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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)

NCT03589326

Description:

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 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), as measured by the minimal residual disease (MRD)-negative complete remission (CR) at the end of induction.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: Ponatinib-3001
  • SECONDARY ID: 2018-000397-30
  • NCT ID: NCT03589326

Conditions

  • Lymphoblastic Leukemia, Acute, Adult
  • Acute Lymphoid Leukemia
  • Leukemia, Acute Lymphoblastic
  • Leukemia, Lymphoblastic
  • Ph1 Chromosome
  • Leukemia, Lymphoblastic, Acute, Philadelphia-Positive

Interventions

DrugSynonymsArms
PonatinibIclusigCohort A: Ponatinib 30 mg
ImatinibGleevecCohort B: Imatinib
VincristineCohort A: Ponatinib 30 mg
DexamethasoneCohort A: Ponatinib 30 mg
CytarabineCohort A: Ponatinib 30 mg
MethotrexateCohort A: Ponatinib 30 mg
PrednisoneCohort A: Ponatinib 30 mg

Purpose

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 philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), as measured by the minimal residual disease (MRD)-negative complete remission (CR) at the end of induction.

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 patients. Patients 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).

      This multi-center trial will be conducted worldwide. 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 complete response (CR), have an
      unacceptable toxicity, have withdrawn consent, have proceeded to hematopoietic stem cell
      transplant (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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A: Ponatinib 30 mgExperimentalPonatinib 30 mg, tablets, orally, once daily, along 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 through 4 and Days 11 through 14 in each 28-day cycle for up to 3 cycles in induction phase followed by ponatinib 30 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 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 odd cycles (cycle 1, 3 and 5) in consolidation phase followed by ponatinib 30 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 cycle from Cycle 10 to 20 in maintenance phase.
  • Ponatinib
  • Vincristine
  • Dexamethasone
  • Cytarabine
  • Methotrexate
  • Prednisone
Cohort B: ImatinibActive ComparatorImatinib 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 years [yrs]) and 20 mg (≥60 yrs), orally, once on Days 1 through 4 and Days 11 through 14 in each cycle 28-day 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 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 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 cycle from Cycle 10 to 20 in maintenance phase.
  • Imatinib
  • Vincristine
  • Dexamethasone
  • Cytarabine
  • Methotrexate
  • Prednisone

Eligibility Criteria

        Inclusion Criteria:

          1. Newly diagnosed philadelphia chromosome-positive (Ph+) or breakpoint cluster
             region-Abelson (BCR-ABL)1-positive acute lymphoblastic leukemia (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 (ie, e1a2) or
             p210 (ie, 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 cancer, with
             the exception of an optional prephase therapy, 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 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. Active serious infection requiring antibiotics within 14 days before the first dose of
        study drug.

        6. Major surgery within 28 days before randomization (minor surgical procedures such as
        catheter placement or bone marrow (BM) biopsy are not exclusionary criteria).

        7. Ongoing or active systemic infection, known seropositive human immunodeficiency virus
        (HIV), 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 mg/dL). 10. With nonmelanoma skin
        cancer or carcinoma in situ of any type are excluded if they have not 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. Active ALL in the CNS (confirmed by cerebrospinal fluid [CSF] analysis). 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.

        16. Had a significant bleeding disorder unrelated to ALL.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants with Minimal Residual Disease (MRD)-Negative Complete Remission (CR)
Time Frame:From cycle 1 through cycle 3 (approximately 3 months)
Safety Issue:
Description:MRD-negative CR is achieved when a participant meets 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 DNA (cDNA) with ≥10,000 ABL1 transcripts. CR: meeting all the following for at least 4 weeks (ie, no recurrence):1. No circulating blasts and <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/μl (or >1.0*10^9/L). 5. Platelets >100,000/μl (or >100*10^9/L).

Secondary Outcome Measures

Measure:Event-free survival (EFS)
Time Frame:Baseline up to 3 years
Safety Issue:
Description: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% breakpoint cluster region-Abelson (BCR-ABL1/ABL1), or undetectable BCR-ABL1 transcripts in complementary DNA (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.
Measure:Percentage of Participants with CR and Incomplete Complete Remission (CRi)
Time Frame:End of cycle 1 (approximately 1 month), cycle 2 (approximately 2 months) and cycle 3 (approximately 3 months)
Safety Issue:
Description:CR is defined as meeting all 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). CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC.
Measure:Percentage of Participants with Molecular Response
Time Frame:End of cycle 1 (approximately 1 month), cycle 2 (approximately 2 months) and cycle 3 (approximately 3 months)
Safety Issue:
Description: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.
Measure:Percentage of Participants with Primary Induction Failure (PIF)
Time Frame:Up to 3 months
Safety Issue:
Description:PIF is defined as participants who received treatment for chromosome-positive 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. CR is defined as meeting all 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). CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC.
Measure:Percentage of Participants with Overall Response Rate (ORR)
Time Frame:Up to 3 months
Safety Issue:
Description:ORR is defined as CR + CRi. CR is defined as meeting all 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). CRi is defined as hematologic complete remission with incomplete hematologic recovery and meeting all criteria for CR except platelet count and/or ANC.
Measure:Duration of MRD-Negative CR
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Duration of CR
Time Frame:Up to 5 years
Safety Issue:
Description: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 (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). Relapse from CR: Reappearance of blasts in the blood or BM (≥5%) or in any extramedullary site after a CR.
Measure:Time to Treatment Failure
Time Frame:Every year after 3 years up to 5 years
Safety Issue:
Description: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% breakpoint cluster region-Abelson (BCR-ABL1/ABL1), or undetectable BCR-ABL1 transcripts in complementary DNA (cDNA) with ≥10,000 ABL1 transcripts. CR: meeting all the following for at least 4 weeks (ie, no recurrence):1. No circulating blasts and <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/μl (or >1.0*10^9/L). 5. Platelets >100,000/μl (or >100*10^9/L).
Measure:Percentage of Participants with MR4.5 Including Best Response
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Duration of MR4.5
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Percentage of On-Study Participants with Overall Survival (OS)
Time Frame:Every year after 3 years up to 5 years
Safety Issue:
Description: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.
Measure:Percentage of On-Study Participants with Relapse From CR
Time Frame:Every year after 3 years up to 5 years
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • Ponatinib
  • Imatinib mesylate
  • Bcr-Abl Tyrosine Kinase
  • Bcr-abl fusion proteins
  • Iclusig
  • Gleevec

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