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Phase III Randomized Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard Daunorubicin & 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)


Phase 3
60 Years
N/A
Open (Enrolling)
Both
Leukemia

Thank you

Trial Information

Phase III Randomized Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard Daunorubicin & 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)


OBJECTIVES:

Primary

- To compare the overall survival of older patients with newly diagnosed acute myeloid
leukemia (AML) treated with clofarabine as induction therapy and consolidation therapy
vs standard daunorubicin hydrochloride and cytarabine.

Secondary

- To evaluate complete remission (CR) rates, duration of remission, and
toxicity/treatment-related mortality of patients treated with these regimens.

- To evaluate the feasibility of consolidation therapy with reduced-intensity
conditioning and allogeneic hematopoietic stem cell transplantation from HLA-identical
donors, in terms of the incidence of successful engraftment, acute and chronic
graft-vs-host disease, and transplant-related mortality in select patients age 60-69
years who achieve a response to induction therapy.

- To determine the impact of reduced-intensity conditioning and allogeneic stem cell
transplantation on overall survival of select patients.

- To compare the duration of remission and disease-free survival of patients in CR
following completion of consolidation therapy who are subsequently randomized to
receive decitabine as maintenance therapy vs observation.

- To perform expression and methylation profiling in patients treated with decitabine as
maintenance therapy and to correlate their integrated epigenetic signatures with
response to decitabine.

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

- To explore the possible association of response to clofarabine with nucleoside
transporters hENT1, hCNT3, and ABC-transporter P-glycoprotein.

- To assess the intensity of expression of CXCR4 on diagnostic leukemia cells and to
correlate this parameter with other established prognostic factors.

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

Tertiary

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

- To measure the change in health-related QOL that occurs over time.

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

- To determine if components of a comprehensive geriatric assessment or QOL scale predict
ability to complete treatment for AML.

- To describe the impact of transplantation on QOL in patients with AML over 60 years of
age.

OUTLINE: This is a multicenter study. Patients are stratified according to age (60-69 years
vs ≥ 70 years), , disease type (secondary vs de novo), therapy-related AML (yes vs no), and
antecedent hematologic disorder (yes vs no).

- Induction therapy: Patients are randomized to 1 of 2 treatment arms.

- Arm I (standard therapy): Patients receive daunorubicin hydrochloride 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 incomplete (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. Patients undergoing second induction
who do not achieve CR by day 56 of the start of re-induction are taken off protocol.

- 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.

- 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.

Patients complete quality-of-life questionnaires periodically, including health-related
quality of life, physical and functional well-being, and fatigue questionnaires.

Peripheral blood, bone marrow, and karyotype samples are collected periodically for
cytogenetic analysis and other correlative laboratory studies.

After completion of study treatment, patients are followed up periodically for ≥ 5 years.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Newly diagnosed acute myeloid leukemia (AML)

- Considered candidates for intensive chemotherapy based on examination of peripheral
blood or bone marrow aspirate specimens or touch preparations of the bone marrow
biopsy obtained within the past 2 weeks

- Bone marrow aspirate is required for enrollment, however, if there is
discordance between percentage of myeloblasts on the differential of the
peripheral blood or aspirate, the peripheral blood criteria are sufficient for
diagnosis

- Patients with secondary AML (defined as AML that has developed in a person with a
history of antecedent blood count abnormalities, myelodysplastic syndromes [MDS], or
a myeloproliferative disorder [excluding chronic myeloid leukemia], or a history of
prior chemotherapy or radiotherapy for a disease other than AML) are eligible

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

- No blastic transformation of chronic myelogenous leukemia

- No documented CNS involvement

- Concurrent registration on ECOG-E3903 (Ancillary Laboratory Protocol for the
Collecting of Diagnostic Samples from Patients With Leukemia or Related Hematologic
Disorders Being Considered for ECOG Treatment Clinical Trials) required (except for
patients participating at CTSU institutions; these patients are exempt from this
requirement)

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

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

- Peripheral blood stem cell donor meeting 1 of the following criteria:

- HLA-identical sibling (6/6)

- Low-resolution HLA typing (A,B,DR) allowed

- Matched unrelated donor (10/10)

- High-resolution class I and II typing (A,B,C,DRB1 and DQ) should be matched
at all 10 loci

PATIENT CHARACTERISTICS:

- ECOG performance status (PS) 0-3 (ECOG PS 0-2 if ≥ 70 years of age)

- AST and ALT ≤ grade 1

- Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ grade 1)

- Serum creatinine ≤ 1 mg/dL (≤ grade 1)

- Cardiac ejection fraction ≥ 45% by MUGA or 2-D ECHO

- Fertile patients must use effective contraception

- No concurrent active malignancy requiring treatment (other than MDS)

- No active, uncontrolled infection

- No known HIV infection

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior chemotherapy for AML (except for hydroxyurea for increased blast count or
leukapheresis for leukocytes)

- No prior treatment with azacitidine, decitabine, or low-dose cytarabine

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall survival

Safety Issue:

No

Principal Investigator

James M. Foran, MD, FRCPC

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic

Authority:

Unspecified

Study ID:

CDR0000659585

NCT ID:

NCT01041703

Start Date:

January 2011

Completion Date:

Related Keywords:

  • Leukemia
  • untreated adult acute myeloid leukemia
  • secondary acute myeloid leukemia
  • adult acute minimally differentiated myeloid leukemia (M0)
  • adult acute myeloblastic leukemia without maturation (M1)
  • adult acute myeloblastic leukemia with maturation (M2)
  • adult acute myelomonocytic leukemia (M4)
  • adult acute monoblastic leukemia (M5a)
  • adult acute monocytic leukemia (M5b)
  • adult erythroleukemia (M6a)
  • adult pure erythroid leukemia (M6b)
  • adult acute megakaryoblastic leukemia (M7)
  • 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)
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid

Name

Location

Mayo Clinic ScottsdaleScottsdale, Arizona  85259
Mayo Clinic - JacksonvilleJacksonville, Florida  32224
Mayo Clinic Cancer CenterRochester, Minnesota  55905
Cardinal Bernardin Cancer Center at Loyola University Medical CenterMaywood, Illinois  60153-5500
CCOP - Christiana Care Health ServicesWilmington, Delaware  19899
CCOP - Illinois Oncology Research AssociationPeoria, Illinois  61602
George Bray Cancer Center at the Hospital of Central Connecticut - New Britain CampusNew Britain, Connecticut  06050
Mercy Medical Center - Sioux CitySioux City, Iowa  51104
Siouxland Hematology-Oncology Associates, LLPSioux City, Iowa  51101
St. Luke's Regional Medical CenterSioux City, Iowa  51104
Baystate Regional Cancer Program at D'Amour Center for Cancer CareSpringfield, Massachusetts  01199
Bronson Methodist HospitalKalamazoo, Michigan  49007
West Michigan Cancer CenterKalamazoo, Michigan  49007-3731
Borgess Medical CenterKalamazooaa, Michigan  49001
MeritCare BemidjiBemidji, Minnesota  56601
Duluth Clinic Cancer Center - DuluthDuluth, Minnesota  55805-1983
CCOP - DuluthDuluth, Minnesota  55805
Miller - Dwan Medical CenterDuluth, Minnesota  55805
MeritCare BroadwayFargo, North Dakota  58122
CCOP - MeritCare HospitalFargo, North Dakota  58122
Aultman Cancer Center at Aultman HospitalCanton, Ohio  44710-1799
Jewish Hospital Cancer CenterCincinnati, Ohio  45236
St. Rita's Medical CenterLima, Ohio  45801
Abramson Cancer Center of the University of PennsylvaniaPhiladelphia, Pennsylvania  19104-4283
Geisinger Medical Group - Scenery ParkState College, Pennsylvania  16801
Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical CenterWilkes-Barre, Pennsylvania  18711
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
University of Wisconsin Paul P. Carbone Comprehensive Cancer CenterMadison, Wisconsin  53792-6164
Medical College of Wisconsin Cancer CenterMilwaukee, Wisconsin  53226
Methodist Medical Center of IllinoisPeoria, Illinois  61636
CCOP - Montana Cancer ConsortiumBillings, Montana  59101
CCOP - DaytonKettering, Ohio  45429
CCOP - Grand RapidsGrand Rapids, Michigan  49503
CCOP - St. Louis-Cape GirardeauSaint Louis, Missouri  63141
Waukesha Memorial Hospital Regional Cancer CenterWaukesha, Wisconsin  53188
Florida Hospital Cancer Institute at Florida Hospital OrlandoOrlando, Florida  32803-1273
Mary Babb Randolph Cancer Center at West Virginia University HospitalsMorgantown, West Virginia  26506
Lewistown HospitalLewistown, Pennsylvania  17044
Mount Nittany Medical CenterState College, Pennsylvania  16803
Saint Anthony's Hospital at Saint Anthony's Health CenterAlton, Illinois  62002
Good Samaritan Regional Health CenterMt. Vernon, Illinois  62864
Battle Creek Health System Cancer Care CenterBattle Creek, Michigan  49017
Munson Medical CenterTraverse City, Michigan  49684
David C. Pratt Cancer Center at St. John's MercySt. Louis, Missouri  63141
Hematology-Oncology Centers of the Northern Rockies - BillingsBillings, Montana  59101
St. Peter's HospitalHelena, Montana  59601
Kalispell Regional Medical CenterKalispell, Montana  59901
Glacier Oncology, PLLCKalispell, Montana  59901
Montana Cancer Center at St. Patrick Hospital and Health Sciences CenterMissoula, Montana  59802
MBCCOP - Medical College of Georgia Cancer CenterAugusta, Georgia  30912-3730
Swedish-American Regional Cancer CenterRockford, Illinois  61104-2315
Butterworth Hospital at Spectrum HealthGrand Rapids, Michigan  49503-2560
CCOP - Nevada Cancer Research FoundationLas Vegas, Nevada  89109-2306
Oklahoma University Cancer InstituteOklahoma City, Oklahoma  73104
Geisinger Cancer Institute at Geisinger HealthDanville, Pennsylvania  17822-0001
West Virginia University Health Sciences Center - CharlestonCharleston, West Virginia  25302
Gundersen Lutheran Center for Cancer and BloodLa Crosse, Wisconsin  54601
Robert H. Lurie Comprehensive Cancer Center at Northwestern UniversityChicago, Illinois  60611
Decatur Memorial Hospital Cancer Care InstituteDecatur, Illinois  62526
Hematology Oncology Associates - SkokieSkokie, Illinois  60076
Joan Karnell Cancer Center at Pennsylvania HospitalPhiladelphia, Pennsylvania  19107
St. Joseph Medical CenterBloomington, Illinois  61701
Graham HospitalCanton, Illinois  61520
Memorial HospitalCarthage, Illinois  62321
Hematology and Oncology AssociatesChicago, Illinois  60611
Eureka Community HospitalEureka, Illinois  61530
Mason District HospitalHavana, Illinois  62644
North Shore Oncology and Hematology Associates, Limited - LibertyvilleLibertyville, Illinois  60048
McDonough District HospitalMacomb, Illinois  61455
BroMenn Regional Medical CenterNormal, Illinois  61761
Community Cancer CenterNormal, Illinois  61761
Community Hospital of OttawaOttawa, Illinois  61350
Oncology Hematology Associates of Central Illinois, PC - OttawaOttawa, Illinois  61350
Cancer Treatment Center at Pekin HospitalPekin, Illinois  61554
Oncology Hematology Associates of Central Illinois, PC - PeoriaPeoria, Illinois  61615
OSF St. Francis Medical CenterPeoria, Illinois  61637
Proctor HospitalPeoria, Illinois  61614
Illinois Valley Community HospitalPeru, Illinois  61354
Perry Memorial HospitalPrinceton, Illinois  61356
St. Francis Hospital and Health Centers - Beech Grove CampusBeech Grove, Indiana  46107
Fort Wayne Medical Oncology and HematologyFort Wayne, Indiana  46815
Mecosta County Medical CenterBig Rapids, Michigan  49307
St. Joseph's Medical CenterBrainerd, Minnesota  56401
Saint Francis Medical CenterCape Girardeau, Missouri  63701
Cancer Institute of New Jersey at Cooper - VoorheesVoorhees, New Jersey  08043
Samaritan North Cancer Care CenterDayton, Ohio  45415
Grandview HospitalDayton, Ohio  45405
David L. Rike Cancer Center at Miami Valley HospitalDayton, Ohio  45409
Good Samaritan HospitalDayton, Ohio  45406
Blanchard Valley Medical AssociatesFindlay, Ohio  45840
Charles F. Kettering Memorial HospitalKettering, Ohio  45429
Middletown Regional HospitalMiddletown, Ohio  45044
UVMC Cancer Care Center at Upper Valley Medical CenterTroy, Ohio  45373-1300
Ruth G. McMillan Cancer Center at Greene Memorial HospitalXenia, Ohio  45385
Welch Cancer Center at Sheridan Memorial HospitalSheridan, Wyoming  82801
Tunnell Cancer Center at Beebe Medical CenterLewes, Delaware  19958
Kellogg Cancer Care CenterHighland Park, Illinois  60035
Cancer Care and Hematology Specialists of Chicagoland - NilesNiles, Illinois  60714
Reid Hospital & Health Care ServicesRichmond, Indiana  47374
McFarland Clinic, PCAmes, Iowa  50010
Billings Clinic - DowntownBillings, Montana  59107-7000
Bozeman Deaconess Cancer CenterBozeman, Montana  59715
St. James Healthcare Cancer CareButte, Montana  59701
Great Falls Clinic - Main FacilityGreat Falls, Montana  59405
Sletten Cancer Institute at Benefis HealthcareGreat Falls, Montana  59405
Northern Montana HospitalHavre, Montana  59501
Kalispell Medical Oncology at KRMCKalispell, Montana  59901
Summa Center for Cancer Care at Akron City HospitalAkron, Ohio  44309-2090
Barberton Citizens HospitalBarberton, Ohio  44203
Wayne HospitalGreenville, Ohio  45331
Geisinger Hazleton Cancer CenterHazleton, Pennsylvania  18201
Penn State Hershey Cancer Institute at Milton S. Hershey Medical CenterHershey, Pennsylvania  17033-0850
Hematology and Oncology Associates of Northeastern PennsylvaniaScranton, Pennsylvania  18510
York Cancer Center at Apple Hill Medical CenterYork, Pennsylvania  17405
Regional Cancer Center at Memorial Medical CenterSpringfield, Illinois  62781-0001
Regional Cancer Center at Oconomowoc Memorial HospitalOconomowoc, Wisconsin  53066
Union Hospital of Cecil CountyElkton MD, Maryland  21921
Kinston Medical SpecialistsKinston, North Carolina  28501
West Tennessee Cancer Center at Jackson-Madison County General HospitalJackson, Tennessee  38301
Lacks Cancer Center at Saint Mary's Health CareGrand Rapids, Michigan  49503
Galesburg Clinic, PCGalesburg, Illinois  61401
St. Vincent Healthcare Cancer Care ServicesBillings, Montana  59101
Midwest Hematology Oncology Group, IncorporatedSaint Louis, Missouri  63109
Illinois CancerCare - BloomingtonBloomington%, Illinois  61701
Illinois CancerCare - CantonCanton, Illinois  61520
Illinois CancerCare - CarthageCarthage, Illinois  62321
Illinois CancerCare - EurekaEureka, Illinois  61530
Illinois CancerCare - GalesburgGalesburg, Illinois  61401
Illinois CancerCare - HavanaHavana, Illinois  62644
Illinois CancerCare - Kewanee ClinicKewanee, Illinois  61443
Illinois CancerCare - MacombMacomb, Illinois  61455
OSF Holy Family Medical CenterMonmouth, Illinois  61462
Illinois CancerCare - MonmouthMonmouth, Illinois  61462
Illinois CancerCare - Community Cancer CenterNormal, Illinois  61761
Illinois CancerCare - PekinPekin, Illinois  61603
Illinois CancerCare - PeruPeru, Illinois  61354
Illinois CancerCare - PrincetonPrinceton, Illinois  61356
Illinois CancerCare - Spring ValleySpring Valley, Illinois  61362
Mercy General Health PartnersMuskegon, Michigan  49443
Provena St. Mary's Regional Cancer Center - KankakeeKankakee, Illinois  60901
Tufts Medical Center Cancer CenterBoston, Massachusetts  02111
Roger Maris Cancer Center at MeritCare HospitalFargo, North Dakota  58122
D.N. Greenwald CenterMukwonago, Wisconsin  53149