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Azacitidine With or Without E...

Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

Last Updated: 2017-02-02

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

197 participants

Study Classification

INTERVENTIONAL

Study Start Date

2006-08-31

Study Completion Date

2013-07-31

Brief Summary

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This randomized phase II trial studies azacitidine with or without entinostat to see how well they work compared to azacitidine alone in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may work better in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.

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Detailed Description

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PRIMARY OBJECTIVES:

I. To estimate the overall response rate (complete, partial, and hematologic improvement-major by International Working Group \[IWG\] criteria) in response to azacitidine and entinostat.

II. To estimate the major response rate (complete and partial responses by the IWG response criteria) to a 10-day regimen of azacitidine and to the same regimen of azacitidine in combination with entinostat administered orally on days 3 and 10 of each cycle in patients with de novo myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMMoL) (dysplastic) and acute myeloid leukemia with trilineage dysplasia (AML-TLD), as well as in patients with treatment-induced MDS, CMMoL (dysplastic) and AML-TLD.

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of azacitidine and entinostat in this patient population.

II. To identify changes in gene promoter methylation and gene expression which may be associated with response to azacitidine and entinostat.

III. To identify other molecular mechanisms (such as deoxyribonucleic acid \[DNA\] damage) which may be associated with response to azacitidine and entinostat.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive azacitidine subcutaneously (SC) once daily (QD) on days 1-10.

ARM B: Patients receive azacitidine as in Arm A and entinostat orally (PO) on days 3 and 10.

In both arms, treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 5 years.

Conditions

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Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Adult Acute Myeloid Leukemia in Remission Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1 Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA Alkylating Agent-Related Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndrome Previously Treated Myelodysplastic Syndrome Recurrent Adult Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Secondary Myelodysplastic Syndrome Untreated Adult Acute Myeloid Leukemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm A (azacitidine)

Patients receive azacitidine SC QD on days 1-10. Treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Given SC

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Arm B (azacitidine, entinostat)

Patients receive azacitidine as in Arm A and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Given SC

Entinostat

Intervention Type DRUG

Given PO

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Interventions

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Azacitidine

Given SC

Intervention Type DRUG

Entinostat

Given PO

Intervention Type DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type OTHER

Other Intervention Names

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5 AZC 5-AC 5-Azacytidine 5-AZC Azacytidine Azacytidine, 5- Ladakamycin Mylosar U-18496 Vidaza HDAC inhibitor SNDX-275 MS 27-275 MS-275 SNDX-275

Eligibility Criteria

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Inclusion Criteria

* The following diagnoses will be eligible for this study:
* Myelodysplastic syndromes: the diagnosis of MDS must be confirmed by a bone marrow aspirate and/or biopsy within two weeks prior to registration; NOTE: blast count must be \< 20%; patients with any International Prognostic Score (IPSS) are eligible; patients with low or intermediate (INT)-1 IPSS must have a platelet count \< 50,000/mm\^3 and/or absolute neutrophil count (ANC) \< 500/mm\^3 within seven days prior to registration
* Chronic myelomonocytic leukemia (dysplastic subtype): the diagnosis of CMMoL must be confirmed by a bone marrow aspirate and/or biopsy within two weeks prior to registration; patients with CMMoL must have a WBC \< 12,000/mm\^3, documented within 4 weeks prior to study entry (two sets of counts that are 2 weeks apart will be taken)
* Acute myeloid leukemia with multilineage dysplasia: the diagnosis of AML-TLD must be confirmed by a bone marrow aspirate and/or biopsy within two weeks prior to registration; NOTE: there must be evidence of \>= 20% blasts on the review of the bone marrow aspirate and/or biopsy; AML-TLD will be interpreted to include patients formerly diagnosed by French-American-British (FAB) criteria as refractory anemia with excess blasts in transformation (RAEB-t), as well as patients with no history of antecedent hematologic disorder who have AML which meets criteria for AML-TLD by World Health Organization (WHO) criteria; patients with AML-TLD must have a white blood cell (WBC) =\< 30,000/mm\^3 documented within 4 weeks prior to study entry (two sets of counts that are 2 weeks apart will be taken); patients whose WBC has doubled within this period of time and is greater than 20,000/mm\^3 at the time of screening will not be eligible
* Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within two weeks prior to registration to rule out pregnancy
* Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception
* Patient must have Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
* Patient must have no prior treatment with azacitidine, decitabine or entinostat
* Patients must not have active infections at the time of registration
* Serum creatinine \< 2.0 mg/dL; test must be done within seven days prior to registration
* Total serum bilirubin within institutional limits unless due to intra- or extramedullary hemolysis or Gilbert's syndrome; test must be done within seven days prior to registration
* Aspartate transaminase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine transaminase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal (ULN); tests must be done within seven days prior to registration
* Patients must not have received any AML induction chemotherapy or stem cell transplantation; any other treatment for their disease, including hematopoietic growth factors may not be given, within three weeks prior to registration, and should have recovered from all toxicities of prior therapy (to grade 0 or 1)
* Patients must have no clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia
* Patients must have no serious or uncontrolled medical conditions
* Patients who have therapy-induced MDS, CMMoL (dysplastic) and AML-TLD are eligible and will be treated as separate cohorts from the patients with de novo MDS, CMMoL (dysplastic) and AML-TLD
* Patients should have a life expectancy of at least six months
* Patients must not have advanced malignant hepatic tumors
* Patients must not have a known hypersensitivity to azacitidine or mannitol
* Southwest Oncology Group (SWOG) ONLY: all SWOG patients must be registered on SWOG-9007 ("Cytogenetic Studies in Leukemia Patients"); collection of the pretreatment bone marrow specimen (or of peripheral blood if the marrow is not aspirable) must be completed within 28 days before registration; the pretreatment specimen must be submitted to a SWOG-approved cytogenetics laboratory as described in protocol SWOG-9007; note that submission of bone marrow cytogenetic studies are required to calculate the IPSS score (stratification issue); in addition, cytogenetic response will be measured at follow-up requiring a second cytogenetic study at the end of protocol treatment; NOTE: In addition to SWOG-9007, SWOG patients must be offered participation in S9910, the leukemia centralized reference laboratories and tissue repositories ancillary study; If consent is given, collection of pretreatment blood and/or marrow specimens must be completed within 14 days prior to registration. If the patient consents to participate in S9910, pretreatment specimens of marrow and/or peripheral blood must be submitted to the Southwest Oncology Group Myeloid Repository at the University of New Mexico for cellular and molecular studies; S9910 also requests submission of remission and relapse specimens

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Steven Gore

Role: PRINCIPAL_INVESTIGATOR

ECOG-ACRIN Cancer Research Group

Locations

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Mayo Clinic in Arizona

Scottsdale, Arizona, United States

Site Status

Providence Saint Joseph Medical Center/Disney Family Cancer Center

Burbank, California, United States

Site Status

Los Angeles Oncology Institute

Los Angeles, California, United States

Site Status

Stanford Cancer Institute

Palo Alto, California, United States

Site Status

Sutter Roseville Medical Center

Roseville, California, United States

Site Status

Sutter General Hospital

Sacramento, California, United States

Site Status

The Medical Center of Aurora

Aurora, Colorado, United States

Site Status

Boulder Community Hospital

Boulder, Colorado, United States

Site Status

Penrose-Saint Francis Healthcare

Colorado Springs, Colorado, United States

Site Status

Porter Adventist Hospital

Denver, Colorado, United States

Site Status

Presbyterian - Saint Lukes Medical Center - Health One

Denver, Colorado, United States

Site Status

SCL Health Saint Joseph Hospital

Denver, Colorado, United States

Site Status

Rose Medical Center

Denver, Colorado, United States

Site Status

Colorado Cancer Research Program NCORP

Denver, Colorado, United States

Site Status

Swedish Medical Center

Englewood, Colorado, United States

Site Status

Poudre Valley Hospital

Fort Collins, Colorado, United States

Site Status

Front Range Cancer Specialists

Fort Collins, Colorado, United States

Site Status

Saint Mary's Hospital and Regional Medical Center

Grand Junction, Colorado, United States

Site Status

North Colorado Medical Center

Greeley, Colorado, United States

Site Status

Saint Anthony Hospital

Lakewood, Colorado, United States

Site Status

Sky Ridge Medical Center

Lone Tree, Colorado, United States

Site Status

Longmont United Hospital

Longmont, Colorado, United States

Site Status

McKee Medical Center

Loveland, Colorado, United States

Site Status

Saint Mary Corwin Medical Center

Pueblo, Colorado, United States

Site Status

North Suburban Medical Center

Thornton, Colorado, United States

Site Status

SCL Health Lutheran Medical Center

Wheat Ridge, Colorado, United States

Site Status

Beebe Medical Center

Lewes, Delaware, United States

Site Status

Christiana Care Health System-Christiana Hospital

Newark, Delaware, United States

Site Status

Sibley Memorial Hospital

Washington D.C., District of Columbia, United States

Site Status

Emory University/Winship Cancer Institute

Atlanta, Georgia, United States

Site Status

Rush - Copley Medical Center

Aurora, Illinois, United States

Site Status

MacNeal Hospital and Cancer Center

Berwyn, Illinois, United States

Site Status

Saint Joseph Medical Center

Bloomington, Illinois, United States

Site Status

Illinois CancerCare-Bloomington

Bloomington, Illinois, United States

Site Status

Graham Hospital Association

Canton, Illinois, United States

Site Status

Illinois CancerCare-Canton

Canton, Illinois, United States

Site Status

Illinois CancerCare-Carthage

Carthage, Illinois, United States

Site Status