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

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIIBiomarker/Laboratory analysis, Treatment60 and overE2906
NCI-2011-01992, CDR0000659585, ECOG-E2906, NCT01041703

Trial Description

Summary

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.

Further Study Information

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.

Eligibility Criteria

Inclusion Criteria:

CONSOLIDATION CRITERIA:

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

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

ADDITIONAL INDUCTION ELIGIBILITY CRITERIA:

AST =< grade 1

Bilirubin =< grade 1

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

Patients must have an ECOG performance status of 0-2

Any significant medical complications related to induction must have resolved

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

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

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

Patient must not have an active, uncontrolled infection

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

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

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

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

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

MAINTENANCE CRITERIA:

Patients must have a creatinine and AST =< grade 1

Serum creatinine =< grade 1

ALLOGENEIC TRANSPLANTATION:

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 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

HLA typing should be performed at registration, if possible

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

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

Diagnostic bone marrow and peripheral blood specimens must be submitted for immunophenotyping and selected molecular testing

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

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 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 total serum bilirubin =< 1.5 x ULN (grade =< 1) and a serum creatinine =< grade 1

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

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 have resolved any serious infectious complications related to consolidation cycle 2

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

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

Patients must have an ECOG performance status of 0 -2

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

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

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

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

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

Patients may not have received prior chemotherapy for AML with the exception of hydroxyurea for increased blast count or leukapheresis for leukocytosis; patients who have received a limited and short-term exposure of ATRA (all trans retinoid acid) while AML-M3 (acute promyelocytic leukemia) was being ruled out, and which has been discontinued, will be eligible

Pre-registration: Diagnostic bone marrow and peripheral blood specimens must be submitted for eligibility testing by multiparameter flow cytometry; testing will be performed by the Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging Network (ACRIN) Leukemia Translational Studies Laboratory and reported to the institution

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

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

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

Patients must be > 28 days from the start of induction or re-induction chemotherapy, or from the start of 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”)

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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

ECOG-ACRIN Cancer Research Group

  • National Cancer Institute
James MacLeod Foran, Principal Investigator

Trial Sites

U.S.A.

Colorado
Denver

Colorado Cancer Research Program CCOP

Keren Sturtz
Ph: 888-785-6789

Keren Sturtz
Principal Investigator

Georgia
Atlanta

Atlanta Regional CCOP

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Northside Hospital

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Piedmont Hospital

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Saint Joseph's Hospital of Atlanta

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Austell

Well Star Cobb Hospital

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Columbus

John B Amos Cancer Center

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Decatur

Dekalb Medical Center

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Fayetteville

Piedmont Fayette Hospital

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Lawrenceville

Gwinnett Medical Center

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Marietta

Wellstar Kennestone Hospital

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Riverdale

Southern Regional Medical Center

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Rome

Harbin Clinic Medical Oncology and Clinical Research

Thomas Edwin Seay
Ph: 404-303-3355

Thomas Edwin Seay
Principal Investigator

Illinois
Macomb

Mcdonough District Hospital

Nguyet Anh Le-Lindqwister
Ph: 800-793-2262

Nguyet Anh Le-Lindqwister
Principal Investigator

Monmouth

Holy Family Medical Center

Nguyet Anh Le-Lindqwister
Ph: 800-793-2262

Nguyet Anh Le-Lindqwister
Principal Investigator

Illinois CancerCare-Monmouth

Nguyet Anh Le-Lindqwister
Ph: 800-793-2262

Nguyet Anh Le-Lindqwister
Principal Investigator

Normal

Community Cancer Center Foundation

Nguyet Anh Le-Lindqwister
Ph: 800-793-2262

Nguyet Anh Le-Lindqwister
Principal Investigator

Ottawa

Ottawa Regional Hospital and Healthcare Center

Nguyet Anh Le-Lindqwister
Ph: 800-793-2262

Nguyet Anh Le-Lindqwister
Principal Investigator

Peoria

Illinois Oncology Research Association CCOP

Nguyet Anh Le-Lindqwister
Ph: 800-793-2262

Nguyet Anh Le-Lindqwister
Principal Investigator

Proctor Hospital

Nguyet Anh Le-Lindqwister
Ph: 800-793-2262

Nguyet Anh Le-Lindqwister
Principal Investigator

Peru

Illinois Valley Hospital

Nguyet Anh Le-Lindqwister
Ph: 800-793-2262

Nguyet Anh Le-Lindqwister
Principal Investigator

Minnesota
Fergus Falls

Lake Region Healthcare Corporation-Cancer Care

Preston D. Steen
Ph: 701-234-6161

Preston D. Steen
Principal Investigator

Missouri
Saint Louis

Saint Louis-Cape Girardeau CCOP

Bethany Graham Sleckman
Ph: 913-948-5588

Bethany Graham Sleckman
Principal Investigator

Montana
Billings

Montana Cancer Consortium CCOP

Benjamin T. Marchello
Ph: 800-648-6274

Benjamin T. Marchello
Principal Investigator

Nevada
Reno

Saint Mary's Regional Medical Center

Cecilia Ysabel Arana Yi
Ph: 505-272-6972

Cecilia Ysabel Arana Yi
Principal Investigator

Tennessee
Jackson

Jackson-Madison County General Hospital

Brion Vincent Randolph
Ph: 731-425-6865

Brion Vincent Randolph
Principal Investigator

Wisconsin
Milwaukee

Aurora Cancer Care-Milwaukee South

Rubina Qamar
Ph: 888-709-2080

Rubina Qamar
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01041703

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.