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An Efficacy Study Comparing Ponatinib Versus Imatinib, Administered in Combination With Reduced-Intensity Chemotherapy, in Participants With Newly Diagnosed Ph+ ALL

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ClinicalTrials.gov Identifier: NCT03589326
Recruitment Status : Recruiting
First Posted : July 17, 2018
Last Update Posted : August 28, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
The purpose of this study is to compare the efficacy of ponatinib versus imatinib, administered as first-line therapy in combination with reduced-intensity chemotherapy, in participants with newly diagnosed Ph+ ALL, as measured by the minimal residual disease (MRD)-negative complete remission (CR) at the end of induction.

Condition or disease Intervention/treatment Phase
Lymphoblastic Leukemia, Acute, Adult Acute Lymphoid Leukemia Leukemia, Acute Lymphoblastic Leukemia, Lymphoblastic Ph1 Chromosome Leukemia, Lymphoblastic, Acute, Philadelphia-Positive Drug: Ponatinib Drug: Imatinib Drug: Vincristine Drug: Dexamethasone Drug: Cytarabine Drug: Methotrexate Drug: Prednisone Phase 3

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 230-320 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: It is an open-label trial, therefore investigators and participants are unblinded.
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : August 10, 2018
Estimated Primary Completion Date : May 15, 2021
Estimated Study Completion Date : September 30, 2025


Arm Intervention/treatment
Experimental: Cohort A: Ponatinib 30 milligram (mg)
Ponatinib 30 mg, tablets, orally, once daily (QD), along with vincristine 1.4 mg/m^2 (maximum [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 and Days 11 to 14 in 28-day cycle for up to 3 cycles in induction phase followed by ponatinib last dose of induction phase tablets, orally, QD, along 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 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 28-day odd cycles(Cycle 1, 3, and 5) in consolidation phase followed by ponatinib last dose of consolidation phase, 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 to 5 in 28-day cycle for up to 11 cycles in maintenance phase.
Drug: Ponatinib
Ponatinib Tablets.
Other Name: Iclusig

Drug: Vincristine
Vincristine IV injection.

Drug: Dexamethasone
Dexamethasone Tablets.

Drug: Cytarabine
Cytarabine IV infusion.

Drug: Methotrexate
Methotrexate IV infusion.

Drug: Prednisone
Prednisone Tablets.

Active Comparator: Cohort B: Imatinib 600 mg
Imatinib 600 mg, tablets, orally, once daily, along 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 through 4 and Days 11 through 14 in each 28-day cycle for up to 3 cycles in induction phase followed by imatinib 600 mg, tablets, orally, once daily, along 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, once daily, 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 for up to 11 cycles in maintenance phase.
Drug: Imatinib
Imatinib Tablets.
Other Name: Gleevec

Drug: Vincristine
Vincristine IV injection.

Drug: Dexamethasone
Dexamethasone Tablets.

Drug: Cytarabine
Cytarabine IV infusion.

Drug: Methotrexate
Methotrexate IV infusion.

Drug: Prednisone
Prednisone Tablets.




Primary Outcome Measures :
  1. Number of Participants with Minimal Residual Disease (MRD)-Negative Complete Remission (CR) [ Time Frame: From Cycle 1 through Cycle 3 (approximately 3 months) (Cycle length is equal to [=] 28 days) ]
    MRD-negative CR is achieved when a participant meets the criteria for both MRD negativity and CR. MRD-negativity: less than or equal to (<=) 0.01 percent (%) breakpoint cluster region-Abelson (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 (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).


Secondary Outcome Measures :
  1. Event-free survival (EFS) [ Time Frame: Baseline up to 3 years ]
    EFS is defined as the dates of randomization until death due to any cause or failure to achieve MRD-negative CR by end of induction or relapse from CR. 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.

  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. 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 3 years ]
    MRD is defined as the percentage of participants achieving CR who are MRD-negative. 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.

  7. Duration of MRD-Negative CR [ Time Frame: Up to 5 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. Relapse from CR: Reappearance of blasts in the blood or BM (>=5%) or in any extramedullary site after a CR.

  8. Duration of CR [ Time Frame: Up to 5 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.

  9. Time to Treatment Failure [ Time Frame: Every year after 3 years up to 5 years ]
    Time to treatment failure is defined as time to being off study randomized treatment (except for hematopoietic stem cell transplantation [HSCT] without loss of MRD-negative CR) due to both safety and/or loss of efficacy benefit 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).

  10. Percentage of Participants with MR4.5 Including Best Response [ Time Frame: Up to 5 years ]
    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. Duration of MR4.5 [ Time Frame: Up to 5 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.

  12. Percentage of On-Study Participants with Overall Survival (OS) [ Time Frame: Every year after 3 years up to 5 years ]
    On-study participants with or without HSCT will be evaluated. OS is defined as the interval between the first dose date of study drug and death due to any cause, censored at the last contact date when the participant was alive.

  13. Percentage of On-Study Participants with Relapse From CR [ Time Frame: Every year after 3 years up to 5 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.

  14. Overall Survival (OS) [ Time Frame: Up to 5 years ]
    OS is defined as interval between the first dose date of study drug and death due to any cause, censored at the last contact date when the participant was alive.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. Molecular assessment of BCR-ABL1 must demonstrate the presence of a p190 (that is e1a2) or p210 (that is, e13a2 or e14a2 [also known as b2a2 or b3a2]) transcript type.
  3. 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.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03589326


Contacts
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Contact: Takeda Study Registration Call Center +1-866-835-2233 globaloncologymedinfo@takeda.com

  Show 27 Study Locations
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.

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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03589326     History of Changes
Other Study ID Numbers: Ponatinib-3001
2018-000397-30 ( EudraCT Number )
U1111-1206-2370 ( Other Identifier: World Health Organization )
HC6-24-c220300 ( Registry Identifier: Health Canada )
AP24534 ( Registry Identifier: Korea Food and Drug Administration (KFDA) )
First Posted: July 17, 2018    Key Record Dates
Last Update Posted: August 28, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Ponatinib
Imatinib mesylate
Bcr-Abl Tyrosine Kinase
Bcr-abl fusion proteins
Iclusig
Gleevec
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Acute Disease
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Translocation, Genetic
Chromosome Aberrations
Cytarabine
Dexamethasone
Dexamethasone acetate
Prednisone
Methotrexate
Vincristine
Imatinib Mesylate
Ponatinib
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents