NK Cell Based Non-Myeloablative Transplantation in Acute Myeloid Diseases

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Masonic Cancer Center, University of Minnesota
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT01370213
First received: June 8, 2011
Last updated: May 15, 2014
Last verified: May 2014
  Purpose

This is a phase II multi-institutional therapeutic study of NK-cell based nonmyeloablative haploidentical transplantation for the treatment of high-risk acute myeloid diseases. Enrollment will use a two-stage design. Stage 1 will enroll 15 patients unless an early stopping rule is met. If 9 or more of these first 15 patients achieve leukemia free neutrophil engraftment at day +28 accrual will move to stage 2. In stage 2, an additional 28 patients will be enrolled for a total of 43 patients. Patients will be followed for disease response for 2 years.


Condition Intervention Phase
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Drug: Preparative Regimen
Biological: NK Cells
Drug: Interleukin-2
Biological: Anti-thymocyte globulin
Biological: Donor TCR α/β-depleted 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: Multi-Center Phase II Trial of NK Cell Based Non-Myeloablative Haploidentical Transplantation for Patients With High-Risk Acute Myeloid Diseases

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Rate of Donor Neutrophil Engraftment [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
    The rate of donor neutrophil engraftment in the absence of leukemia at day +28 will be determined. Successful neutrophil engraftment is defined as an absolute donor-derived neutrophil count of >500 cells/μl. Leukemia free is defined as <5% bone marrow blasts, absence of blasts with Auer rods; absence of extramedullary disease; but cytogenetic or molecular minimal residual disease is allowed.


Secondary Outcome Measures:
  • Disease Free Survival [ Time Frame: At 6 Months ] [ Designated as safety issue: No ]
  • Treatment Related Mortality (TRM) [ Time Frame: At 6 Months ] [ Designated as safety issue: Yes ]
    Cumulative incidence will be used to estimate TRM.

  • Incidence of Relapse [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
    Cumulative incidence will be used to estimate relapse.

  • Rate of Early In Vivo Expansion of Natural Killer (NK) Cells [ Time Frame: Day 0 ] [ Designated as safety issue: No ]
    Successful in vivo donor NK cell expansion will be defined by measuring an absolute circulating donor-derived NK cell count of >100 cells/μl in patient's peripheral blood 12 days after infusion.


Estimated Enrollment: 43
Study Start Date: September 2011
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: High-Risk Acute Myeloid Disease
Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and same donor TCR α/β-depleted cells infusion.
Drug: Preparative Regimen

Preparative Regimen:

1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,

Other Names:
  • Fludara
  • Cytoxan
  • radiation
Biological: NK Cells
CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.
Other Name: Natural Killer cells
Drug: Interleukin-2
Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion
Other Name: IL-2
Biological: Anti-thymocyte globulin
rabbit anti-thymocyte globulin will be administered on day -5 (0.5 mg/kg) and day -4 (2.5 mg/kg) pretransplant per institutional guidelines
Other Name: ATG
Biological: Donor TCR α/β-depleted Cells
Single donor TCR α/β-depleted filgrastim-mobilized peripheral blood stem cells (PBSC) graft (minimum cell dose of 5 x 10^6/kg) on day 0
Other Name: stem cell graft

Detailed Description:

A reduced intensity conditioning using Fludara, Cytoxan, and irradiation will start on day -22, followed by infusion of donor NK (natural killer) cells on day-17, 6 doses of interleukin-2 (IL-2) to promote NK expansion (day -17 to day -7), 2 doses of ATG for additional immunosuppression to promote engraftment (day -5 to -4), and infusion of a TCR α/β-depleted same donor graft on day 0.

  Eligibility

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

Inclusion Criteria:

  • Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

RAEB-1 or RAEB-2 fitting within one of the following disease groups:

  • Primary induction failure (PIF): Patients who have not achieved a complete remission (CR) after two induction cycles of cytotoxic therapy (i.e. 7+ 3, MEC, FLAG, etc.) and having ≤ 10,000 absolute circulating blasts measured at least 21 days from prior therapy. Hydroxyurea may be used to control blasts count. Demethylating agents do not count as induction therapy; however early re-induction therapy based on residual disease on a day 14 BM will count as a 2nd cycle
  • Relapsed Disease with low disease burden (AML or MDS with ≤ 10,000 absolute circulating blasts. No re-induction attempts are required, but a maximum of 2 reinduction attempts are allowed to be eligible.
  • CR3 or greater: This will include CRp defined as CR without platelet recovery to 100,000/mcL.
  • CR1 or CR2 with high risk features: Includes therapy induced, prior MDS or MPD, high risk cytogenetic or molecular phenotype with no available donor (sibling or unrelated adult)

Patients with known prior central nervous system (CNS) involvement are eligible provided that it has been treated and CSF is clear for at least 2 weeks prior to enrollment. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.

  • Available related HLA-haploidentical adult donor by at least Class I serologic typing at the A&B locus
  • Karnofsky score > 50%
  • Adequate organ function within 28 days of study registration defined as:

    • Hepatic: AST ≤ 3 x upper limit of institutional normal, total bilirubin ≤ 2.0 mg/dl
    • Renal: estimated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m^2
    • Pulmonary: Oxygen saturation ≥ 90% on room air and DLCOcor ≥ 40%
    • Cardiac: Ejection Fraction ≥ 35% and no uncontrolled angina, severe uncontrolled ventricular or arterial arrhythmias, or any evidence of acute ischemia or active conduction system abnormalities (rate controlled atrial fibrillation is not an exclusion)
  • Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to NK cell infusion (except for those prescribed as part of the study)
  • Women of child bearing potential must have a negative pregnancy test within 28 days prior to study registration and agree to use adequate birth control during study treatment
  • Voluntary written consent

Exclusion Criteria:

  • Biphenotypic leukemia
  • Allogeneic transplant for AML within previous 6 months
  • New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has not been evaluated with bronchoscopy, if feasible. Infiltrates attributed to infection must be stable/improving (with associated clinical improvement) after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections).
  • Uncontrolled bacterial, fungal or viral infections including HIV - chronic asymptomatic viral hepatitis is allowed
  • Known hypersensitivity to any of the study agents
  • Received any investigational drugs within the 14 days before 1st dose of fludarabine
  • Requires agents other than hydroxyurea to control blast count

Donor Selection:

  • Related donor (sibling, parent, offspring, parent or offspring of an HLA identical sibling) 12-75 years of age. (It is recognized individual institutions may have differing donor age guidelines. This is acceptable as long as no donor is younger than 12 years or older than 75 years).
  • Body weight of at least 40 kilograms
  • In general good health as determined by the medical provider
  • HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus
  • Able and willing to have up to 4 separate apheresis collections
  • Not pregnant
  • Voluntary written consent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01370213

Contacts
Contact: Sarah Cooley, M.D. 612-624-4024 cool0023@umn.edu

Locations
United States, Georgia
Emory University Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Edmund Waller, M.D.         
Sub-Investigator: Edmund Waller, M.D.         
United States, Minnesota
University of Minnesota, Masonic Cancer Center Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Timothy Krepski, RN    612-273-2800    tkrepsk1@fairview.org   
Principal Investigator: Sarah Cooley, M.D.         
United States, Missouri
Washington University Not yet recruiting
St. Louis, Missouri, United States, 63110
Contact: John DiPersio, M.D.         
Contact: Todd Fehninger         
Principal Investigator: John DiPersio, M.D.         
United States, Ohio
Ohio State University Not yet recruiting
Columbus, Ohio, United States, 43210
Contact: Steven Devine, M.D.         
Principal Investigator: Steven Devine, M.D.         
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Sarah Cooley, M.D. Masonic Cancer Center, University of Minnesota
  More Information

No publications provided

Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT01370213     History of Changes
Other Study ID Numbers: 2011LS027, MT2011-05
Study First Received: June 8, 2011
Last Updated: May 15, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Masonic Cancer Center, University of Minnesota:
non-myeloablative haploidentical transplant
hematopoietic cell transplant
natural killer cells
adoptive cellular therapy

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Antilymphocyte Serum
Interleukin-2
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on July 26, 2014