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

Myeloblastic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00799799
• Other study ID #: NK TRIAL
• Status: Recruiting
• Phase: Phase 1
• First received: November 28, 2008
• Last updated: September 23, 2009
• Start date: October 2005
• Est. completion date: December 2009

Study information

• Verified date: September 2009
• Source: University of Bologna
• Contact: Roberto M Lemoli, MD
• Phone: +39 051 636
• Email: roberto.lemoli[@]unibo.it
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: December 2009
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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)

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myeloblastic Leukemia

Intervention

Biological:
• NK cells
NK cells infusion after immunosuppressive chemotherapy

Locations

Country	Name	City	State
Italy	Institute of Hematology "L. & A. Seragnoli"	Bologna	Bo

Sponsors (1)

Lead Sponsor	Collaborator
University of Bologna

Country where clinical trial is conducted

Italy, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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		every 6 months	Yes
Primary	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		every 6 months	Yes
Secondary	To evaluate the microchimerism of AML patients receiving haploidentical human NK cells for adoptive immunotherapy		every 6 months	Yes
Secondary	To evaluate, in vitro and in vivo, the antitumor activity of haploidentical NK cells infused in AML patients		every 6 months	Yes
Secondary	To assess the percentage of patients entering complete remission (CR) after the reinfusion of highly purified haploidentical NK cells		every 6 months	Yes
Secondary	To assess the disease-free and overall survival of AML patients infused with haploidentical NK cells		every 6 months	Yes
Secondary	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		every 6 months	Yes