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Adoptive Immunotherapy of High Risk Acute Myeloblastic Leukemia Patients Using Haploidentical Kir Ligand-mismatched Natural Killer Cells

Primary Purpose

Myeloblastic Leukemia

Status
Unknown status
Phase
Phase 1
Locations
Italy
Study Type
Interventional
Intervention
NK cells
Sponsored by
University of Bologna
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myeloblastic Leukemia focused on measuring Nk cells infusion, minimal residual disease in AML patients, trafficking of NK cells after infusion, cytolytic effects on leukemic cells

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Signed informed consent.
  • Performance Status ≥ 70% (Karnofsky score) or ≤ 2 (WHO).
  • Age greater than 18 years.
  • Availability of a KIR incompatible haploidentical donor.
  • Adequate renal (serum creatinine < 2 mg/dl), pulmonary (Sat O2 ≥ 96%) and hepatic (ALT/AST < 2.5 x N) function.
  • Patients enrolled in the protocol must have an autologous graft cryopreserved to be reinfused in case of severe myelosuppression induced by haploidentical NK cells. Back-up cells will be reinfused in case of ANC < 0.5 x 109/L at day + 40 from the start of immunosuppressive regimen.

Exclusion Criteria:

  • Age < 18.
  • People unable to give informed consent.
  • HIV positivity.
  • HCV positivity with high viral load.
  • Intercurrent organ damage or medical problems that would interfere with therapy.
  • Pregnant or nursing females.
  • Current uncontrolled infection.
  • No availability of a cryopreserved autologous stem cell graft to be reinfused in case of severe myelosuppression.
  • Signs or symptoms of fluid retention (e.g. pleural effusion)

Sites / Locations

  • Institute of Hematology "L. & A. Seragnoli"Recruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

NK

Arm Description

patient treated as per protocol

Outcomes

Primary Outcome Measures

To assess the feasibility of the selection and reinfusion of 5x10E6 haploidentical natural killer (NK) cells /Kg of body weight (target cell dose) in at least 40% of adult patients with active acute myeloblastic leukemia (AML) entering the study
To assess the feasibility of the reinfusion of the minimum accepted cell dose (1x10E6 haploidentical NK cells /Kg) in all patients enrolled into the protocol

Secondary Outcome Measures

To evaluate the microchimerism of AML patients receiving haploidentical human NK cells for adoptive immunotherapy
To evaluate, in vitro and in vivo, the antitumor activity of haploidentical NK cells infused in AML patients
To assess the percentage of patients entering complete remission (CR) after the reinfusion of highly purified haploidentical NK cells
To assess the disease-free and overall survival of AML patients infused with haploidentical NK cells
To assess the safety of infusion of haploidentical NK cells, following immunosuppressive chemotherapy, considered as the incidence of adverse event (graded according to WHO) and clinically significant abnormal laboratory values following reinfusion

Full Information

First Posted
November 28, 2008
Last Updated
September 23, 2009
Sponsor
University of Bologna
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1. Study Identification

Unique Protocol Identification Number
NCT00799799
Brief Title
Adoptive Immunotherapy of High Risk Acute Myeloblastic Leukemia Patients Using Haploidentical Kir Ligand-mismatched Natural Killer Cells
Official Title
Adoptive Immunotherapy of High Risk Acute Myeloblastic Leukemia Patients Using Haploidentical Kir Ligand-mismatched Natural Killer Cells
Study Type
Interventional

2. Study Status

Record Verification Date
September 2009
Overall Recruitment Status
Unknown status
Study Start Date
October 2005 (undefined)
Primary Completion Date
December 2009 (Anticipated)
Study Completion Date
December 2009 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
University of Bologna

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
AML patients with de-novo or secondary disease with age greater than 18 years not eligible for stem cell transplantation for medical contraindications, lack of donor or lack of stem cells,are eligible. Leukemias other than AML and M3 FAB subtype will be excluded from the study. Immunosuppressive chemotherapy prior to NK cell infusion will include: fludarabine and cyclophosphamide 4g/m2 (Flu/Cy). The therapy will be administered over 6 days on inpatient basis. Haploidentical NK cells will be selected from a steady-state large volume leukapheresis product from a suitable KIR ligand incompatible donor. Donor-recipients pairs will be selected on the basis of known KIR ligands. In particular, haploidentical donors will be included if present at least one allele mismatch at a class I locus among the following ones: HLA-C alleles with Asn77-Lys80, HLA-C alleles with Ser77-Asn80, HLA-Bw4 alleles. Immunomagnetic enrichment of NK cells will follow two subsequent steps: 1) depletion of CD3+ T cells followed by 2) positive selection of CD56+ NK cells. Contaminating CD3+ T cells will be carefully evaluated.
Detailed Description
When previously cryproserved NK cells are still available, further re-infusions may be performed, according to PI's evaluation. The number of remaining NK cells must be sufficient for the reinfusion of at least the minimum dose of cells (106/kg). At least two months should elapse between two consecutive infusion procedures.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myeloblastic Leukemia
Keywords
Nk cells infusion, minimal residual disease in AML patients, trafficking of NK cells after infusion, cytolytic effects on leukemic cells

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
NK
Arm Type
Experimental
Arm Description
patient treated as per protocol
Intervention Type
Biological
Intervention Name(s)
NK cells
Intervention Description
NK cells infusion after immunosuppressive chemotherapy
Primary Outcome Measure Information:
Title
To assess the feasibility of the selection and reinfusion of 5x10E6 haploidentical natural killer (NK) cells /Kg of body weight (target cell dose) in at least 40% of adult patients with active acute myeloblastic leukemia (AML) entering the study
Time Frame
every 6 months
Title
To assess the feasibility of the reinfusion of the minimum accepted cell dose (1x10E6 haploidentical NK cells /Kg) in all patients enrolled into the protocol
Time Frame
every 6 months
Secondary Outcome Measure Information:
Title
To evaluate the microchimerism of AML patients receiving haploidentical human NK cells for adoptive immunotherapy
Time Frame
every 6 months
Title
To evaluate, in vitro and in vivo, the antitumor activity of haploidentical NK cells infused in AML patients
Time Frame
every 6 months
Title
To assess the percentage of patients entering complete remission (CR) after the reinfusion of highly purified haploidentical NK cells
Time Frame
every 6 months
Title
To assess the disease-free and overall survival of AML patients infused with haploidentical NK cells
Time Frame
every 6 months
Title
To assess the safety of infusion of haploidentical NK cells, following immunosuppressive chemotherapy, considered as the incidence of adverse event (graded according to WHO) and clinically significant abnormal laboratory values following reinfusion
Time Frame
every 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed informed consent. Performance Status ≥ 70% (Karnofsky score) or ≤ 2 (WHO). Age greater than 18 years. Availability of a KIR incompatible haploidentical donor. Adequate renal (serum creatinine < 2 mg/dl), pulmonary (Sat O2 ≥ 96%) and hepatic (ALT/AST < 2.5 x N) function. Patients enrolled in the protocol must have an autologous graft cryopreserved to be reinfused in case of severe myelosuppression induced by haploidentical NK cells. Back-up cells will be reinfused in case of ANC < 0.5 x 109/L at day + 40 from the start of immunosuppressive regimen. Exclusion Criteria: Age < 18. People unable to give informed consent. HIV positivity. HCV positivity with high viral load. Intercurrent organ damage or medical problems that would interfere with therapy. Pregnant or nursing females. Current uncontrolled infection. No availability of a cryopreserved autologous stem cell graft to be reinfused in case of severe myelosuppression. Signs or symptoms of fluid retention (e.g. pleural effusion)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Roberto M Lemoli, MD
Phone
+39 051 636
Ext
3680
Email
roberto.lemoli@unibo.it
First Name & Middle Initial & Last Name or Official Title & Degree
Antonio Curti, MD
Phone
+39 051 636
Ext
3680
Email
antonio.curti2@unibo.it
Facility Information:
Facility Name
Institute of Hematology "L. & A. Seragnoli"
City
Bologna
State/Province
Bo
ZIP/Postal Code
40138
Country
Italy
Individual Site Status
Recruiting

12. IPD Sharing Statement

Citations:
PubMed Identifier
11896281
Citation
Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002 Mar 15;295(5562):2097-100. doi: 10.1126/science.1068440.
Results Reference
background
PubMed Identifier
21791425
Citation
Curti A, Ruggeri L, D'Addio A, Bontadini A, Dan E, Motta MR, Trabanelli S, Giudice V, Urbani E, Martinelli G, Paolini S, Fruet F, Isidori A, Parisi S, Bandini G, Baccarani M, Velardi A, Lemoli RM. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood. 2011 Sep 22;118(12):3273-9. doi: 10.1182/blood-2011-01-329508. Epub 2011 Jul 25.
Results Reference
derived

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Adoptive Immunotherapy of High Risk Acute Myeloblastic Leukemia Patients Using Haploidentical Kir Ligand-mismatched Natural Killer Cells

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