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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
Open (Enrolling)
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)


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

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

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

- 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

- 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

- 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

- 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

- 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:


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:


Principal Investigator

Mikkael Sekeres

Investigator Role:

Principal Investigator

Investigator Affiliation:

Southwest Oncology Group


United States: Food and Drug Administration

Study ID:




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



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