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

Phase 3Active Not RecruitingNCT03589326

Takeda245 enrolled

Overview

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the primary endpoint, have experienced relapse from CR or have progressive disease, have an unacceptable toxicity, have withdrawn consent, have proceeded to HSCT, or until the sponsor terminates the study, whichever occurs first.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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Interventions

PonatinibDRUG

Ponatinib Tablets.

ImatinibDRUG

Imatinib Tablets.

VincristineDRUG

Vincristine IV injection.

DexamethasoneDRUG

Dexamethasone Tablets.

CytarabineDRUG

Cytarabine IV infusion.

MethotrexateDRUG

Methotrexate IV infusion.

PrednisoneDRUG

Prednisone Tablets.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (92)

University of Alabama at Birmingham

Birmingham, Alabama, United States

City of Hope - Duarte

Duarte, California, United States

University of California Los Angeles

Los Angeles, California, United States

Augusta University Georgia Cancer Center

Augusta, Georgia, United States

Indiana University

Indianapolis, Indiana, United States

Outcomes

Primary Outcomes

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)

Secondary Outcomes

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

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)

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)

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

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

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.