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NCT02085408

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

NCT ID: NCT02085408

Last Updated: 2024-12-13

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

727 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-02-04

Study Completion Date

2022-12-21

Brief Summary

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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

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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 A (STANDARD THERAPY): Patients receive daunorubicin hydrochloride at 60 mg/m\^2 intravenously (IV) over 10-15 minutes on days 1-3 and cytarabine at 100 mg/m\^2 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 B: Patients receive clofarabine at 30 mg/m\^2 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 (Arms C and D). 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 C (STANDARD THERAPY): Patients receive cytarabine at 1500 mg/m\^2 IV over 1 hour once or twice daily on days 1-6. Treatment repeats every 4-6 weeks for 2 courses.

ARM D: Patients receive clofarabine at 20 mg/m\^2 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 are randomized to one of the two maintenance therapy arms (Arms E and F).

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 E.

ARM E: Patients undergo observation monthly for 12 months.

ARM F: Patients receive decitabine at 20 mg/m\^2 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 (Arm G): Patients begin reduced-intensity conditioning 30-90 days after the initiation of induction therapy.

CONDITIONING REGIMEN: Patients receive fludarabine phosphate at 30 mg/m\^2 IV over 30 minutes on days -7 to -3, busulfan at 0.8 mg/kg IV over 2 hours every 6 hours on days -4 and -3 (for a total of 8 doses), and anti-thymocyte globulin at 2.5 mg/kg/day 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.

Conditions

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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

Keywords

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acute myeloid leukemia Clofarabine Daunorubicin Cytarabine Decitabine

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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A (Induction:daunorubicin/cytarabine; consolidation:cytarabine; maintenance:observation/transplant)

See Detailed Description

Group Type ACTIVE_COMPARATOR

Daunorubicin

Intervention Type DRUG

Given IV

Cytarabine

Intervention Type DRUG

Given IV

Observation

Intervention Type OTHER

Undergo clinical observation

Allogeneic hematopoietic stem cell transplantation

Intervention Type PROCEDURE

Patients with an HLA-identical donor proceed to allogeneic stem cell transplantation.

B (Induction: clofarabine; Consolidation: clofarabine; Maintenance: decitabine or transplant)

See Detailed Description

Group Type EXPERIMENTAL

Clofarabine

Intervention Type DRUG

Given IV

Decitabine

Intervention Type DRUG

Given IV

Allogeneic hematopoietic stem cell transplantation

Intervention Type PROCEDURE

Patients with an HLA-identical donor proceed to allogeneic stem cell transplantation.

Interventions

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Daunorubicin

Given IV

Intervention Type DRUG

Cytarabine

Given IV

Intervention Type DRUG

Clofarabine

Given IV

Intervention Type DRUG

Decitabine

Given IV

Intervention Type DRUG

Observation

Undergo clinical observation

Intervention Type OTHER

Allogeneic hematopoietic stem cell transplantation

Patients with an HLA-identical donor proceed to allogeneic stem cell transplantation.

Intervention Type PROCEDURE

Other Intervention Names

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Daunomycin Cerubidine Rubidomycin Ara-C Arabinosyl Cytosar-U cytosine arabinoside CLOLAR Cl-F-Ara-A, 2-chloro-9-(2-deoxy-2-fluoro-β-Darabinofuranosyl)adenine Dacogen® 5-aza-2'-deoxycytidine 5-aza-CdR AlloSCT

Eligibility Criteria

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Inclusion Criteria

* Sexually active males must be strongly advised to use an accepted and effective method of contraception
* Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin =\< grade 1
* 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
* ECOG performance status (PS) 0-3 (restricted to ECOG PS 0-2 if \>= 70 years of age)
* 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
* 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
* Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if adequate number of circulating blasts (\>10\^9/l) from peripheral blood
* 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

* NOTE: All patients achieving complete remission (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
* 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 within 48 hours prior to registration

* 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
* 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

* Patients must be \> 28 days from the start of induction or re-induction chemotherapy, or from the start Consolidation Cycle 1 (if received) and \< 90 days following recovery from most recent treatment; and they must have achieved and maintained a response to induction therapy (CR, CRi, or "morphologic disease-free state")
* 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; AST \<= 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

Exclusion Criteria

* Concurrent active malignancy for which they are receiving treatment (other than myelodysplastic syndromes \[MDS\])
* Active, uncontrolled infection
* 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
* Blastic transformation of chronic myelogenous leukemia
* Prior therapy of MDS with decitabine, low-dose cytarabine, or azacitidine
* Prior chemotherapy for AML with the exception of hydroxyurea for increased blast count or leukapheresis for leukocytosis
* Documented CNS involvement
* Previous treatment for antecedent hematological disorders (AHD) with 5-azacitidine, decitabine, or low dose cytarabine
* Human immunodeficiency virus (HIV) infection

* Hypersensitivity to Escherichia (E.) coli-derived products
* Human immunodeficiency virus (HIV) infection; patients with immune dysfunction are at a significantly higher risk of toxicities from intensive immunosuppressive therapies

Minimum Eligible Age

60 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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James Foran

Role: PRINCIPAL_INVESTIGATOR

Eastern Cooperative Oncology Group

Locations

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University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status

Mayo Clinic in Arizona

Scottsdale, Arizona, United States

Site Status

Arizona Cancer Center at University Medical Center North

Tucson, Arizona, United States

Site Status

University of Arizona Health Sciences Center

Tucson, Arizona, United States

Site Status

The Medical Center of Aurora

Aurora, Colorado, United States

Site Status

Boulder Community Hospital

Boulder, Colorado, United States

Site Status

Penrose-Saint Francis Healthcare

Colorado Springs, Colorado, United States

Site Status

Saint Anthony Central Hospital

Denver, Colorado, United States

Site Status

Porter Adventist Hospital

Denver, Colorado, United States

Site Status

Exempla Saint Joseph Hospital

Denver, Colorado, United States

Site Status

Presbyterian - Saint Lukes Medical Center - Health One

Denver, Colorado, United States

Site Status

Rose Medical Center

Denver, Colorado, United States

Site Status

Colorado Cancer Research Program CCOP

Denver, Colorado, United States

Site Status

Swedish Medical Center

Englewood, Colorado, United States

Site Status

North Colorado Medical Center

Greeley, Colorado, United States

Site Status

Littleton Adventist Hospital

Littleton, Colorado, United States

Site Status

Sky Ridge Medical Center

Lone Tree, Colorado, United States

Site Status

Longmont United Hospital

Longmont, Colorado, United States

Site Status

McKee Medical Center

Loveland, Colorado, United States

Site Status

Parker Adventist Hospital

Parker, Colorado, United States

Site Status

Saint Mary Corwin Medical Center

Pueblo, Colorado, United States

Site Status

North Suburban Medical Center

Thornton, Colorado, United States

Site Status

Exempla Lutheran Medical Center

Wheat Ridge, Colorado, United States

Site Status

Saint Francis Hospital and Medical Center

Hartford, Connecticut, United States

Site Status

The Hospital of Central Connecticut

New Britain, Connecticut, United States

Site Status

Beebe Medical Center

Lewes, Delaware, United States

Site Status

Christiana Care Health System-Christiana Hospital

Newark, Delaware, United States

Site Status

University of Florida

Gainesville, Florida, United States

Site Status

Mayo Clinic in Florida

Jacksonville, Florida, United States

Site Status

Florida Hospital

Orlando, Florida, United States

Site Status

Piedmont Hospital

Atlanta, Georgia, United States

Site Status

Atlanta Regional CCOP

Atlanta, Georgia, United States

Site Status

Northside Hospital

Atlanta, Georgia, United States

Site Status

Saint Joseph's Hospital of Atlanta

Atlanta, Georgia, United States

Site Status

Georgia Regents University

Augusta, Georgia, United States

Site Status

Well Star Cobb Hospital

Austell, Georgia, United States

Site Status

John B Amos Cancer Center

Columbus, Georgia, United States

Site Status

Dekalb Medical Center

Decatur, Georgia, United States

Site Status

Piedmont Fayette Hospital

Fayetteville, Georgia, United States

Site Status

Gwinnett Medical Center

Lawrenceville, Georgia, United States

Site Status

Wellstar Kennestone Hospital

Marietta, Georgia, United States

Site Status

Southern Regional Medical Center

Riverdale, Georgia, United States

Site Status