NK Cell Based Non-Myeloablative Transplantation in Acute Myeloid Diseases

NCT01370213 | Completed Phase 2 Results

• 2 other identifiers: 2011LS027MT2011-05
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome

Keywords

non-myeloablative haploidentical transplant; hematopoietic cell transplant; natural killer cells; adoptive cellular therapy

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Donor Neutrophil Engraftment

  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.

  Day 28

Secondary Outcomes (4)

• Number of Participants With Disease Free Survival

  At 6 Months

• Number of Participants With Treatment Related Mortality (TRM)

  At 6 Months

• Number of Participants Who Relapse

  2 Years

• Number of Participants With Early In Vivo Expansion of Natural Killer (NK) Cells

  Day 12

Study Arms (2)

CD34 Schema - High-Risk Acute Myeloid Disease

EXPERIMENTAL

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 filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor.

Drug: Preparative Regimen; Biological: NK Cells; Drug: Interleukin-2; Biological: CD34 Graft/Anti-thymocyte globulin

TCRα/β Schema - High-Risk Acute Myeloid Disease

EXPERIMENTAL

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; Biological: NK Cells; Drug: Interleukin-2; Biological: Donor TCR α/β-depleted Graft/ATG

Interventions

Preparative Regimen DRUG

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,

Also known as: Fludara, Cytoxan, radiation

CD34 Schema - High-Risk Acute Myeloid Disease; TCRα/β Schema - High-Risk Acute Myeloid Disease

NK Cells BIOLOGICAL

CD3\^- CD19\^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.

Also known as: Natural Killer cells

CD34 Schema - High-Risk Acute Myeloid Disease; TCRα/β Schema - High-Risk Acute Myeloid Disease

Interleukin-2 DRUG

Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion

Also known as: IL-2

CD34 Schema - High-Risk Acute Myeloid Disease; TCRα/β Schema - High-Risk Acute Myeloid Disease

CD34 Graft/Anti-thymocyte globulin BIOLOGICAL

Single donor filgrastim mobilized CD34+ selected peripheral blood stem cell graft (minimum cell dose of 5 x 10\^6/kg) on day 0. Rabbit anti-thymocyte globulin (ATG) will be administered on day -1 (0.5 mg/kg) and day +1 and +2 (2.5 mg/kg) pretransplant per institutional guidelines. ATG dosing not identical for all patients.

Also known as: ATG

CD34 Schema - High-Risk Acute Myeloid Disease

Donor TCR α/β-depleted Graft/ATG BIOLOGICAL

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. ATG will be administered on days -6 and -5 (3mg/kg) for most patients.

Also known as: stem cell graft

TCRα/β Schema - High-Risk Acute Myeloid Disease

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota: lead

Study Sites (4)

Emory University

Atlanta, Georgia, 30322, United States

Location

University of Minnesota, Masonic Cancer Center

Minneapolis, Minnesota, 55455, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

fludarabine phosphate; Cyclophosphamide; Radiation; IL32 protein, human; Interleukin-2

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Physical Phenomena; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Results Point of Contact

• Title: Dr. Jeffrey Miller
• Organization: Masonic Cancer Center, University of Minnesota

mille011@umn.edu

612-626-4024

Study Officials

• Jeffrey Miller, M.D.

  Masonic Cancer Center, University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 8, 2011
• First Posted: June 9, 2011
• Study Start: September 1, 2011
• Primary Completion: April 1, 2016
• Study Completion: April 1, 2017
• Last Updated: May 13, 2020
• Results First Posted: December 16, 2019

Record last verified: 2020-04

Locations

US (4)