Azacitidine With or Without Lenalidomide or Vorinostat in Treating Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia
Condition: Chronic Myelomonocytic Leukemia; Chronic Myelomonocytic Leukemia-1; Chronic Myelomonocytic Leukemia-2; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Myelodysplastic Syndrome With Excess Blasts-1; Myelodysplastic Syndrome/Acute Myeloid Leukemia
MeSH terms: Leukemia; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Anemia, Refractory, with Excess of Blasts; Syndrome
Intervention: Azacitidine; Laboratory Biomarker Analysis; Lenalidomide; Vorinostat
Intervention description: Given SC or IV; Correlative studies; Given PO; Given PO
Intervention MeSH terms: Lenalidomide; Azacitidine; Vorinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 282.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

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