Haploidentical Transplant With NK Cell Infusion for Pediatric Acute Leukemia and Solid Tumors

Reduced Intensity Haploidentical Transplantation With NK Cell Infusion for Pediatric Acute Leukemia and High Risk Solid Tumors, BMT06407

This study will assess the feasibility of utilizing a reduced intensity conditioning regimen, in the setting of haploidentical transplantation, for patients with recurrent acute lymphoblastic leukemia (ALL), AML and high risk or refractory solid tumors. In addition, the feasibility and safety of administering post-transplant NK cell infusions will be evaluated. Data obtained from this study will help determine the efficacy of allogeneic HSCT in the treatment of pediatric sarcomas and add to the small body of literature utilizing haploidentical HSCT to treat acute leukemia in pediatric patients. This study will also further elucidate the role of NK cells in mediating a graft vs. tumor effect in allogeneic HSCT. The main benefit to society is that this study will explore a novel therapy for children with highly refractory cancer who are felt to be incurable with conventional approaches. If feasibility is demonstrated, and there is evidence of anti-tumor activity, then this will open up a new area of clinical research to better define the efficacy of this approach for specific childhood malignancies.

Study Overview

• Status: Terminated
• Conditions: Leukemia; Solid Tumors
• Intervention / Treatment: Device: Clinimacs Cell Separation System; Drug: conditioning chemotherapy; Other: DLI

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53972
      • Kenneth DeSantes., MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Solid tumors that have failed auto transplant or are ineligible to receive auto transplant
• Relapsed AML in 1st relapse or 2nd or 3rd CR
• Relapsed ALL if they fail to attain an initial remission or if they relapse within 1 year following the discontinuation of chemotherapy.
• Greater than or equal to 6 months and <26 years old
• Suitable haploidentical donor available

Exclusion Criteria:

• Leukemia with >25% blasts in bone marrow at the time of admission to the HSCT unit.
• Serum bilirubin >3 mg/dl
• GFR <40 ml/min/1.73 mw
• Cardiac left ventricular ejection fraction <40%
• HIV+
• Pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 1; patients will undergo a standard pre-transplant evaluation, but will also have blood drawn to evaluate their HLA class I killer immunoglobulin-like receptor (KIR) ligand typing. Parents will undergo KIR genotyping and phenotyping, and a donor will be selected based on which parent shows the greatest degree of KIR receptor-ligand mismatching. Once the donor has been selected he/she will undergo a peripheral blood stem cell (PBSC) collection utilizing G-CSF and GM-CSF for stem cell mobilization. The PBSC collection will be performed utilizing standard procedures. The PBSC will then be processed in the UW BMT Laboratory in order to deplete the graft of T cells. This will be accomplished using the CliniMACS cell separation system. T cell depletion is a standard procedure for patients receiving haploidentical stem cell grafts. The resulting stem cell product will be analyzed for T cell, stem cell and NK cell content.

Device: Clinimacs Cell Separation System; Depletion of T-cells; Drug: conditioning chemotherapy; Methylprednisolone, Equine ATG, Cyclosporine, Fludarabine, Melphalan, Thiotepa and Rituximab.; Other: DLI; NK Cell selected DLI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grade III or IV GVHD	Skin Grade III: Stage 0-4 GVHD, where 0 is no rash and 4 is generalized erythroderma with bullous formation and/or with desquamation Grade IV: Stage 4 GVHD, generalized erythroderma with bullous formation and/or with desquamation GI (diarrhea) Grade III: Stage 2-4 GVHD, where 2 is > 1000 mL/day but ≤ 1500 mL/day or 556-833 mL/m2, and 4 is severe abdominal pain +/- ileus or stool with frank blood or melena Grade IV: Stage 0-4 GVHD, where 0 is < 500 mL/day or 280 mL/m2, and 4 is severe abdominal pain +/- ileus or stool with frank blood or melena Overall: Grade III: Grade III Skin and/or GI as well as bilirubin 3.1-15 mg/dl Grade IV: Grade IV Skin and/or GI as well as bilirubin > 15 mg/dl	Day 100
Engraftment Failure	Utilize non-myeloablative conditioning regimen in the haploidentical transplant setting. Primary engraftment failure: failure to achieve ANC of ≥500/uL prior to day +28 Late engraftment failure: Initial engraftment achieved with ANC ≥500/uL by day +28 followed by loss of graft Autologous Cells Infused: achieved hematologic recovery following infusions of autologous stem cells Second Haploidentical Transplant: re-transplantation utilizing an alternative haploidentical donor	28 days
Number of Days Until Engraftment Criteria Were Met	Utilize non-myeloablative conditioning regimen in the haploidentical transplant setting. Engraftment is defined as achieving an absolute neutrophil count ≥ 500 by 28 days post-transplant; platelets and red blood cells will also be measured up to 28 days: Neutrophils: ≥500/uL for 3 days; Platelets: ≥20 K/uL for 3 days without transfusion; Red blood cells: the date of the last RBC transfusion after achieving transfusion independence Results are reported as number of days until engraftment criteria was met, per neutrophil, platelet and red blood cell measurements, above.	28 days
Mortality Rate	Mortality rate at 100 days post-transplant.	100 days post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NK Expression Levels	Natural Killer (NK) cell expression levels will be explored. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12.	Up to 12 months
Association Between Parental KIR Genotypes and NK Cell Cytotoxicities	NK cells express killer-cell immunoglobulin-like receptors (KIR) and have cytotoxic activity. The association between NK cell cytotoxicity over time and KIR genotypes will be examined. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12.	Day 60
Analysis of NK Cell KIR Expression Over Time	NK cell KIR expression over time will be examined. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12.	Up to 12 months

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: Miltenyi Biomedicine GmbH
• Investigators: Principal Investigator: Kenneth DeSantes, M.D., University of Wisconsin, Madison

Publications and helpful links

Helpful Links

• University of Wisconsin Carbone Cancer Center

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: December 19, 2007
• First Submitted That Met QC Criteria: December 27, 2007
• First Posted (Estimate): December 28, 2007

Study Record Updates

• Last Update Posted (Actual): December 9, 2019
• Last Update Submitted That Met QC Criteria: November 19, 2019
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Recurrent or Refractory Leukemia or Solid Tumors in Pediatrics
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia
• Other Study ID Numbers: BMT06407; A536700 (Other Identifier: UW Madison); SMPH\PEDIATRICS\PEDIATRICS (Other Identifier: UW Madison); H-2006-0297 (Other Identifier: UW IRB); 2012-0661 (Other Identifier: UW IRB); NCI-2011-00687 (Registry Identifier: NCI Trial ID)