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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by Eastern Cooperative Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:
NCT02085408
First received: March 11, 2014
Last updated: NA
Last verified: August 2013
History: No changes posted
  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.


Condition Intervention Phase
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
Drug: clofarabine
Drug: daunorubicin hydrochloride
Other: clinical observation
Drug: cytarabine
Drug: decitabine
Other: laboratory biomarker analysis
Procedure: quality-of-life assessment
Other: questionnaire administration
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Eastern Cooperative Oncology Group:

Primary Outcome Measures:
  • Overall survival [ Time Frame: Time between randomization and death from any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    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:
  • Mortality rate [ Time Frame: 30 days ] [ Designated as safety issue: No ]
  • Induction complete response rates [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    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.

  • Disease-free survival (DFS) [ Time Frame: Time from the second randomization to relapse or death without relapse, assessed up to 5 years ] [ Designated as safety issue: No ]
    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.

  • Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    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.

  • Epidemiological factors, measured using the Acute Leukemia Epidemiology and Survival in ECOG (ALESE) questionnaire [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • Change in the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score [ Time Frame: Baseline to 30 days after beginning induction therapy ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Epigenetic signatures, determined by expression and methylation profiling [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    The methods described in Thompson et.al will be used to identify epigenetics signatures which are different between patients who relapsed and patients who did not relapse. Signatures identified by epigenetic analysis will be correlated with DFS using a least angle regression and shrinkage (LARS)/least absolute shrinkage and selection operator (LASSO) approach for each maintenance arm.

  • Gene expression levels [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Genes will be filtered by examining ratios of standard deviation to the mean. Genes will be hierarchically clustered to find genes with high/low fold change/differences. Supervised analyses will be used to identify genes that are differentially expressed between patients who relapsed and patients who did not relapsed. Genes or epigenetic signatures identified by gene expression or epigenetic analysis will be correlated with DFS using LARS/LASSO approach.

  • Predictive mutations [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    For each mutation a stratified log-rank test will be performed (using the strata at randomization) adjusted for multiple testing using resampling and the min-p method of Westfall and Young as implemented in the R package multtest. In addition tests for interaction between treatment assignment and mutational status will be performed to identify potential predictive mutations. The prognostic relevance of known mutations on overall survival and response to therapy will be assessed, and novel mutations identified in discovery studies and by other efforts will also be included.

  • Prognostic risk groups [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Prognostic risk groups will be identified by using recursive partitioning and logistic regression, both of which are highly suitable for binary predictors. A randomly chosen subsample of 423 (2/3 of 635) patients will be used for training these models and the remaining 212 for validation.

  • Pgp levels [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    The possible association of response to clofarabine with Pgp will be explored using a Wilcoxon rank-sum test.

  • CXCR4 expression levels [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Expression intensity of CXCR4 will be divided into three groups (low, intermediate, high). The grading will be further simplified as high/intermediate vs. low. Data will be first analyzed by induction treatment arms. When data are available, logistic and Cox regression analysis, adjusted by treatment effect and prognostic factors (including cytogenetics), will be used to assess whether CXCR4 expression level is an independent predictor for response or survival.


Estimated Enrollment: 747
Study Start Date: December 2010
Estimated Primary Completion Date: February 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (daunorubicin hydrochloride and cytarabine)
See Detailed Description
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Cerubidin
  • Cerubidine
  • daunomycin hydrochloride
  • daunorubicin
  • RP-13057
Other: clinical observation
Undergo clinical observation
Other Name: observation
Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Other: laboratory biomarker analysis
Correlative studies
Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Other: questionnaire administration
Ancillary studies
Experimental: Arm II (clofarabine)
See Detailed Description
Drug: clofarabine
Given IV
Other Names:
  • CAFdA
  • Clofarex
  • Clolar
Drug: decitabine
Given IV
Other Names:
  • 5-aza-dCyd
  • 5AZA
  • DAC
Other: laboratory biomarker analysis
Correlative studies
Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Other: questionnaire administration
Ancillary studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   60 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02085408

  Show 273 Study Locations
Sponsors and Collaborators
Eastern Cooperative Oncology Group
Investigators
Principal Investigator: James Foran Eastern Cooperative Oncology Group
  More Information

No publications provided

Responsible Party: Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier: NCT02085408     History of Changes
Other Study ID Numbers: E2906, NCI-2011-01992, CDR0000659585, ECOG-E2906, E2906, E2906, U10CA021115
Study First Received: March 11, 2014
Last Updated: March 11, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Leukemia
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Chronic
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Cytarabine
Decitabine
Clofarabine
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on August 28, 2014