Decitabine Followed by Idarubicin and Cytarabine in Treating Patients With Relapsed or Refractory AML and MDS

Study Overview
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Brief Summary
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The goals of this study are to learn about the effectiveness, the side-effects, if waiting to give the idarubicin and cytarabine may change the side effects or effectiveness, and to identify factors to predict for responses to this therapy. The trial will examine combination of three chemotherapy drugs. These drugs are decitabine, idarubicin, and cytarabine.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the morphologic complete remission (CR) rates using a decitabine (DAC)-priming followed by idarubicin (IDA) and cytarabine (ARAC) in patients with relapsed or refractory acute myeloid leukemia (AML). SECONDARY OBJECTIVES: I. To determine CR without minimal residual disease (CRMRD-), CR with incomplete blood count recovery (CRi), CR with minimal residual disease (CRMRD+), and CR with incomplete blood count recovery and with minimal residual disease (CRiMRD+) rates. II. To estimate the frequency and severity of regimen-related toxicities. III. To identify biomarkers (e.g., deoxyribonucleic acid [DNA] methylation and expression changes including interferon regulatory factor [IRF]8) associated with clinical responses. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive decitabine intravenously (IV) over 1 hour on days -4 to 0, cytarabine IV continuously over 24 hours on days 1-7, and idarubicin IV over 10-15 minutes on days 1-3. ARM II: Patients receive decitabine IV over 1 hour on days -9 to -5 and cytarabine and idarubicin as in Arm I. In both arms, treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for 5 years.

Official Title
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Phase II Trial Examining Epigenetic Priming With Decitabine Followed by Idarubicin and Cytarabine for Patients With Relapsed or Refractory AML.

Conditions
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Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts

Intervention / Treatment
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* Drug: decitabine
* Drug: idarubicin
* Drug: cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent All patients except those with acute promyelocytic leukemia (APL) who have morphological diagnosis of myelodysplastic syndromes (MDS) refractory anemia with excess blasts (RAEB)-II or AML by World Health Organization (WHO) diagnostic criteria and have either refractory or early relapsed disease; NOTE: Diagnosis of refractory or relapsed disease must be based on evaluation of a bone marrow (BM) aspirate or peripheral blood (PB) flow cytometry; other standard MDS and AML prognostic studies such as cytogenetics, flow, and molecular testing are highly recommended prior to initiating DAC A previous BM evaluation or PB flow cytometry from an outside facility are acceptable if the results have been deemed to be adequate for confirming the diagnosis and staging by University of Washington (UW)/Seattle Cancer Care Alliance (SSCA)/Fred Hutchinson Cancer Research Center (FHCRC) review A BM biopsy is not routinely required but should be obtained if the previous evaluation is not deemed to be adequate for confirming diagnosis and staging by UW/SCCA/FHCRC review Must have received at least one previous cycle of treatment for myelodysplastic syndrome (MDS) or AML and be either refractory as defined as not responded to this therapy or in early relapse as defined as developing recurrence of the disease within 12 months of obtaining a CR May have previously received demethylating agents (e.g., DAC, 5-azacytidine [5AZA]) or histone deacetylases (e.g., suberoylanilide hydroxamic acid) for their MDS or AML if these demethylating agents were not used in combination with systemic anthracycline and ARAC chemotherapy May have received hematopoietic growth factors, thalidomide/lenalidomide, signal transduction inhibitors, or low dose cytarabine (=< 20 mg/m2/day) May not have received any therapy for their MDS or AML other than hydroxyurea or leukapheresis for at least 14 days prior to start of the first dose of DAC; all non-hematologic toxicities must have resolved to < grade 2 Must have a simplified treatment-related mortality (TRM) score =< 9.2 Females of childbearing potential must have a negative pregnancy test prior to initiation of the protocol therapy; females are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 12 weeks after treatment discontinuation Patients with an active or history of other malignancies are eligible, if their projected overall survival for that malignancy is at least 6 months Prior hormonal therapy such as aromatase inhibitors, selective estrogen receptor modulators, estrogen receptor down-regulators, luteinizing hormone-releasing hormone (LHRH) agonists and antagonists, and anti-androgens, must be completed at least 30 days prior to initiation of protocol therapy and must remain off hormonal therapy until the patient has finished chemotherapy for their MDS-RAEBII or AML Direct bilirubin =< 2.5 mg/dL (assessed within 14 days prior to registration) unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis No known hypersensitivity to decitabine (DAC), aracytidine triphosphate (ARAC), or idarubicin hydrochloride (IDA) No clinical evidence of central nervous system (CNS) involvement with leukemia, unless a lumbar puncture confirms the absence of leukemic blasts in the cerebrospinal fluid (CSF) No prior positive test for the human immunodeficiency virus (HIV) No uncontrolled systemic infection Exclusion Criteria: Previous therapy with demethylating agents (e.g., DAC, 5AZA, etc.) or histone deacetylases (e.g., suberoylanilide hydroxamic acid, etc.) that was combined with daunorubicin (DNR) or IDA and ARAC Patients with acute promyelocytic leukemia (APL) Known hypersensitivity to DAC, ARAC, or IDA Clinical evidence of CNS involvement with leukemia, unless a lumbar puncture confirms the absence of leukemic blasts in the CSF Prior positive test for HIV Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) A simplified TRM score > 9.2 Bilirubin > 2.5 mg/dl (assessed within 14 days prior to registration), unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis Patients who have a projected overall survival < 6 months due to malignancies other than MDS or AML Documented symptomatic congestive heart failure or a documented left ventricular ejection fraction < 40% assessed by multigated acquisition (MUGA), echocardiography, or heart catheterization within 21 days prior to start of decitabine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm1: decitabine, idarubicin, cytarabine<br>Patients receive decitabine IV over 1 hour on days -4 to 0, cytarabine IV continuously over 24 hours on days 1-7, and idarubicin IV over 10-15 minutes on days 1-3. | Drug: decitabine<br>* Given IV<br>* Other names: DAC;Drug: idarubicin<br>* Given IV<br>* Other names: IDA;Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;|
| Experimental: Arm2: decitabine, idarubicin, cytarabine<br>Patients receive decitabine IV over 1 hour on days -9 to -5 and cytarabine and idarubicin as in Arm I. | Drug: decitabine<br>* Given IV<br>* Other names: DAC;Drug: idarubicin<br>* Given IV<br>* Other names: IDA;Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieved Morphologic CR | Morphologic complete remission (CR): Absolute Neutrophil Count (ANC)≥1,000/uL, platelet count ≥100,000/uL, <5% Bone Marrow (BM) blasts, no Auer rods (cytoplasmic inclusions which result from an abnormal fusion of the primary (azurophilic) granules), no morphologic dysplasia, and no evidence of extramedullary disease | Participants were monitored up until the point when they went off study following completion of the treatment (3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resistant Disease Defined as Patient Survives at Least 14 Days After Completion of the Last Dose of Induction or Re-induction But Has Persistent Leukemia in Peripheral Blood (PB) or BM |  | Assessed for up to 90 days | 
| Cytogenetic Response Defined as no Detectable Cytogenetic Abnormality in a Subsequent BM Specimen After Induction or Re-induction |  | Assessed for up to 5 years | 
| CRMRD- Defined as Morphologic CR Without Evidence of Minimal Residual Disease by Flow Cytometry, Cytogenetics, or Other Known Molecular Biomarkers |  | Assessed for up to 5 years | 
| CRi Defined as Meeting All Criteria for a Morphologic CR But ANC Remains Less Than 1,000/μL and/or Platelet Count Less Than 100,000/μL |  | Assessed for up to 5 years | 
| CRMRD+ Defined as a Morphologic CR But With Minimal Residual Disease by Flow Cytometry, Cytogenetics, or Other Known Molecular Biomarkers |  | Assessed for up to 5 years | 
| CRiMRD+ Defined as Meeting All Criteria for a CRi But With Evidence of Minimal Residual Disease by Flow Cytometry, Cytogenetics, or Other Known Molecular Biomarkers |  | Assessed for up to 5 years | 
| TRM With Each Course of Decitabine-priming, Idarubicin, and Cytarabine |  | Assessed for up to Day 30 | 
| Frequency and Severity of Grade 3, 4, and 5 Toxicities With Each Course of Decitabine-priming, Idarubicin, and Cytarabine According to NCI Common Terminology Criteria for Adverse Events Version (CTCAE) 4.0 |  | Assessed for up to 3 months after completion study treatment | 
| Severe Prolonged Aplasia |  | Assessed for up to 45 days | 
| Duration of Severe Neutropenia Defined as an ANC Less Than 500 |  | Assessed for up to 5 years | 
| Duration of Moderate Neutropenia Defined as an ANC Less Than 1000 |  | Assessed for up to 5 years | 
| Duration of Thrombocytopenia Defined as Platelet Count Less Than 100,000 |  | Assessed for up to 5 years |