Clinical Trials /

Clofarabine or Daunorubicin Hydrochloride and Cytarabine Followed By Decitabine or Observation in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

NCT02085408

Description:

This randomized phase III trial studies clofarabine to see how well it works compared with daunorubicin hydrochloride and cytarabine when followed by decitabine or observation in treating older patients with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as clofarabine, daunorubicin hydrochloride, cytarabine, and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which chemotherapy regimen is more effective in treating acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Clofarabine or Daunorubicin Hydrochloride and Cytarabine Followed By Decitabine or Observation in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia
  • Official Title: Phase III Randomized Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard Daunorubicin &Amp; Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission Therapy, Followed by Decitabine Maintenance vs. Observation in Newly-Diagnosed Acute Myeloid Leukemia in Older Adults (Age >/= 60 Years)

Clinical Trial IDs

  • ORG STUDY ID: E2906
  • SECONDARY ID: NCI-2011-01992
  • SECONDARY ID: CDR0000659585
  • SECONDARY ID: ECOG-E2906
  • SECONDARY ID: E2906
  • SECONDARY ID: E2906
  • SECONDARY ID: U10CA021115
  • NCT ID: NCT02085408
  • NCT ALIAS: NCT01041703

Conditions

  • Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
clofarabineCAFdA, Clofarex, ClolarArm II (clofarabine)
daunorubicin hydrochlorideCerubidin, Cerubidine, daunomycin hydrochloride, daunorubicin, RP-13057Arm I (daunorubicin hydrochloride and cytarabine)
cytarabineARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinosideArm I (daunorubicin hydrochloride and cytarabine)
decitabine5-aza-dCyd, 5AZA, DACArm II (clofarabine)

Purpose

This randomized phase III trial studies clofarabine to see how well it works compared with daunorubicin hydrochloride and cytarabine when followed by decitabine or observation in treating older patients with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as clofarabine, daunorubicin hydrochloride, cytarabine, and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which chemotherapy regimen is more effective in treating acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the effect of clofarabine induction and consolidation therapy on overall
      survival in comparison with standard therapy (daunorubicin [daunorubicin hydrochloride] &
      cytarabine) in newly-diagnosed acute myeloid leukemia (AML) patients age >= 60 years.

      SECONDARY OBJECTIVES:

      I. To evaluate complete remission (CR) rates, duration of remission, and
      toxicity/treatment-related mortality of clofarabine in comparison with standard therapy
      (daunorubicin & cytarabine) in newly-diagnosed AML patients age >= 60 years.

      II. To evaluate the feasibility of consolidation with reduced-intensity conditioning and
      allogeneic hematopoietic stem cell transplantation from human leukocyte antigen
      (HLA)-identical donors in patients who achieve a response to induction therapy, including the
      incidence of successful engraftment, acute and chronic graft-versus-host disease,
      transplant-related mortality, and its impact on overall survival in comparison to patients
      receiving chemotherapy.

      III. To evaluate the duration of remission and disease-free survival of patients in complete
      remission following completion of consolidation therapy who are subsequently randomized to
      receive scheduled low-dose decitabine maintenance in comparison with observation.

      IV. To perform expression and methylation profiling on all patients receiving decitabine and
      to correlate their integrated epigenetic signatures with response to decitabine.

      V. To examine the epigenetic profiles of remission marrow in patients randomized to
      observation vs. decitabine to determine whether epigenetic signature of apparently
      morphologically normal bone marrow is predictive of relapse or response to decitabine
      maintenance.

      VI. To explore the possible association of response to clofarabine with ABC-transporter
      P-glycoprotein (Pgp).

      VII. To assess the intensity of expression of CXC chemokine receptor type 4 (CXCR4) on
      diagnostic leukemia cells and to correlate this parameter with other established prognostic
      factors.

      VIII. To assess the entire spectrum of somatic mutations and affected pathways at diagnosis
      of AML and elucidate the association between gene mutation and outcome.

      IX. To examine the impact of smoking, obesity, regular acetaminophen use, regular aspirin
      use, benzene exposure, living in a rural/farm environment and some other underlying exposures
      and lifestyle factors associated with AML development on overall survival (OS).

      X. To investigate potential correlative results between array comparative genomic
      hybridization (CGH) findings and acute myeloid leukemia patient characteristics.

      TERTIARY OBJECTIVES:

      I. To compare health-related quality of life (QOL) (physical, functional, leukemia-specific
      well-being) and fatigue in elderly AML patients receiving standard induction therapy with
      those receiving clofarabine.

      II. To measure the change in health-related QOL that occurs over time (within treatment
      groups).

      III. To comprehensively assess patient function at the time of study enrollment.

      IV. To determine if components of a comprehensive geriatric assessment or QOL scales predict
      ability to complete AML treatment.

      V. To describe the impact of transplant on QOL in AML patients above age 60.

      OUTLINE:

      INDUCTION THERAPY: Patients are randomized to 1 of 2 treatment arms.

      ARM I (STANDARD THERAPY): Patients receive daunorubicin hydrochloride intravenously (IV) over
      10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients with residual
      disease or those who do not achieve an aplastic bone marrow on day 12-14 (i.e., < 5% blasts
      and < 20% cellularity or markedly/moderately hypocellular) may receive a second course of
      induction therapy beginning no sooner than day 14.

      ARM II: Patients receive clofarabine IV over 1 hour on days 1-5. Patients with residual
      disease or those who do not achieve an aplastic bone marrow on day 12-14 (i.e., < 5% blasts
      and < 20% cellularity or markedly/moderately hypocellular) may receive a second course of
      induction therapy beginning no sooner than day 21 and no later than day 56.

      Patients who achieve a complete remission (CR) or CR with incomplete marrow recovery (CRi)
      after induction therapy proceed to consolidation therapy. Patients who are 60-69 years of age
      who achieve a "morphologic leukemia-free state" after induction therapy and who have an
      HLA-identical donor proceed to allogeneic stem cell transplantation.

      CONSOLIDATION THERAPY: Beginning within 60 days after documentation of CR or CRi, patients
      receive consolidation therapy in the same arm they were randomized to for induction therapy.

      ARM I (STANDARD THERAPY): Patients receive cytarabine IV over 1 hour once or twice daily on
      days 1-6. Treatment repeats every 4-6 weeks for 2 courses.

      ARM II: Patients receive clofarabine IV over 1 hour on days 1-5. Treatment repeats every 4-6
      weeks for 2 courses.

      Patients who remain in CR after completion of consolidation therapy proceed to maintenance
      therapy.

      MAINTENANCE THERAPY: Beginning within 60 days after completion of consolidation therapy,
      patients receive maintenance therapy and are randomized to 1 of 2 arms. Patients not eligible
      for randomization to decitabine maintenance after recovery from consolidation will be
      followed according to Arm I.

      ARM I: Patients undergo observation monthly for 12 months.

      ARM II: Patients receive decitabine IV over 1 hour on days 1-3. Treatment repeats every 4
      weeks for 12 months the absence of unacceptable toxicity.

      ALLOGENEIC STEM CELL TRANSPLANTATION WITH REDUCED-INTENSITY CONDITIONING REGIMEN: Patients
      begin reduced-intensity conditioning 30-90 days after the initiation of induction therapy.

      CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to
      -3, busulfan IV over 2 hours every 6 hours on days -4 and -3 (for a total of 8 doses), and
      anti-thymocyte globulin IV over 4-6 hours on days -4 to -2.

      TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation on
      day 0.

      After completion of study treatment, patients are followed up every 3 months for 4 years,
      every 6 months for 1 year, and then annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (daunorubicin hydrochloride and cytarabine)Active ComparatorSee Detailed Description
  • daunorubicin hydrochloride
  • cytarabine
Arm II (clofarabine)ExperimentalSee Detailed Description
  • clofarabine
  • decitabine

Eligibility Criteria

        Inclusion Criteria:

          -  Sexually active males must be strongly advised to use an accepted and effective method
             of contraception

          -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< grade 1

          -  Total bilirubin =< grade 1

               -  Note: If total bilirubin is 2 to 3 mg/dL, but direct bilirubin is normal, then
                  the patient will be considered eligible

          -  Patient must not have a concurrent active malignancy for which they are receiving
             treatment (other than myelodysplastic syndromes [MDS])

          -  Patient must not have an active, uncontrolled infection

          -  ADDITIONAL INDUCTION ELIGIBILITY CRITERIA:

          -  Newly-diagnosed AML patients according to World Health Organization (WHO)
             classification who are considered candidates for intensive chemotherapy based upon
             examination of peripheral blood or bone marrow aspirate specimens or touch
             preparations of the bone marrow biopsy obtained within two weeks prior to
             randomization; a bone marrow aspirate is required for enrollment; however, on occasion
             there is discordance between percentage of myeloblasts on the differential of the
             peripheral blood or aspirate; the peripheral blood criteria are sufficient for
             diagnosis; confirmatory immunophenotyping will be performed centrally

               -  NOTE: patients must be registered to E3903 (Ancillary Laboratory Protocol for the
                  Collection of Diagnostic Material on Patients Considered for Eastern Cooperative
                  Oncology Group (ECOG) Treatment Trials for Leukemia or Related Hematologic
                  Disorders) and must undergo eligibility testing for the study by multiparameter
                  flow cytometry

               -  NOTE: Southwest Oncology Group (SWOG)/Cancer Trials Support Unit (CTSU)
                  institutions: E3903 is not open at the CTSU; therefore, baseline submissions must
                  be submitted on E2906

          -  ECOG performance status (PS) 0-3 (restricted to ECOG PS 0-2 if >= 70 years of age)

          -  Patients with acute promyelocytic leukemia (APL) confirmed either by the presence of
             t(15;17)(q22;q21) or promyelocytic leukemia (PML)/retinoic acid receptor (RAR) alpha
             transcripts will be excluded

          -  Patients must not have blastic transformation of chronic myelogenous leukemia

          -  Patients with secondary AML are eligible for enrollment onto the trial; secondary AML
             is defined as AML that has developed in a person with a history of antecedent blood
             count abnormalities, or myelodysplastic syndrome (MDS), or a myeloproliferative
             disorder (excluding chronic myeloid leukemia); or a history of prior chemotherapy or
             radiation therapy for a disease other than AML

               -  NOTE: Prior therapy of MDS with decitabine, low-dose cytarabine, or azacitidine
                  is excluded

          -  Patients may not have received prior chemotherapy for AML with the exception of
             hydroxyurea for increased blast count or leukapheresis for leukocytosis

          -  Total serum bilirubin =< 1.5 times upper limit of normal (ULN) (=< grade 1); if total
             bilirubin is 2 to 3 mg/dL, but direct bilirubin is normal, then the patient will be
             considered eligible

          -  Patients with a serum creatinine > 1 are eligible if they have a calculated glomerular
             filtration rate (GFR) of >= 60 ml/min (i.e. class I or class II chronic kidney disease
             ) using the Modification of Diet in Renal Disease (MDRD) formula

               -  Note: Daily creatinine and MDRD formula are only for the 1st induction cycle

          -  Cardiac ejection fraction >= 45% or within institutional normal limits; a nuclear
             medicine gated blood pool examination is preferred; a two-dimensional (2-D)
             echocardiogram (ECHO) scan is acceptable if a calculated ejection fraction is obtained
             and follow-up measurement of the cardiac ejection fraction will also be performed by
             echocardiography; measurement of cardiac ejection fraction should be within two weeks
             prior to receiving treatment

               -  NOTE: when a multi gated acquisition scan (MUGA) or echocardiogram cannot be
                  obtained due to weekend or holiday, then patients may be enrolled provided there
                  is no history of significant cardiovascular disease and a measurement of cardiac
                  ejection fraction will be performed within 5 days of study enrollment

          -  Patients with suspected central nervous system (CNS) involvement should undergo lumbar
             puncture; those with documented CNS involvement will be excluded

          -  Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if
             adequate number of circulating blasts (>10^9/l) from peripheral blood; this must be
             done via E3903

               -  NOTE: SWOG/CTSU institutions: E3903 is not open at the CTSU; therefore, baseline
                  submissions must be submitted on E2906

          -  Patients who have received previous treatment for antecedent hematological disorders
             (AHD) with 5-azacitidine, decitabine, or low dose cytarabine will be excluded

          -  Patients with known human immunodeficiency virus (HIV) infection are excluded

          -  HLA typing should be performed at registration, if possible

          -  Diagnostic bone marrow and peripheral blood specimens must be submitted for
             immunophenotyping and selected molecular testing; this must be done via E2906

               -  NOTE: SWOG/CTSU institutions: E3903 is not open at the CTSU; therefore, baseline
                  submissions must be submitted on E2906

          -  CONSOLIDATION CRITERIA:

          -  NOTE: All patients achieving CR or complete remission with incomplete blood count
             recovery (CRi) will receive consolidation when fit

          -  NOTE: Patients proceeding to transplant are allowed up to one cycle of consolidation
             treatment

          -  Consolidation cycle 1 must commence within sixty days of the bone marrow aspirate and
             biopsy that confirmed the presence of a CR or CRi

          -  Patients must have achieved a CR or CRi (or morphologic leukemia-free state for those
             patients proceeding to Arm G transplant)

          -  Patients who have achieved a CR or CRi must have maintained peripheral blood evidence
             of a CR or CRi

          -  Patients must have an ECOG performance status of 0-2

          -  Patients must have resolved any serious infectious complications related to induction

               -  NOTE: Patients with an HLA-matched donor and proceeding to transplant will be
                  allowed up to one cycle of consolidation treatment

          -  Any significant medical complications related to induction must have resolved

          -  Patients must have a creatinine and AST =< grade 1

          -  MAINTENANCE CRITERIA:

          -  Maintenance should commence within 60 days of recovery of peripheral blood counts
             after consolidation cycle 2; patients must begin consolidation cycle 2 within 60 days
             of recovery to be eligible for further therapy

          -  Patients must have maintained peripheral blood evidence of a remission and must have a
             CR or CRi, confirmed on restaging bone marrow (BM) aspirate and biopsy and cytogenetic
             analysis

          -  Patients must have an ECOG performance status of 0 -2

          -  Patients must have resolved any serious infectious complications related to
             consolidation cycle 2

          -  Any significant medical complications related to consolidation cycle 2 must have
             resolved

          -  Total serum bilirubin =< 1.5 x ULN

               -  NOTE: if total bilirubin is 2-3 mg/dL, but direct bilirubin is normal, then the
                  patient will be considered eligible

          -  Serum creatinine =< grade 1

          -  The absolute neutrophil count (ANC) must be > 1000 mm^3 prior to starting every cycle
             of treatment with decitabine; decitabine may be delayed for up to 4 weeks between
             cycles (i.e. may be administered as infrequently as every (q) 8 weeks) while waiting
             for counts to recover

          -  The platelet count must be > 75,000 mm^3 prior to starting every cycle of treatment
             with decitabine; decitabine may be delayed for up to 4 weeks between cycles (i.e. may
             be administered as infrequently as every (q) 8 weeks) while waiting for counts to
             recover

          -  ALLOGENEIC TRANSPLANTATION:

          -  Patients must be > 30 days and < 90 days from the start of induction or re-induction
             chemotherapy, or > 30 days and < 90 days of recovery from consolidation cycle 1 (if
             received), and must have achieved a response to induction therapy (CR, CRi, or
             "morphologic disease-free state", documented > 27 days after start of most-recent
             chemotherapy)

          -  Patients must have recovered from the effects of induction, re-induction, or
             consolidation chemotherapy (all toxicities =< grade I with the exception of reversible
             electrolyte abnormalities), and have no ongoing active infection requiring treatment

          -  Patients must have a total serum bilirubin =< 1.5 x ULN (grade =< 1) and a serum
             creatinine =< grade 1

          -  An eligible HLA-identical donor (either related or unrelated) should be available; in
             sibling donors, low resolution HLA typing (A,B,DR) will be considered sufficient; in
             the case of unrelated donors, high-resolution class I and II typing (A, B, C, DRB1 and
             DQ) should be matched at all 10 loci; donors must be willing and able to undergo
             peripheral blood progenitor mobilization

               -  HLA-identical sibling (6/6): the donor must be determined to be an HLA-identical
                  sibling (6/6) by serologic typing for class (A, B) and low resolution molecular
                  typing for class II (DRB1)

               -  Matched unrelated donor (10/10): high resolution molecular typing at the
                  following loci is required: HLA-A, -B, -C, -DRBL, and -DQB1

               -  NOTE: for matched donors - will allow select 1 antigen mismatched sibling donors
                  and unrelated donors in accordance with site institutional standard, as long as
                  matched at HLA-A, HLA-B, HLA-C, and DRB1, and with advanced discussion/approval
                  by the Study Chair and the bone marrow transplant (BMT) co-chair

          -  Patients must be considered reliable enough to comply with the medication regimen and
             follow-up, and have social support necessary to allow this compliance

          -  Patients must have a cardiac ejection fraction of >= 40%, or within institutional
             normal limits; a nuclear medicine gated blood pool examination is preferred; a 2-D
             ECHO scan is acceptable if a calculated ejection fraction is obtained and follow-up
             measurement of the cardiac ejection fraction will also be performed by
             echocardiography; measurement of cardiac ejection fraction should be within two weeks
             prior to allogeneic transplantation

          -  Diffusion capacity of carbon monoxide (DLCO) > 40% with no symptomatic pulmonary
             disease

          -  No known hypersensitivity to Escherichia (E.) coli-derived products

          -  No human immunodeficiency virus (HIV) infection; patients with immune dysfunction are
             at a significantly higher risk of toxicities from intensive immunosuppressive
             therapies

          -  Creatinine =< grade 1

          -  Bilirubin =< grade 1

               -  If bilirubin is 2-3 mg/dL, but direct bilirubin is normal then patient will be
                  considered eligible

          -  AST =< grade 1
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:Time between randomization and death from any cause, assessed up to 5 years
Safety Issue:
Description:Due to the potential confounding by maintenance therapy on the induction comparison, a weighted analysis (weighted Cox regression) will be used for the primary analysis.

Secondary Outcome Measures

Measure:Mortality rate
Time Frame:30 days
Safety Issue:
Description:
Measure:Induction complete response rates
Time Frame:Up to 5 years
Safety Issue:
Description:The induction response (CR + CRi) rates will be compared between the clofarabine arm and the standard treatment arm. At the end of the study, the 95% confidence interval on the difference in the CR + CRi rates (CR + CRi rate of standard treatment - CR + CRi rate of clofarabine) will be computed based on the normal approximation to the difference of two independent binomial proportions.
Measure:Disease-free survival (DFS)
Time Frame:Time from the second randomization to relapse or death without relapse, assessed up to 5 years
Safety Issue:
Description:The primary analysis of DFS will use a one-sided log rank test stratified on the induction therapy and on patient age and cytogenetics to determine the effect of decitabine on DFS as a maintenance therapy in comparison with observation.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:To evaluate the impact of consolidation with non-ablative conditioning and allogeneic hematopoietic stem cell transplantation with an HLA-identical sibling on overall survival in patients who achieve a 'morphologic leukemia-free state, a one-sided log rank test stratified on age, therapy-related AML, the presence of AHD at the time of diagnosis of AML, and the induction therapy they received will be used.
Measure:Epidemiological factors, measured using the Acute Leukemia Epidemiology and Survival in ECOG (ALESE) questionnaire
Time Frame:Baseline
Safety Issue:
Description:The proportions of obese patients and patients who had benzene exposure, ever smoked in their lifetime, took aspirin regularly, took acetaminophen regularly, ever lived in rural/farm environments, or had other exposures or lifestyle factors will be calculated separately, along with their 95% confidence intervals.
Measure:Change in the Functional Assessment of Cancer Therapy (FACT)-Leukemia-specific (Leu) Trial Outcome Index (TOI) score
Time Frame:Baseline to 30 days after beginning induction therapy
Safety Issue:
Description:Descriptive statistics will be provided and Cronbach's alpha will be calculated at each time point to assess reliability. Repeated measures analysis techniques will also be utilized to examine the treatment effect and time effect on FACT-Leu TOI score. For patients randomized to the induction treatments, the longitudinal scores collected from time of randomization, two weeks after beginning induction therapy (at the time of nadir), and at 28-30 days after beginning induction therapy, will be analyzed according to the methods described in Schluchter and Schluchter, Greene and Beck.
Measure:Change in the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score
Time Frame:Baseline to 30 days after beginning induction therapy
Safety Issue:
Description:Descriptive statistics will be provided and Cronbach's alpha will be calculated at each time point to assess reliability. Repeated measures analysis techniques will also be utilized to examine the treatment effect and time effect on FACIT Fatigue score. For patients randomized to the induction treatments, the longitudinal scores collected from time of randomization, two weeks after beginning induction therapy (at the time of nadir), and at 28-30 days after beginning induction therapy, will be analyzed according to the methods described in Schluchter and Schluchter, Greene and Beck.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Eastern Cooperative Oncology Group

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