Decitabine and Vorinostat With CD3/CD19 Depleted Haploidentical Donor NK Cells for Treatment of High Risk Myelodysplastic Syndromes

This study is currently recruiting participants.
Verified October 2013 by Masonic Cancer Center, University of Minnesota
Sponsor:
Collaborator:
Mayo Clinic
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT01593670
First received: May 4, 2012
Last updated: October 8, 2013
Last verified: October 2013
  Purpose

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 Intervention Phase
Myelodysplastic Syndrome
Drug: Decitabine
Drug: Vorinostat
Biological: Interleukin-2
Other: Natural killer (NK) cells
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Objective Response Rate [ Time Frame: After 2 Courses of Treatment (Approx. 3 months) ] [ Designated as safety issue: No ]
    Defined as Complete response (CR) + partial response (PR) + hematologic improvement (HI).


Secondary Outcome Measures:
  • Safety and Tolerability [ Time Frame: Day 1 through Month 3 ] [ Designated as safety issue: Yes ]
    Assess the safety and tolerability of Decitabine and Vorinostat followed by an infusion of CD3-/CD19-donor natural killer (NK) cells and a short course of IL-2 when given in the outpatient setting in patients with high risk myelodysplastic syndrome (MDS).

  • Number of Patients Who Became Transfusion Independent [ Time Frame: 4-6 Months Post Start of Cycle 1 ] [ Designated as safety issue: No ]
  • Natural Killer Cell Expansion [ Time Frame: After Cycle 2 (approx. 3 months) ] [ Designated as safety issue: No ]
    Defined as patients with in vivo expansion.

  • Overall Survival [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
    Patients alive at 1 year.


Estimated Enrollment: 46
Study Start Date: March 2013
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Dacogen
Drug: Vorinostat
200 mg by mouth (PO) twice a day on days 6-15
Other Name: Zolinza
Biological: Interleukin-2
6 million Units subcutaneous (SQ) 3 times a week for 3 doses beginning day 17
Other Name: IL-2
Other: Natural killer (NK) cells
infusion intravenously (IV) over 15 to 60 minutes day 17

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 as defined below within 14 days (28 days for cardiac) of enrollment:

    • Renal: Creatinine: ≤ 2.0 mg/dL
    • Hepatic: SGOT/SGPT < 5 x upper limit of institutional normal (ULN)
    • Pulmonary: oxygen saturation ≥ 90% on room air
    • Cardiac:Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) ≥ 40%, no uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. QTc < 500 msec
  • Ability to be off prednisone and other immunosuppressive drugs for at least 3 days prior to the natural killer (NK) cell infusion (excluding pre-meds)
  • Women of child bearing potential must agree to use effective methods of contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) from the time of signing the consent form and for 2 months after the last dose of chemotherapy.
  • Voluntary written consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn at any time without prejudice to future medical care.

Exclusion Criteria:

  • Pregnant or lactating. The agents used in this study are known to be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Confirmation that the patient is not pregnant must be established by a negative pregnancy test result obtained during screening. Pregnancy testing is not required for surgically sterilized or post-menopausal women.
  • 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01593670

Contacts
Contact: Erica Warlick, M.D. 612-625-5467 ewarlick@umn.edu

Locations
United States, Minnesota
Masonic Cancer Center, University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Erica Warlick, M.D.    612-625-5467    ewarlick@umn.edu   
Principal Investigator: Erica Warlick, M.D.         
Mayo Clinic Not yet recruiting
Rochester, Minnesota, United States, 55901
Contact: Mark R. Litzow, MD    507-284-2358    litzow.mark@mayo.edu   
Principal Investigator: Mark R. Litzow, MD         
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Mayo Clinic
Investigators
Principal Investigator: Erica Warlick, M.D. Masonic Cancer Center, University of Minnesota
  More Information

No publications provided

Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT01593670     History of Changes
Other Study ID Numbers: 2011LS124, MT2012-04
Study First Received: May 4, 2012
Last Updated: October 8, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Masonic Cancer Center, University of Minnesota:
high risk myelodysplastic syndrome
natural killer cells

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Decitabine
Vorinostat
Interleukin-2
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Histone Deacetylase Inhibitors

ClinicalTrials.gov processed this record on April 20, 2014