Decitabine and Vorinostat Conditioning Followed by CD3-/CD19- NK Cells Infusion for High Risk Myelodysplastic Syndromes

Study Overview
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Brief Summary
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This is a Phase II therapeutic trial combining Decitabine days 1-5 with oral Vorinostat twice daily days 6-15 followed by a single infusion of CD3-/CD19- enriched donor natural killer (NK) cells on day 17 and a short course of Interleukin-2 (IL-2) to facilitate NK cell survival and expansion. Two courses of treatment will be given separated by 6-8 weeks. The intent is to administer all treatment in the outpatient setting.

Detailed Description
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A single donor apheresis will be collected on day 15 of cycle 1, enriched for NK cells with the large scale CliniMacs device (Miltenyi) and activated by overnight incubation with IL-2. After washing, the final NK cell product will be divided in two, with half given fresh on day 17 of course #1 and half stored frozen until day 17 of course #2. Clinical response will be formally assessed 4-6 weeks after the start of 2nd course based on International Working Group (IWG) criteria; however, bone marrow evaluations will be completed to assess for any sign of significant disease progression between cycle 1 and 2.

Official Title
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Decitabine and Vorinostat With CD3/CD19 Depleted Haploidentical Donor Natural Killer (NK) Cells for the Treatment of High Risk Myelodysplastic Syndromes (MDS)

Conditions
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Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Decitabine
* Drug: Vorinostat
* Biological: Interleukin-2
* Other: Natural killer (NK) cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of high risk myelodysplastic (MDS) that meets one of the following disease classifications and is requiring treatment: International Prognostic Scoring System (IPSS) Category: INT-2 or High Risk WHO Classification: RAEB-1 or RAEB-2 High risk cytogenetic abnormality as defined by presence of Monosomy 7, complex karytope, or monosomal karyotype WHO Based Prognostic Scoring System (WPSS): High or Very High Risk Patients may be untreated or have had a maximum of 2 cycles of hypomethylating agents (azacitidine or decitabine) without evidence of treatment failure as defined by progression to more advanced MDS Who classification or AML. Patients must not have received treatment for their MDS within 4 weeks of beginning the trial. Treatments allowed prior to that time include azacitidine or decitabine and hematopoietic growth factors. No prior AML-like induction therapy allowed. Age ≥ 18 years of age Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Available related HLA-haploidentical NK cell donor by at least Class I serologic typing at the A&B locus Have acceptable organ function within 14 days of enrollment Ability to be off prednisone and other immunosuppressive drugs for at least 3 days prior to the natural killer (NK) cell infusion Women of child bearing potential must agree to use effective methods of contraception Voluntary written consent Exclusion Criteria: Pregnant or lactating. Prior 7 + 3 (cytarabine given continuously for 7 days with an anthracycline drug, such as daunorubicin or idarubicin given for the 1st 3 days of treatment) or other AML-type induction chemotherapy New progressive pulmonary infiltrates on screening chest x-ray or chest computed tomography (CT) scan that has not been evaluated with bronchoscopy (when feasible) Uncontrolled bacterial or viral infections - chronic asymptomatic viral hepatitis is allowed Pleural effusion moderate to large in size that are detectable on chest xray Known hypersensitivity to one or more of the study agents Prior hypomethylating treatment greater than 2 cycles or with documented treatment failure Prior use of histone deacetylase inhibitors Serious medical or psychiatric illness likely to interfere with participation in this clinical study in the opinion of the enrolling investigator Inability to swallow capsules Active human immunodeficiency virus (HIV) Other active and potentially life threatening malignancy excluding localized basal or squamous cell skin cancer, cervical carcinoma in situ, superficial bladder cancer, localized prostate cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients With High Risk MDS<br>Patients who received treatment for high risk myelodysplastic syndromes (MDS). Treatment Received: Decitabine 10 mg/m^2/day intravenous (IV) over 1 hour days 1-5; Vorinostat 200 mg by mouth (PO) twice a day days 6-15; Il-2 activated donor natural killer cells (NK) infusion IV over 15 to 60 minutes day 17; Interleukin-2 6 million units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17. Repeat treatment course 6 to 8 weeks after cycle 1 start date. | Drug: Decitabine<br>* administered intravenous (IV), 10 mg/m^2/day over 1 hour on days 1-5.<br>* Other names: Dacogen;Drug: Vorinostat<br>* 200 mg by mouth (PO) twice a day on days 6-15<br>* Other names: Zolinza;Biological: Interleukin-2<br>* 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17<br>* Other names: IL-2;Other: Natural killer (NK) cells<br>* infusion intravenously (IV) over 15 to 60 minutes day 17<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Patients Who Achieved a Clinical Response | Clinical response includes: Complete Response (less than 5% myeloblasts present in the bone marrow and in the peripheral blood a hemoglobin of at least 11g/dl, platelets of at least 100 X 10E9/L, neutrophils of at least 1.0 X 10E9/L, and blasts 0%); Partial Response (all Complete Response criteria if previously abnormal except bone marrow myeloblasts are decreased by more than 50% over pre-treatment, but still greater than 5%); and hematologic improvement (a hemoglobin increase of greater than 1.5g/dl or decreased red blood cell transfusions by at least 4 per 8 week period, a platelet increase of more than 30 X 10E9/L for patients with a baseline of more than 20 X 10E9/L or an increase by 100% for those with a baseline of less than 20 X 10E9/L, and a neutrophil increase of at least 100% and an absolute increase of greater than 0.5 X 10E9/L. | After 2 Courses of Treatment (Approx. 3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Experienced Grade 3 or Higher Non-hematologic Adverse Events | Adverse events (AEs) will be graded using Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Non-hematologic adverse events are defined as untoward medical occurrences associated with the use of a study drug whether or not considered study drug related, excluding those events involving white blood cells, neutrophils, red blood cells or platelets. In general, grade 3 AEs are defined as 1) being severe or medically significant but,not immediately life-threatening; 2) requiring hospitalization or prolongation of hospitalization; 3) disabling; or 4) limiting self care activities. Grade 4 AEs are defined as 1) having life-threatening consequences; or 2) requiring urgent intervention. Grade 5 AEs are defined as causing death related to an adverse event. | Day 1 through Month 3 | 
| Number of Patients Who Became Transfusion Independent |  | 4-6 Months Post Start of Cycle 1 | 
| Number of Patients Who Had Natural Killer (NK) Cell Expansion | NK cell expansion is defined as the presence of donor NK cells in the recipient at Day 8 post NK cell infusion. | After Cycle 2 (approx. 3 months) | 
| Overall Survival | Patients alive at 1 year. | 1 Year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high risk myelodysplastic syndrome, natural killer cells