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

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT01593670
• Collaborator: Mayo Clinic (Other)
• Enrollment: 9
• Locations: 2
• Arm: 1
• Duration (Months): 67.7
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome	Drug: Decitabine; Drug: Vorinostat; Biological: Interleukin-2; Other: Natural killer (NK) cells	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Decitabine and Vorinostat With CD3/CD19 Depleted Haploidentical Donor Natural Killer (NK) Cells for the Treatment of High Risk Myelodysplastic Syndromes (MDS)
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Oct 23, 2018
• Actual Study Completion Date: Oct 23, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Patients With High Risk MDS 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; administered intravenous (IV), 10 mg/m^2/day over 1 hour on days 1-5.; Other Names: Dacogen ; Drug: Vorinostat; 200 mg by mouth (PO) twice a day on days 6-15; Other Names: Zolinza ; Biological: Interleukin-2; 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17; Other Names: IL-2 ; Other: Natural killer (NK) cells; infusion intravenously (IV) over 15 to 60 minutes day 17

Outcome Measures

Primary Outcome Measures

1. The Number of Patients Who Achieved a Clinical Response [After 2 Courses of Treatment (Approx. 3 months)]

   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.

Secondary Outcome Measures

1. Number of Patients Who Experienced Grade 3 or Higher Non-hematologic Adverse Events [Day 1 through Month 3]

   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.

2. Number of Patients Who Became Transfusion Independent [4-6 Months Post Start of Cycle 1]

3. Number of Patients Who Had Natural Killer (NK) Cell Expansion [After Cycle 2 (approx. 3 months)]

   NK cell expansion is defined as the presence of donor NK cells in the recipient at Day 8 post NK cell infusion.

4. Overall Survival [1 Year]

   Patients alive at 1 year.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota	United States	55455
2	Mayo Clinic	Rochester	Minnesota	United States	55901

Sponsors and Collaborators

• Masonic Cancer Center, University of Minnesota
• Mayo Clinic

Investigators

• Principal Investigator: Erica Warlick, M.D., Masonic Cancer Center, University of Minnesota

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 28, 2014

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT01593670
• Other Study ID Numbers: 2011LS124; MT2012-04
• First Posted: May 8, 2012
• Last Update Posted: May 21, 2019
• Last Verified: May 1, 2019

• Keywords provided by Masonic Cancer Center, University of Minnesota: high risk myelodysplastic syndrome; natural killer cells
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Decitabine; Interleukin-2; Vorinostat

Study Results

Participant Flow

Arm/Group Title	Patients With High Risk MDS
Arm/Group Description	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. Decitabine: administered intravenous (IV), 10 mg/m^2/day over 1 hour on days 1-5. Vorinostat: 200 mg by mouth (PO) twice a day on days 6-15 Interleukin-2: 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17 Natural killer (NK) cells: infusion intravenously (IV) over 15 to 60 minutes day 17
Period Title: Overall Study
STARTED	9
COMPLETED	9
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Patients With High Risk MDS
Arm/Group Description	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. Decitabine: administered intravenous (IV), 10 mg/m^2/day over 1 hour on days 1-5. Vorinostat: 200 mg by mouth (PO) twice a day on days 6-15 Interleukin-2: 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17 Natural killer (NK) cells: infusion intravenously (IV) over 15 to 60 minutes day 17
Overall Participants	9
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 66.7%
>=65 years	3 33.3%
Sex: Female, Male (Count of Participants)
Female	5 55.6%
Male	4 44.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	9 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	The Number of Patients Who Achieved a Clinical Response
Description	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.
Time Frame	After 2 Courses of Treatment (Approx. 3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With High Risk MDS
Arm/Group Description	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. Decitabine: administered intravenous (IV), 10 mg/m^2/day over 1 hour on days 1-5. Vorinostat: 200 mg by mouth (PO) twice a day on days 6-15 Interleukin-2: 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17 Natural killer (NK) cells: infusion intravenously (IV) over 15 to 60 minutes day 17
Measure Participants	9
Count of Participants [Participants]	5 55.6%

2. Secondary Outcome

Title	Number of Patients Who Experienced Grade 3 or Higher Non-hematologic Adverse Events
Description	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.
Time Frame	Day 1 through Month 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With High Risk MDS
Arm/Group Description	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. Decitabine: administered intravenous (IV), 10 mg/m^2/day over 1 hour on days 1-5. Vorinostat: 200 mg by mouth (PO) twice a day on days 6-15 Interleukin-2: 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17 Natural killer (NK) cells: infusion intravenously (IV) over 15 to 60 minutes day 17
Measure Participants	9
Count of Participants [Participants]	7 77.8%

3. Secondary Outcome

Title	Number of Patients Who Became Transfusion Independent
Time Frame	4-6 Months Post Start of Cycle 1

Outcome Measure Data

Analysis Population Description

7 of the 9 patients were not evaluable for this outcome measure - 5 went on to stem cell transplant and 2 died before reaching the 4-6 month post start of cycle 1 milestone.This left 2 evaluable patients for the outcome measure, and thus this endpoint is not informative due to lack of evaluable patients.

Arm/Group Title	Patients With High Risk MDS
Arm/Group Description	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. Decitabine: administered intravenous (IV), 10 mg/m^2/day over 1 hour on days 1-5. Vorinostat: 200 mg by mouth (PO) twice a day on days 6-15 Interleukin-2: 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17 Natural killer (NK) cells: infusion intravenously (IV) over 15 to 60 minutes day 17
Measure Participants	2
Count of Participants [Participants]	0 0%

4. Secondary Outcome

Title	Number of Patients Who Had Natural Killer (NK) Cell Expansion
Description	NK cell expansion is defined as the presence of donor NK cells in the recipient at Day 8 post NK cell infusion.
Time Frame	After Cycle 2 (approx. 3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With High Risk MDS
Arm/Group Description	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. Decitabine: administered intravenous (IV), 10 mg/m^2/day over 1 hour on days 1-5. Vorinostat: 200 mg by mouth (PO) twice a day on days 6-15 Interleukin-2: 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17 Natural killer (NK) cells: infusion intravenously (IV) over 15 to 60 minutes day 17
Measure Participants	9
Count of Participants [Participants]	0 0%

5. Secondary Outcome

Title	Overall Survival
Description	Patients alive at 1 year.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With High Risk MDS
Arm/Group Description	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. Decitabine: administered intravenous (IV), 10 mg/m^2/day over 1 hour on days 1-5. Vorinostat: 200 mg by mouth (PO) twice a day on days 6-15 Interleukin-2: 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17 Natural killer (NK) cells: infusion intravenously (IV) over 15 to 60 minutes day 17
Measure Participants	9
Count of Participants [Participants]	3 33.3%

Adverse Events

Time Frame	1 Year
Arm/Group Title	Patients With High Risk MDS
Arm/Group Description	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. Decitabine: administered intravenous (IV), 10 mg/m^2/day over 1 hour on days 1-5. Vorinostat: 200 mg by mouth (PO) twice a day on days 6-15 Interleukin-2: 6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17 Natural killer (NK) cells: infusion intravenously (IV) over 15 to 60 minutes day 17
All Cause Mortality
	Patients With High Risk MDS
	Affected / at Risk (%)	# Events
Total	7/9 (77.8%)
Serious Adverse Events
	Patients With High Risk MDS
	Affected / at Risk (%)	# Events
Total	6/9 (66.7%)
Blood and lymphatic system disorders
Febrile Neutropenia	2/9 (22.2%)
Ear and labyrinth disorders
Ear Pain	1/9 (11.1%)
Otomastoiditis	1/9 (11.1%)
Gastrointestinal disorders
Nausea	1/9 (11.1%)
Infections and infestations
Infection, Source Unknown	1/9 (11.1%)
Renal and urinary disorders
Renal Colic	1/9 (11.1%)
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Infection	1/9 (11.1%)
Hypoxia	1/9 (11.1%)
Vascular disorders
Hypotension	1/9 (11.1%)
Other (Not Including Serious) Adverse Events
	Patients With High Risk MDS
	Affected / at Risk (%)	# Events
Total	9/9 (100%)
Blood and lymphatic system disorders
Febrile Neutropenia	6/9 (66.7%)
Ear and labyrinth disorders
Ear Pain	1/9 (11.1%)
Gastrointestinal disorders
Nausea	1/9 (11.1%)
Diarrhea	2/9 (22.2%)
General disorders
Chills	7/9 (77.8%)
Edema, NOS	4/9 (44.4%)
Fatigue	3/9 (33.3%)
Fever	4/9 (44.4%)
Infusion Related Reaction	2/9 (22.2%)
Injection Site Reaction	6/9 (66.7%)
Edema, Ankle	1/9 (11.1%)
Hepatobiliary disorders
Cholecystitis	1/9 (11.1%)
Infections and infestations
Para-Influenza	1/9 (11.1%)
Bacteremia	1/9 (11.1%)
Cellulitis, Toe	1/9 (11.1%)
Urinary Tract Infection	1/9 (11.1%)
Investigations
Creatinine Increased	4/9 (44.4%)
White Blood Cell Decreased	4/9 (44.4%)
Neutrophil Count Decreased	7/9 (77.8%)
Platelet Count Decreased	7/9 (77.8%)
Alanine Aminotransferase Increased	1/9 (11.1%)
Aspartate Aminotransferase Increased	2/9 (22.2%)
Blood Bilirubin Increased	1/9 (11.1%)
Cholesterol High	1/9 (11.1%)
Metabolism and nutrition disorders
Anorexia	1/9 (11.1%)
Hypocalcemia	1/9 (11.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/9 (11.1%)
Pain, Toe	1/9 (11.1%)
Nervous system disorders
Headache	1/9 (11.1%)
Renal and urinary disorders
Renal Calculi	1/9 (11.1%)
Renal Colic	1/9 (11.1%)
Respiratory, thoracic and mediastinal disorders
Cough	1/9 (11.1%)
Dyspnea	8/9 (88.9%)
Hypoxia	3/9 (33.3%)
Nasal Drainage	1/9 (11.1%)
Skin and subcutaneous tissue disorders
Itchy Nose	1/9 (11.1%)
Pruritus	1/9 (11.1%)
Rash	3/9 (33.3%)
Vascular disorders
Hypertension	6/9 (66.7%)
Hypotension	2/9 (22.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.