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A Randomized Phase II Study of Azacitidine in Combination With Lenalidomide (NSC-703813) vs. Azacitidine Alone vs. Azacititdine in Combination With Vorinostat (NSC-701852) for Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Refractory Anemia With Excess Blasts, Secondary Myelodysplastic Syndromes

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Trial Information

A Randomized Phase II Study of Azacitidine in Combination With Lenalidomide (NSC-703813) vs. Azacitidine Alone vs. Azacititdine in Combination With Vorinostat (NSC-701852) for Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)


PRIMARY OBJECTIVES:

I. To test whether the response rate (complete remission, partial remission, or hematologic
improvement) of patients with higher-risk myelodysplastic syndromes (MDS) or chronic
myelomonocytic leukemia (CMML) who receive either the combination of lenalidomide and
azacitidine or the combination of vorinostat and azacitidine is improved compared to
patients who receive single-agent azacitidine.

II. To estimate relapse-free survival, overall survival and cytogenetic response rate of
patients treated on each regimen.

III. To estimate the frequency and severity of toxicities of the three regimens in this
patient population.

IV. To investigate in a preliminary manner the frequency of subgroups from pre-study
cytogenetic studies and correlate these subgroups with clinical outcomes in this patient
population.

V. To collect specimens for banking for use in future research studies.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) on days 1-7 or
days 1-5 and 8-9, and lenalidomide orally (PO) once daily (QD) on days 1-21.

ARM II: Patients receive azacitidine as in arm I.

ARM III: Patients receive azacitidine as in arm I and vorinostat PO twice daily (BID) on
days 3-9.

In all arms, courses repeat every 28 days for up to 5 years in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 5
years.


Inclusion Criteria:



- Patients must have morphologically confirmed diagnosis of myelodysplastic syndromes
(MDS) or chronic myelomonocytic leukemia (CMML) based on one of the following:

- French-American-British (FAB) classifications:

- Refractory anemia with excess blasts (RAEB - defined as having 5-20%
myeloblasts in the bone marrow)

- CMML with 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the
blood

- World Health Organization (WHO) Classifications:

- RAEB-1 (defined as having 5-9% myeloblasts in the bone marrow)

- RAEB-2 (defined as having 10-19% myeloblasts in the bone marrow and/or
5-19% blasts in the blood)

- CMML-1 (defined as having < 5% myeloblasts in the bone marrow and/or < 10%
blasts in the blood)

- CMML-2 (defined as having 10-19% myeloblasts in the bone marrow and/or
5-19% blasts in the blood)

- International prognostic score (IPSS) of Intermediate 2 (1.5-2.0 points) or High
(>= 2.5 points); a score of Intermediate 1 (0.5-1.0 points) is only allowable in
the setting of >= 5% myeloblasts

- Patients with acute myeloid leukemia (AML) are not eligible

- Procedures to obtain specimens for establishing baseline disease must be done
within 30 days prior to registration

- Patients must not have received lenalidomide, azacitidine, vorinostat, or decitabine
as treatment previously; any hematopoietic growth factors must be stopped for at
least 14 days prior to registration

- Patients may have received low-dose cytarabine for MDS treatment previously, but
they must have discontinued its use for at least 28 days prior to registration

- Patients must not have received radiation therapy, chemotherapy, or cytotoxic therapy
to treat conditions other than MDS within 12 months prior to registration

- Patients must not have undergone prior allogeneic stem cell or bone marrow
transplantation at any time; patients that have undergone an autologous stem cell
transplant are eligible

- Patients must not have used or be using histone deacetylase (HDAC) inhibitor agents
for anticancer treatment

- Patients may not have received agents such as valproic acid for epilepsy within 30
days prior to registration

- Patients must have Zubrod performance status of 0-2

- Patients must not have any pre-existing neurotoxicity/neuropathy of >= grade 2
according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC)
Version 4.0, or prior >= grade 3 allergic reaction/hypersensitivity or rash to
thalidomide that has not resolved to < grade 2

- Patients must not have any serious medical condition, laboratory abnormality, or
psychiatric illness that, in the view of the treating physician, would place the
participant at an unacceptable risk if he or she were to participate in the study or
would prevent that person from giving informed consent

- Patients must not have history of thromboembolic event or other condition requiring
current use of anticoagulation with Coumadin (warfarin) or low molecular-weight
heparin

- Patients must not have known or suspected hypersensitivity to mannitol

- Patients must receive a 12-lead electrocardiogram (EKG), chest x-ray, serum
creatinine, complete metabolic panel including serum glutamic oxaloacetic
transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT), electrolytes, and
bilirubin testing within 28 days prior to registration in order to establish baseline
measurements; questions regarding patient safety in regards to results of these tests
should be directed to the Study Coordinator

- Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to
registration; FCBP must agree to have a second pregnancy test within 24 hours prior
to starting course 1 if randomized to receive lenalidomide

- A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least
24 consecutive months (i.e., has had menses at any time in the preceding 24
consecutive months)

- Patients must commit to the following if they are randomized to receive lenalidomide;
FCBP must either commit to continued abstinence from heterosexual intercourse or
begin TWO acceptable methods of birth control: one highly effective method and one
additional effective method AT THE SAME TIME, at least 28 days before starting
lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to
use a latex condom during sexual contact with a FCBP, even if they have had a
successful vasectomy

- All patients must be counseled by a trained counselor every 28 days about
pregnancy precautions and risks of fetal exposure

- Patients not randomized to receive lenalidomide will not be required to undergo
serial pregnancy testing or lenalidomide counseling after registration

- No prior malignancy is allowed except for adequately treated basal cell (or squamous
cell) skin cancer, in situ cervical cancer, or other cancer for which the patient has
been disease-free for three years

- Cytogenetics requirements:

- Southwestern Oncology Group (SWOG) (and other sites not affiliated with Cancer
and Leukemia Group B [CALGB] or Eastern Cooperative Oncology Group [ECOG]):
Pretreatment cytogenetics must be performed on all patients; collection of
pretreatment specimens must be completed within 14 days prior to registration to
SWOG-S1117

- CALGB: CALGB patients must enroll on CALGB 8461, the cytogenetics protocol

- ECOG: Pretreatment cytogenetics must be performed on all patients; collection of
pretreatment specimens must be completed within 30 days prior to registration to
S1117

- Banking requirements:

- SWOG and ECOG (and other sites not affiliated with CALGB): Patients must be
offered participation in specimen banking

- CALGB: CALGB patients must be offered participation in CALGB 9665, the CALGB
Leukemia Tissue bank protocol

- National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG): NCIC CTG
patients must be offered participation in specimen submission and banking

- All patients must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and federal
guidelines

- As a part of the OPEN registration process the treating institution's identity is
provided in order to ensure that the current (within 365 days) date of institutional
review board approval for this study has been entered in the system

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response rate (RR) (any of complete hematological remission [CR], partial response [PR], or hematologic improvement [HI])

Outcome Description:

The final analysis will consist of two one-sided tests of whether the RR is improved in either of the combination arms compared to the single-agent azacitidine arm. Each test will be performed at the 0.05 level.

Outcome Time Frame:

Up to 5 years

Safety Issue:

No

Principal Investigator

Mikkael Sekeres

Investigator Role:

Principal Investigator

Investigator Affiliation:

Southwest Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-00242

NCT ID:

NCT01522976

Start Date:

March 2012

Completion Date:

Related Keywords:

  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Previously Treated Myelodysplastic Syndromes
  • Refractory Anemia With Excess Blasts
  • Secondary Myelodysplastic Syndromes
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Leukemia
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute

Name

Location

Albert Einstein College of MedicineBronx, New York  10461
Louisiana State UniversityNew Orleans, Louisiana  70112-2282
Johns Hopkins UniversityBaltimore, Maryland  21205
Cleveland Clinic FoundationCleveland, Ohio  44195
Roswell Park Cancer InstituteBuffalo, New York  14263
Mayo ClinicRochester, Minnesota  55905
University of Iowa Hospitals and ClinicsIowa City, Iowa  52242
University of Mississippi Medical CenterJackson, Mississippi  39216-4505
Boulder Community HospitalBoulder, Colorado  80301-9019
Porter Adventist HospitalDenver, Colorado  80210
Rose Medical CenterDenver, Colorado  80220
Swedish Medical CenterEnglewood, Colorado  80110
Sky Ridge Medical CenterLone Tree, Colorado  80124
West Michigan Cancer CenterKalamazoo, Michigan  49007-3731
Fairview Ridges HospitalBurnsville, Minnesota  55337
Hutchinson Area Health CareHutchinson, Minnesota  55350
United HospitalSt. Paul, Minnesota  55102
Ridgeview Medical CenterWaconia, Minnesota  55387
Loyola University Medical CenterMaywood, Illinois  60153
Massachusetts General Hospital Cancer CenterBoston, Massachusetts  02114
CentraCare ClinicSaint Cloud, Minnesota  56303
Rapid City Regional HospitalRapid City, South Dakota  57709
Marshfield ClinicMarshfield, Wisconsin  54449
Lehigh Valley HospitalAllentown, Pennsylvania  18103
Reading Hospital and Medical CenterReading, Pennsylvania  19612-6052
Waukesha Memorial HospitalWaukesha, Wisconsin  53188
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
North Shore University HospitalManhasset, New York  11030
Eastern Maine Medical CenterBangor, Maine  04401
Baystate Medical CenterSpringfield, Massachusetts  01199
Kaiser Permanente Medical Center - Santa ClaraSanta Clara, California  95051-5386
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Weill Medical College of Cornell UniversityNew York, New York  10021
Thompson Cancer Survival CenterKnoxville, Tennessee  37916
Montefiore Medical CenterBronx, New York  10467-2490
Parma Community General HospitalParma, Ohio  44129
North Colorado Medical CenterGreeley, Colorado  80631
McKee Medical CenterLoveland, Colorado  80539
Munson Medical CenterTraverse City, Michigan  49684
Bozeman Deaconess HospitalBozeman, Montana  59715
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
City of Hope Medical CenterDuarte, California  91010
Mercy Health SystemJanesville, Wisconsin  53545
Front Range Cancer SpecialistsFort Collins, Colorado  80528
Poudre Valley HospitalFort Collins, Colorado  80524
Beebe Medical CenterLewes, Delaware  19958
Hematology and Oncology AssociatesChicago, Illinois  60611
Galesburg ClinicGalesburg, Illinois  61401
Iredell Memorial HospitalStatesville, North Carolina  28677
Providence Milwaukie HospitalMilwaukie, Oregon  97222
Exempla Lutheran Medical CenterWheat Ridge, Colorado  80033
Mercy HospitalCoon Rapids, Minnesota  55433
Trinity Medical CenterMoline, Illinois  61265-1291
Saint Joseph Mercy HospitalAnn Arbor, Michigan  48106
Fairview-Southdale HospitalEdina, Minnesota  55435
Abbott-Northwestern HospitalMinneapolis, Minnesota  55407
Regions HospitalSaint Paul, Minnesota  55101
Saint Francis Regional Medical CenterShakopee, Minnesota  55379
Rice Memorial HospitalWillmar, Minnesota  56201
Swedish American HospitalRockford, Illinois  61104
Randolph HospitalAsheboro, North Carolina  27203
Miami Valley HospitalDayton, Ohio  45409
Spartanburg Regional Medical CenterSpartanburg, South Carolina  29303
Marshfield Clinic Cancer Care at Regional Cancer CenterEau Claire, Wisconsin  54701
Marshfield Clinic - Weston CenterWeston, Wisconsin  54476
Marshfield Clinic - Wisconsin Rapids CenterWisconsin Rapids, Wisconsin  54494
Longmont United HospitalLongmont, Colorado  80501
Union Hospital of Cecil CountyElkton MD, Maryland  21921
Cancer Centers of the Carolinas - Grove CommonsGreenville, South Carolina  29605
Cancer Centers of the Carolinas - SenecaSeneca, South Carolina  29672
Cancer Centers of the Carolinas - SpartanburgSpartanburg, South Carolina  29307
Mayo Clinic in ArizonaScottsdale, Arizona  85259-5404
Memorial Medical CenterSpringfield, Illinois  62781
Doylestown HospitalDoylestown, Pennsylvania  18901
Northwestern UniversityChicago, Illinois  60611
Hennepin County Medical CenterMinneapolis, Minnesota  
University of RochesterRochester, New York  14642
Case Western Reserve UniversityCleveland, Ohio  44106
Wayne State UniversityDetroit, Michigan  48202
University of Arizona Health Sciences CenterTucson, Arizona  85724
University of Massachusetts Medical SchoolWorcester, Massachusetts  01605
Providence Portland Medical CenterPortland, Oregon  97213-3635
Mid Dakota ClinicBismarck, North Dakota  58501
Presbyterian - Saint Lukes Medical Center - Health OneDenver, Colorado  80218
University of KentuckyLexington, Kentucky  40536-0098
Huntsman Cancer Institute/University of UtahSalt Lake City, Utah  84112
Metro-Minnesota CCOPSt. Louis Park, Minnesota  
Lakeview HospitalStillwater, Minnesota  55082
Decatur Memorial HospitalDecatur, Illinois  62526
Florida HospitalOrlando, Florida  32803
Hillcrest Hospital Cancer CenterMayfield Heights, Ohio  44124
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
University of Southern CaliforniaLos Angeles, California  90033
Providence Newberg Medical CenterNewberg, Oregon  97132
Parker Adventist HospitalParker, Colorado  80138
Froedtert and the Medical College of WisconsinMilwaukee, Wisconsin  53226
Kaiser Permanente-OaklandOakland, California  94611
Kaiser Permanente-RichmondRichmond, California  94801
Kaiser Permanente-South SacramentoSacramento, California  95823
Kaiser Permanente - SacramentoSacramento, California  95825
Kaiser Permanente-San FranciscoSan Francisco, California  94115
Kaiser Permanente-Santa Teresa-San JoseSan Jose, California  95119
Kaiser Permanente-San RafaelSan Rafael, California  94903
Kaiser Permanente-South San FranciscoSouth San Francisco, California  94080
Kaiser Permanente-Walnut CreekWalnut Creek, California  94596
The Medical Center of AuroraAurora, Colorado  80012
Penrose-Saint Francis HealthcareColorado Springs, Colorado  80907
Saint Anthony Central HospitalDenver, Colorado  80204
Exempla Saint Joseph HospitalDenver, Colorado  80218
Colorado Cancer Research Program CCOPDenver, Colorado  80224-2522
Saint Mary Corwin Medical CenterPueblo, Colorado  81004
Saint Francis Hospital and Medical CenterHartford, Connecticut  06105
The Hospital of Central ConnecticutNew Britain, Connecticut  06050
Oncare Hawaii Inc-POB IIHonolulu, Hawaii  96813
Oncare Hawaii Inc-KuakiniHonolulu, Hawaii  96817
University of HawaiiHonolulu, Hawaii  96813
Evanston CCOP-NorthShore University HealthSystemEvanston, Illinois  60201
Illinois CancerCare-Ottawa ClinicOttawa, Illinois  61350
Illinois Oncology Research Association CCOPPeoria, Illinois  61615
Illinois CancerCare-PeoriaPeoria, Illinois  61615
Premier Oncology Hematology AssociatesMerrillville, Indiana  46410
McFarland ClinicAmes, Iowa  50010
Covenant Medical CenterWaterloo, Iowa  50702
Stormont-Vail Regional Health CenterTopeka, Kansas  66604
Green Bay Oncology - EscanabaEscanaba, Michigan  49431
Grand Rapids Clinical Oncology ProgramGrand Rapids, Michigan  49503
Green Bay Oncology - Iron MountainIron Mountain, Michigan  49801
Unity HospitalFridley, Minnesota  55432
Saint John's Hospital - HealtheastMaplewood, Minnesota  55109
Minnesota Oncology Hematology PA-MaplewoodMaplewood, Minnesota  55109
North Memorial Medical Health CenterRobbinsdale, Minnesota  55422
Park Nicollet Clinic - Saint Louis ParkSaint Louis Park, Minnesota  55416
Minnesota Oncology and Hematology PA-WoodburyWoodbury, Minnesota  55125
Saint Luke's Hospital of Kansas CityKansas City, Missouri  64111
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
Billings ClinicBillings, Montana  59107-7000
Cooper Hospital University Medical CenterCamden, New Jersey  08103
Presbyterian Kaseman HospitalAlbuquerque, New Mexico  87110
Wayne Memorial HospitalGoldsboro, North Carolina  27534
Margaret R Pardee Memorial HospitalHendersonville, North Carolina  28791
Kinston Medical Specialists PAKinston, North Carolina  28501
Cleveland Clinic Cancer Center IndependenceIndependence, Ohio  44131
North Coast Cancer CareSandusky, Ohio  44870
University of ToledoToledo, Ohio  43614
Cleveland Clinic Wooster Specialty CenterWooster, Ohio  44691
Legacy Good Samaritan Hospital and Medical CenterPortland, Oregon  97210
Providence Saint Vincent Medical CenterPortland, Oregon  97225
Greenville CCOPGreenville, South Carolina  29615
Greenville Memorial HospitalGreenville, South Carolina  29605
Upstate Carolina CCOPSpartanburg, South Carolina  29303
Sanford Cancer Center-Oncology ClinicSioux Falls, South Dakota  57104
The Don and Sybil Harrington Cancer CenterAmarillo, Texas  79106
Saint Vincent HospitalGreen Bay, Wisconsin  54301
Green Bay Oncology Limited at Saint Mary's HospitalGreen Bay, Wisconsin  54303
Saint Mary's HospitalGreen Bay, Wisconsin  54303
Green Bay Oncology at Saint Vincent HospitalGreen Bay, Wisconsin  54301-3526
Aurora BayCare Medical CenterGreen Bay, Wisconsin  54311-6519
Dean Hematology and Oncology ClinicMadison, Wisconsin  53717
Vince Lombardi Cancer Clinic-MarinetteMarinette, Wisconsin  54143
Oconomowoc Memorial Hospital-ProHealth Care IncOconomowoc, Wisconsin  53066-3896
Green Bay Oncology - Oconto FallsOconto Falls, Wisconsin  54154
Marshfield Clinic at James Beck Cancer CenterRhinelander, Wisconsin  54501
Marshfield Clinic-Rice Lake CenterRice Lake, Wisconsin  54868
Saint Michael's HospitalStevens Point, Wisconsin  54481
Green Bay Oncology - Sturgeon BaySturgeon Bay, Wisconsin  54235
Jupiter Medical CenterJupiter, Florida  33458
University of IllinoisChicago, Illinois  60612
Roger Maris Cancer CenterFargo, North Dakota  58122
Mount Sinai Medical Center CCOPMiami Beach, Florida  33140
Illinois CancerCare-BloomingtonBloomington%, Illinois  61701
Illinois CancerCare-CantonCanton, Illinois  61520
Illinois CancerCare-CarthageCarthage, Illinois  62321
Illinois CancerCare-EurekaEureka, Illinois  61530
Illinois CancerCare-HavanaHavana, Illinois  62644
Illinois CancerCare-Kewanee ClinicKewanee, Illinois  61443
Illinois CancerCare-MacombMacomb, Illinois  61455
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
University of Missouri - Ellis FischelColumbia, Missouri  65203
Moses Cone Health System-Regional Cancer CenterGreensboro, North Carolina  27403
Annie Penn Memorial HospitalReidsville, North Carolina  27320
Cancer Centers of the Carolinas - FarisGreenville, South Carolina  29605
Cancer Centers of the Carolinas-Greer Medical OncologyGreer, South Carolina  29650
Marshfield Clinic Cancer Care at Saint Michael's HospitalStevens Point, Wisconsin  54481
Aurora Medical Center in SummitSummit, Wisconsin  53066
Monter Cancer CenterLake Success, New York  11042
FirstHealth of the Carolinas-Moore Regional HosiptalPinehurst, North Carolina  28374
Arizona Cancer Center at University Medical Center NorthTucson, Arizona  85719
Kaiser Permanente-Deer Valley Medical CenterAntioch, California  94531
Kaiser Permanente Moanalua Medical CenterHonolulu, Hawaii  96819
Kansas City CCOPPrairie Village, Kansas  66208
Cleveland Clinic Cancer Center BeachwoodBeachwood, Ohio  44122
Cancer Care Associates-MercyOklahoma City, Oklahoma  73120
Saint Francis HospitalGreenville, South Carolina  29601
Gundersen LutheranLa Crosse, Wisconsin  54601
Siouxland Hematology Oncology AssociatesSioux City, Iowa  51101
Georgia Health Sciences UniversityAugusta, Georgia  30912
Sanford Clinic North-FargoFargo, North Dakota  58102
Sanford Medical Center-FargoFargo, North Dakota  58122
Sanford USD Medical Center - Sioux FallsSioux Falls, South Dakota  57117-5134
Sanford Clinic North-BemidgiBemidji, Minnesota  56601
Sanford Bismarck Medical CenterBismarck, North Dakota  58501
Aurora Cancer Care-Milwaukee WestWauwatosa, Wisconsin  53226
Christiana Care Health System-Christiana HospitalNewark, Delaware  19718
Cleveland Clinic Cancer Center/Fairview HospitalCleveland, Ohio  44111
PeaceHealth Southwest Medical CenterVancouver, Washington  98664
Cleveland Clinic Cancer Center-StrongsvilleStrongsville, Ohio  44136
Cancer Care Associates-NormanNorman, Oklahoma  73071
Providence Willamette Falls Medical CenterOregon City, Oregon  97045