Clinical Trials /

Daunorubicin and Cytarabine With or Without Uproleselan in Treating Older Adult Patients With Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy

NCT03701308

Description:

This phase II/III trial studies how well daunorubicin and cytarabine with or without uproleselan works in treating older adult patients with acute myeloid leukemia receiving intensive induction chemotherapy. Drugs used in chemotherapy, such as daunorubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Uproleselan may prevent cancer from returning or getting worse. Giving daunorubicin and cytarabine with uproleselan may work better in treating patients with acute myeloid leukemia compared to daunorubicin and cytarabine alone.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Daunorubicin and Cytarabine With or Without Uproleselan in Treating Older Adult Patients With Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy
  • Official Title: A Randomized Phase II/III Study of Conventional Chemotherapy +/- Uproleselan (GMI-1271) in Older Adults With Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-02130
  • SECONDARY ID: NCI-2018-02130
  • SECONDARY ID: A041701
  • SECONDARY ID: A041701
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT03701308

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Group I (daunorubicin, cytarabine)
DaunorubicinDaunomycin, Daunorrubicina, DNR, Leukaemomycin C, Rubidomycin, RUBOMYCIN CGroup I (daunorubicin, cytarabine)
UproleselanGMI-1271Group II (uproleselan, daunorubicin, cytarabine)

Purpose

This phase II/III trial studies how well daunorubicin and cytarabine with or without uproleselan works in treating older adult patients with acute myeloid leukemia receiving intensive induction chemotherapy. Drugs used in chemotherapy, such as daunorubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Uproleselan may prevent cancer from returning or getting worse. Giving daunorubicin and cytarabine with uproleselan may work better in treating patients with acute myeloid leukemia compared to daunorubicin and cytarabine alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Compare the event-free survival (EFS) of daunorubicin, cytarabine plus uproleselan versus
      daunorubicin and cytarabine in subjects >= age 60 with previously untreated acute myeloid
      leukemia. (Phase II) II. Compare the overall survival (OS) of the daunorubicin, cytarabine
      plus uproleselan to daunorubicin and cytarabine in this patient population. (Phase III)

      SECONDARY OBJECTIVES:

      I. Determine the rates of complete remission (CR), complete remission with incomplete count
      recovery (CRi), complete remission with incomplete hematopoietic recovery (CRh) and
      cytogenetic complete remission (CCyR) for each chemotherapy regimen.

      II. Determine the overall survival (OS), and remission duration of patients for each
      chemotherapy regimen.

      III. Describe the frequency and severity of adverse events for patients for each chemotherapy
      regimen.

      IV. Describe the interaction of pretreatment disease and patient characteristics including
      morphology, cytogenetics, molecular genetic features, white blood cell (WBC) count and
      hemogram, and performance status on clinical outcomes.

      CORRELATIVE SCIENCE OBJECTIVES:

      I. Correlate specific karyotype groups (normal or various primary and secondary chromosomal
      abnormalities) with clinical and laboratory parameters and with response rates, response
      duration, survival and cure in patients treated with various induction and post-induction
      regimens.

      II. Correlate specific karyotype groups with selected molecular abnormalities and with
      measurable residual disease.

      III. To determine karyotype changes at end of consolidation and the influence of the type of
      change (or no change) in karyotype at the end of consolidation on subsequent clinical course.

      IV. To determine karyotype changes at relapse and the influence of the type of change (or no
      change) in karyotype at relapse on subsequent clinical course.

      OUTLINE: Patients are randomized to 1 of 2 groups.

      GROUP 1: INDUCTION: Patients receive daunorubicin intravenously (IV) on days 1-3 and
      cytarabine via continuous intravenous infusion (CIVI) over 168 hours on days 1-7. Patients
      with residual disease indicated by bone marrow examination receive a second induction
      including daunorubicin IV on days 1-3 and cytarabine CIVI over 12 hours on days 1-5.

      CONSOLIDATION: Patients receive cytarabine IV over 3 hours on days 1-5. Treatment repeats
      every 28 days for up to 3 courses in the absence of disease progression or unacceptable
      toxicity.

      GROUP 2: INDUCTION: Patients receive uproleselan IV QD on day 1 and then every 12 hours on
      days 2-10. Patients also receive daunorubicin IV on days 2-4 and cytrarabine CIVI over 168
      hours on days 2-8 over 168 hours. Patients with residual disease indicated by bone marrow
      examination receive a second induction including uprleselan IV QD on day 1 and then every 12
      hours on days 2-10, daunorubicin IV on days 2-3, and cytarabine CIVI over 120 hours on days
      2-6.

      CONSOLIDATION: Patients who achieve a CR or CRi receive uproleselan IV QD on day 1 and every
      12 hours on days 2-8 and cytarabine IV over 3 hours on days 2-6. Treatment repeats every 28
      days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 2 months for 1 year,
      every 3 months in year 2, and then every 6 months for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Group I (daunorubicin, cytarabine)Active ComparatorINDUCTION: Patients receive daunorubicin IV on days 1-3 and cytarabine via CIVI over 168 hours on days 1-7. Patients with residual disease indicated by bone marrow examination receive a second induction including daunorubicin IV on days 1-3 and cytarabine CIVI over 12 hours on days 1-5. CONSOLIDATION: Patients receive cytarabine IV over 3 hours on days 1-5. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
  • Cytarabine
  • Daunorubicin
Group II (uproleselan, daunorubicin, cytarabine)ExperimentalINDUCTION: Patients receive uproleselan IV QD on day 1 and then every 12 hours on days 2-10. Patients also receive daunorubicin IV on days 2-4 and cytrarabine CIVI over 168 hours on days 2-8 over 168 hours. Patients with residual disease indicated by bone marrow examination receive a second induction including uprleselan IV QD on day 1 and then every 12 hours on days 2-10, daunorubicin IV on days 2-3, and cytarabine CIVI over 120 hours on days 2-6. CONSOLIDATION: Patients who achieve a CR or CRi receive uproleselan IV QD on day 1 and every 12 hours on days 2-8 and cytarabine IV over 3 hours on days 2-6. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
  • Cytarabine
  • Daunorubicin
  • Uproleselan

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of acute myeloid leukemia (AML) based on 2017 World Health Organization
             (WHO) criteria excluding acute promyelocytic leukemia with PML-RARA.

               -  Note: Patients with myeloid sarcoma without bone marrow involvement, acute
                  leukemia of ambiguous lineage or blast transformation of chronic myelogenous
                  leukemia (CML) are not eligible.

          -  No activating mutation in the Fms-like tyrosine kinase-3 (FLT3) defined as a ratio of
             mutant to wild-type allele >= 0.05 by capillary electrophoresis or a variant allele
             fraction of >= 5% by next generation sequencing from either bone marrow or peripheral
             blood.

          -  No evidence of CNS involvement of AML.

          -  No prior chemotherapy for myelodysplastic syndrome (MDS) or AML including
             hypomethylating agents (e.g. azacitidine and decitabine) or lenalidomide with the
             following exceptions:

               -  Emergency leukapheresis.

               -  Hydroxyurea.

               -  Growth factor/cytokine support.

               -  All-trans retinoic acid (ATRA).

               -  Single dose of intrathecal cytarabine and/or methotrexate for patients undergoing
                  lumbar puncture to evaluate for CNS involvement.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (EFS) (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:EFS is defined as the time from the date of registration/randomization to the first of failure to achieve a complete remission (CR) during induction, relapse, or death due to any cause, with patients last known to be alive and event-free censored at the date of last contact.

Secondary Outcome Measures

Measure:EFS rate
Time Frame:Up to 1 year
Safety Issue:
Description:Will be formally tested hierarchically in a confirmatory setting at an overall one sided alpha of 0.025 level at the same time as the primary endpoint. Both hazard ratio and p-value for EFS will be presented.
Measure:Impact of off-protocol transplantation
Time Frame:Up to 5 years
Safety Issue:
Description:Sensitivity analyses will be conducted. In addition, the proportion of patients who received transplantation in the two arms will be summarized and compared using a chi-square test.
Measure:Consistency of the treatment effect among each subgroup
Time Frame:From baseline up to 5 years
Safety Issue:
Description:Non-parametric methods such as Kaplan-Meier and log-rank tests will be used within each subgroup. Univariate/multivariate Cox models will be fit within each subgroups; hazard ratios will be used to quantify the treatment effect within each subgroup, along with the 95% confidence intervals.
Measure:Disease-free survival (DFS)
Time Frame:Time from achieving a complete response to time of relapse or death, assessed up to 5 years
Safety Issue:
Description:
Measure:Complete remission (CR) and overall response rate
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Incidence of adverse events assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 5.0
Time Frame:Up to 5 years
Safety Issue:
Description:The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Measure:Prediction of CR, EFS, DFS, and OS by pretreatment characteristics such as age, morphology, cytogenetics, immunophenotype, molecular genetic features, WBC count and hemogram, and performance status with clinical outcomes
Time Frame:Up to 5 years
Safety Issue:
Description:The associations between these baseline factors and CR, EFS, DFS, and OS will be analyzed using Kaplan-Meier curves, log-rank test, contigency table and chi-square test whenever appropriate. Multivariable analysis including Cox proportional hazards models and logistic regression models will be used as well to evaluate the associations.

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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