxyribonucleic acid (cDNA) with greater than or equal to (>=) 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 (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).
1. Event-free survival (EFS)
Time Frame: 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.
2. Percentage of Participants with CR and Incomplete Complete Remission (CRi)
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)
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.
3. Percentage of Participants with Molecular Response
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)
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.
4. Percentage of Participants with Primary Induction Failure (PIF)
Time Frame: 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.
5. Percentage of Participants with Overall Response Rate (ORR)
Time Frame: 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.
6. Percentage of MRD-Negative CR
Time Frame: Up to approximately 3 to 6 years
MRD-Negative CR 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.
7. Duration of MRD-Negative CR
Time Frame: 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.
8. Duration of CR
Time Frame: 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.
9. Time to Treatment Failure
Time Frame: 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.
10. Duration of MR4.5
Time Frame: 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.
11. Percentage of On-Study Participants with Overall Survival (OS)
Time Frame: 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.
12. Percentage of On-Study Participants with Relapse From CR
Time Frame: 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.
13. Overall Survival (OS)
Time Frame: 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.
Takeda Pharmaceutical Company Limited
Institutional Review Board of Chiba Aoba Municipal Hospital
1273-2 Aobacho, Chuo-ku, Chiba-shi, Chiba
+81-43-227-1131
Approval
July. 29, 2021
Yes
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.
NCT03589326
ClinicalTrials.gov Identifier
U1111-1206-2370
WHO Universal Trial Number
2023-508463-71-00
EU CT Number
HC6-24-c220300
Health Canada Identifier
Argentina/Australia/Austria/Brazil/Bulgaria/Canada/China/Finland/France/Greece/Italy/Korea/Mexico/Poland/Romania/Spain/Taiwan/Turkey/United States
