Azacitidine With or Without Lenalidomide or Vorinostat in Treating Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia

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.

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