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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

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

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

NCT ID

NCT00799799

First Posted

November 28, 2008

Last Updated

September 23, 2009

Sponsor

University of Bologna

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

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

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

Time Frame

every 6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

roberto.lemoli@unibo.it

First Name & Middle Initial & Last Name or Official Title & Degree

Antonio Curti, MD

Phone

+39 051 636

Ext

3680

antonio.curti2@unibo.it

Facility Information:

Facility Name

Institute of Hematology "L. & A. Seragnoli"

City

Bologna

State/Province

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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