Myelodysplastic Syndrome Clinical Trial
Azacitidine With or Without Lenalidomide or Vorinostat in Treating Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia
Summary
This randomized phase II/III trial studies how well azacitidine works with or without lenalidomide or vorinostat in treating patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, stopping them from dividing, or by stopping them from spreading. Lenalidomide may stop the growth of cancer cells by stopping blood flow to the cancer. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether azacitidine is more effective with or without lenalidomide or vorinostat in treating myelodysplastic syndromes or chronic myelomonocytic leukemia.
Full Description
PRIMARY OBJECTIVES:
I. To select based on response rate (complete remission, partial remission, or hematologic improvement) either the combination of lenalidomide and azacitidine or the combination of vorinostat and azacitidine for further testing against single-agent azacitidine among patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). (Phase II) II. To compare overall survival between the combination arm selected in the Phase II portion of the trial to single-agent azacitidine among patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). (Phase III)
SECONDARY OBJECTIVES:
I. To estimate relapse-free survival, overall survival and cytogenetic response rate of patients treated on each regimen.
II. To estimate the frequency and severity of toxicities of the three regimens in this patient population.
III. To investigate in a preliminary manner the frequency of subgroups from prestudy cytogenetic studies and correlate these subgroups with clinical outcomes in this patient population.
IV. To collect specimens for banking for use in future research studies.
TERTIARY OBJECTIVES:
I. To evaluate the prevalence of a pre-specified list of molecular lesions (48 total lesions).
II. To assess associations of these lesions with outcomes (response, event-free survival, relapse-free survival, and overall survival).
III. To develop a deoxyribonucleic acid (DNA) methylation biomarker predictive of response to DMTi treatment in MDS.
IV. To harness gene expression profiles as clinical biomarkers of primary resistance to DMTi in MDS.
OUTLINE: Patients are randomized to 1 of 3 treatment arms. In Phase III, patients are randomized to 1 of 2 treatment arms (the combination arm selected in Phase II or the single-agent azacitidine arm).
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, treatment repeats 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.
Eligibility Criteria
Inclusion Criteria:
Patients must have morphologically confirmed diagnosis of myelodysplastic syndrome (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)
Chronic myelomonocytic leukemia (CMML) with 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood
World Health Organization (WHO) classifications:
Refractory anemia with excess blasts-1 (RAEB-1 - defined as having 5-9% myeloblasts in the bone marrow)
Refractory anemia with excess blasts-2 (RAEB-2 - defined as having 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood)
Chronic myelomonocytic leukemia-1 (CMML-1 - defined as having < 10% myeloblasts in the bone marrow and/or < 5% blasts in the blood)
Chronic myelomonocytic leukemia-2 (CMML-2 - defined as having 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood) OR
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
NOTE: 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 may have received prior hydroxyurea per CMML treatment previously, but they must have discontinued its use for at least 7 days prior to registration; these patients will not be eligible if white blood cell (WBC) > 30,000/mm^3
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 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 or computed tomography (CT) scan, serum creatinine, complete metabolic panel including serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate 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 chair
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 cycle 1 if randomized to receive lenalidomide
Further, patients 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; 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); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure
NOTE: 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 Alliance or Eastern Cooperative Oncology Group [ECOG]-American College of Radiology Imaging Network [ACRIN]): Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 30 days prior to registration to S1117; specimens must be submitted to the site's preferred Clinical Laboratory Improvement Amendments (CLIA)-approved cytogenetics laboratory; reports of the results must be submitted as described; note that cytogenetics are required at other timepoints; NOTE: National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) sites may submit specimens to College of American Pathologists (CAP) or Ontario Laboratory Accreditation (OLA)-approved laboratories providing the lab is licensed to perform fluorescent in situ hybridization (FISH) analysis
Alliance: Alliance patients must enroll on Cancer and Leukemia Group B (CALGB) 8461, the cytogenetics protocol; CALGB 8461 provides sample procurement and submission instructions to Alliance-approved institutional cytogeneticists; note that cytogenetics are required at other timepoints
ECOG-ACRIN: Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 30 days prior to registration to S1117; specimens must be submitted to the site's preferred CLIA-approved cytogenetics laboratory; karyotypes and reports must be submitted for review to the Mayo Clinic Cytogenetics Laboratory in Rochester; note that cytogenetics testing is required at other timepoints
Banking requirements:
SWOG, Alliance and ECOG-ACRIN (and other sites not affiliated with NCIC CTG): Patients must be offered participation in specimen banking; with patient consent, specimens must be submitted as outlined
Alliance: (Temporarily Closed 2/28/14): As of February 28, 2014, CALGB 9665 has been temporarily closed, so Alliance patients under consideration for S1117 are NOT to be registered to CALGB 9665 and no specimens for patients enrolled after February 28, 2014 are to be submitted via this ancillary study; these patients should submit specimens per SWOG instructions; patients already enrolled on CALGB 9665 should continue to submit specimens per instructions in CALGB 9665
NCIC CTG: NCIC CTG patients must be offered participation in specimen submission and banking; with patient consent, specimens must be submitted as outlined
All patients or their legally authorized representative 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 Oncology Patient Enrollment Network (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
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There are 266 Locations for this study
Birmingham Alabama, 35233, United States
Mobile Alabama, 36688, United States
Scottsdale Arizona, 85259, United States
Tucson Arizona, 85719, United States
Tucson Arizona, 85719, United States
Little Rock Arkansas, 72205, United States
Antioch California, 94531, United States
Duarte California, 91010, United States
Los Angeles California, 90033, United States
Oakland California, 94611, United States
Palo Alto California, 94304, United States
Richmond California, 94801, United States
Sacramento California, 95823, United States
Sacramento California, 95825, United States
San Francisco California, 94115, United States
San Jose California, 95119, United States
San Rafael California, 94903, United States
Santa Clara California, 95051, United States
Santa Rosa California, 95403, United States
Santa Rosa California, 95403, United States
South San Francisco California, 94080, United States
Vallejo California, 94589, United States
Walnut Creek California, 94596, United States
Aurora Colorado, 80012, United States
Aurora Colorado, 80045, United States
Boulder Colorado, 80301, United States
Colorado Springs Colorado, 80907, United States
Denver Colorado, 80210, United States
Denver Colorado, 80218, United States
Denver Colorado, 80218, United States
Denver Colorado, 80218, United States
Denver Colorado, 80218, United States
Denver Colorado, 80220, United States
Denver Colorado, 80220, United States
Denver Colorado, 80222, United States
Durango Colorado, 81301, United States
Englewood Colorado, 80113, United States
Englewood Colorado, 80113, United States
Fort Collins Colorado, 80524, United States
Golden Colorado, 80401, United States
Greeley Colorado, 80631, United States
Greenwood Village Colorado, 80111, United States
Lakewood Colorado, 80228, United States
Lakewood Colorado, 80228, United States
Littleton Colorado, 80122, United States
Lone Tree Colorado, 80124, United States
Lone Tree Colorado, 80124, United States
Longmont Colorado, 80501, United States
Loveland Colorado, 80539, United States
Parker Colorado, 80138, United States
Parker Colorado, 80138, United States
Pueblo Colorado, 81004, United States
Wheat Ridge Colorado, 80033, United States
Farmington Connecticut, 06030, United States
Hartford Connecticut, 06105, United States
New Britain Connecticut, 06050, United States
Lewes Delaware, 19958, United States
Newark Delaware, 19718, United States
Washington District of Columbia, 20016, United States
Washington District of Columbia, 20422, United States
Gainesville Florida, 32610, United States
Jupiter Florida, 33458, United States
Miami Beach Florida, 33140, United States
Orlando Florida, 32803, United States
Augusta Georgia, 30912, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96817, United States
Honolulu Hawaii, 96819, United States
Boise Idaho, 83706, United States
Post Falls Idaho, 83854, United States
Bloomington Illinois, 61704, United States
Canton Illinois, 61520, United States
Carthage Illinois, 62321, United States
Chicago Illinois, 60611, United States
Chicago Illinois, 60611, United States
Chicago Illinois, 60612, United States
Chicago Illinois, 60637, United States
Decatur Illinois, 62526, United States
Decatur Illinois, 62526, United States
Eureka Illinois, 61530, United States
Evanston Illinois, 60201, United States
Galesburg Illinois, 61401, United States
Havana Illinois, 62644, United States
Kewanee Illinois, 61443, United States
Macomb Illinois, 61455, United States
Maywood Illinois, 60153, United States
Moline Illinois, 61265, United States
Monmouth Illinois, 61462, United States
Normal Illinois, 61761, United States
Ottawa Illinois, 61350, United States
Pekin Illinois, 61554, United States
Peoria Illinois, 61615, United States
Peru Illinois, 61354, United States
Princeton Illinois, 61356, United States
Rockford Illinois, 61104, United States
Rockford Illinois, 61114, United States
Springfield Illinois, 62781, United States
Urbana Illinois, 61801, United States
Merrillville Indiana, 46410, United States
Ames Iowa, 50010, United States
Iowa City Iowa, 52242, United States
Sioux City Iowa, 51101, United States
Waterloo Iowa, 50702, United States
Kansas City Kansas, 66160, United States
Prairie Village Kansas, 66208, United States
Topeka Kansas, 66606, United States
Lexington Kentucky, 40536, United States
Baton Rouge Louisiana, 70809, United States
New Orleans Louisiana, 70121, United States
Shreveport Louisiana, 71103, United States
Bangor Maine, 04401, United States
Baltimore Maryland, 21287, United States
Elkton Maryland, 21921, United States
Boston Massachusetts, 02114, United States
Boston Massachusetts, 02215, United States
Brighton Massachusetts, 02135, United States
Springfield Massachusetts, 01199, United States
Worcester Massachusetts, 01655, United States
Ann Arbor Michigan, 48106, United States
Ann Arbor Michigan, 48106, United States
Battle Creek Michigan, 49017, United States
Detroit Michigan, 48201, United States
Detroit Michigan, 48236, United States
Escanaba Michigan, 49829, United States
Grand Rapids Michigan, 49503, United States
Grand Rapids Michigan, 49503, United States
Grand Rapids Michigan, 49503, United States
Iron Mountain Michigan, 49801, United States
Kalamazoo Michigan, 49007, United States
Muskegon Michigan, 49444, United States
Port Huron Michigan, 48060, United States
Reed City Michigan, 49677, United States
Traverse City Michigan, 49684, United States
Warren Michigan, 48093, United States
Bemidji Minnesota, 56601, United States
Burnsville Minnesota, 55337, United States
Coon Rapids Minnesota, 55433, United States
Duluth Minnesota, 55805, United States
Edina Minnesota, 55435, United States
Fridley Minnesota, 55432, United States
Hutchinson Minnesota, 55350, United States
Maplewood Minnesota, 55109, United States
Maplewood Minnesota, 55109, United States
Minneapolis Minnesota, 55407, United States
Minneapolis Minnesota, 55415, United States
Minneapolis Minnesota, 55417, United States
Robbinsdale Minnesota, 55422, United States
Rochester Minnesota, 55905, United States
Saint Cloud Minnesota, 56303, United States
Saint Louis Park Minnesota, 55416, United States
Saint Louis Park Minnesota, 55416, United States
Saint Paul Minnesota, 55101, United States
Saint Paul Minnesota, 55102, United States
Shakopee Minnesota, 55379, United States
Stillwater Minnesota, 55082, United States
Waconia Minnesota, 55387, United States
Willmar Minnesota, 56201, United States
Woodbury Minnesota, 55125, United States
Jackson Mississippi, 39216, United States
Cape Girardeau Missouri, 63703, United States
Columbia Missouri, 65201, United States
Columbia Missouri, 65212, United States
Kansas City Missouri, 64111, United States
Saint Louis Missouri, 63141, United States
Saint Louis Missouri, 63141, United States
Billings Montana, 59101, United States
Bozeman Montana, 59715, United States
Camden New Jersey, 08103, United States
Albuquerque New Mexico, 87102, United States
Albuquerque New Mexico, 87110, United States
Bronx New York, 10461, United States
Bronx New York, 10467, United States
Buffalo New York, 14263, United States
Lake Success New York, 11042, United States
Manhasset New York, 11030, United States
Mineola New York, 11501, United States
New York New York, 10065, United States
Rochester New York, 14642, United States
Asheboro North Carolina, 27203, United States
Goldsboro North Carolina, 27534, United States
Greensboro North Carolina, 27403, United States
Hendersonville North Carolina, 28791, United States
Kinston North Carolina, 28501, United States
Pinehurst North Carolina, 28374, United States
Reidsville North Carolina, 27320, United States
Statesville North Carolina, 28677, United States
Winston-Salem North Carolina, 27104, United States
Bismarck North Dakota, 58501, United States
Bismarck North Dakota, 58501, United States
Fargo North Dakota, 58122, United States
Fargo North Dakota, 58122, United States
Fargo North Dakota, 58122, United States
Beachwood Ohio, 44122, United States
Cincinnati Ohio, 45219, United States
Cleveland Ohio, 44106, United States
Cleveland Ohio, 44111, United States
Cleveland Ohio, 44195, United States
Columbus Ohio, 43214, United States
Columbus Ohio, 43215, United States
Columbus Ohio, 43219, United States
Columbus Ohio, 43222, United States
Dayton Ohio, 45409, United States
Independence Ohio, 44131, United States
Marietta Ohio, 45750, United States
Mayfield Heights Ohio, 44124, United States
Newark Ohio, 43055, United States
Parma Ohio, 44129, United States
Sandusky Ohio, 44870, United States
Springfield Ohio, 45505, United States
Strongsville Ohio, 44136, United States
Sylvania Ohio, 43560, United States
Toledo Ohio, 43614, United States
Westerville Ohio, 43081, United States
Wooster Ohio, 44691, United States
Norman Oklahoma, 73071, United States
Oklahoma City Oklahoma, 73104, United States
Oklahoma City Oklahoma, 73120, United States
Gresham Oregon, 97030, United States
Milwaukie Oregon, 97222, United States
Newberg Oregon, 97132, United States
Oregon City Oregon, 97045, United States
Portland Oregon, 97210, United States
Portland Oregon, 97213, United States
Portland Oregon, 97225, United States
Allentown Pennsylvania, 18103, United States
Carlisle Pennsylvania, 17015, United States
Danville Pennsylvania, 17822, United States
Doylestown Pennsylvania, 18901, United States
Hazleton Pennsylvania, 18201, United States
Hershey Pennsylvania, 17033, United States
Pittsburgh Pennsylvania, 15232, United States
Sayre Pennsylvania, 18840, United States
West Reading Pennsylvania, 19611, United States
Wilkes-Barre Pennsylvania, 18711, United States
Boiling Springs South Carolina, 29316, United States
Charleston South Carolina, 29401, United States
Greenville South Carolina, 29601, United States
Greenville South Carolina, 29605, United States
Greenville South Carolina, 29605, United States
Greenville South Carolina, 29605, United States
Greenville South Carolina, 29615, United States
Seneca South Carolina, 29672, United States
Spartanburg South Carolina, 29303, United States
Rapid City South Dakota, 57701, United States
Sioux Falls South Dakota, 57104, United States
Sioux Falls South Dakota, 57117, United States
Knoxville Tennessee, 37916, United States
Nashville Tennessee, 37232, United States
Amarillo Texas, 79106, United States
Dallas Texas, 75390, United States
Salt Lake City Utah, 84112, United States
Martinsville Virginia, 24115, United States
Vancouver Washington, 98664, United States
Morgantown West Virginia, 26506, United States
Chippewa Falls Wisconsin, 54729, United States
Eau Claire Wisconsin, 54701, United States
Eau Claire Wisconsin, 54701, United States
Green Bay Wisconsin, 54301, United States
Green Bay Wisconsin, 54301, United States
Green Bay Wisconsin, 54303, United States
Green Bay Wisconsin, 54303, United States
Green Bay Wisconsin, 54311, United States
Janesville Wisconsin, 53548, United States
La Crosse Wisconsin, 54601, United States
Madison Wisconsin, 53717, United States
Marinette Wisconsin, 54143, United States
Marinette Wisconsin, 54143, United States
Marshfield Wisconsin, 54449, United States
Marshfield Wisconsin, 54449, United States
Milwaukee Wisconsin, 53226, United States
Minocqua Wisconsin, 54548, United States
Oconomowoc Wisconsin, 53066, United States
Oconto Falls Wisconsin, 54154, United States
Rhinelander Wisconsin, 54501, United States
Rice Lake Wisconsin, 54868, United States
Stevens Point Wisconsin, 54481, United States
Sturgeon Bay Wisconsin, 54235, United States
Summit Wisconsin, 53066, United States
Waukesha Wisconsin, 53188, United States
Wauwatosa Wisconsin, 53226, United States
Weston Wisconsin, 54476, United States
Wisconsin Rapids Wisconsin, 54494, United States
Calgary Alberta, T2N 4, Canada
Vancouver British Columbia, V5Z 3, Canada
Winnipeg Manitoba, R3E 0, Canada
Moncton New Brunswick, E1C 6, Canada
Saint John New Brunswick, E2L 4, Canada
Halifax Nova Scotia, B3H 2, Canada
Hamilton Ontario, L8V 5, Canada
Toronto Ontario, M4N 3, Canada
Toronto Ontario, M5G 2, Canada
Greenfield Park Quebec, J4V 2, Canada
Montreal Quebec, H2W 1, Canada
Montreal Quebec, H3H 2, Canada
Regina Saskatchewan, S4T 7, Canada
Saskatoon Saskatchewan, S7N 4, Canada
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