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

• ClinicalTrials.gov Identifier: NCT00582816
• Recruitment Status: Terminated
• First Posted: December 28, 2007
• Results First Posted: July 19, 2017
• Last Update Posted: December 9, 2019
• Sponsor: University of Wisconsin, Madison
• Collaborator: Miltenyi Biomedicine GmbH
• Information provided by (Responsible Party): University of Wisconsin, Madison

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Leukemia; Solid Tumors	Device: Clinimacs Cell Separation System; Drug: conditioning chemotherapy; Other: DLI	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Reduced Intensity Haploidentical Transplantation With NK Cell Infusion for Pediatric Acute Leukemia and High Risk Solid Tumors, BMT06407
• Study Start Date: August 2008
• Actual Primary Completion Date: August 2015
• Actual Study Completion Date: August 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Grade III or IV GVHD [ Time Frame: Day 100 ]

   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

2. Engraftment Failure [ Time Frame: 28 days ]

   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

3. Number of Days Until Engraftment Criteria Were Met [ Time Frame: 28 days ]

   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.
4. Mortality Rate [ Time Frame: 100 days post-transplant ]
   Mortality rate at 100 days post-transplant.

Secondary Outcome Measures :

1. NK Expression Levels [ Time Frame: Up to 12 months ]
   Natural Killer (NK) cell expression levels will be explored. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12.
2. Association Between Parental KIR Genotypes and NK Cell Cytotoxicities [ Time Frame: Day 60 ]
   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.
3. Analysis of NK Cell KIR Expression Over Time [ Time Frame: Up to 12 months ]
   NK cell KIR expression over time will be examined. Blood samples will be collected at months 1, 2, 3, 6, 9, and 12.

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 25 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Wisconsin

Kenneth DeSantes., MD

Madison, Wisconsin, United States, 53972

Sponsors and Collaborators

University of Wisconsin, Madison

Miltenyi Biomedicine GmbH

Investigators

• Principal Investigator: Kenneth DeSantes, M.D.; University of Wisconsin, Madison

More Information

Additional Information:

University of Wisconsin Carbone Cancer Center 

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT00582816
• Other Study ID Numbers: BMT06407; H-2006-0297 ( Other Identifier: UW IRB ); 2012-0661 ( Other Identifier: UW IRB ); A536700 ( Other Identifier: UW Madison ); SMPH\PEDIATRICS\PEDIATRICS ( Other Identifier: UW Madison ); NCI-2011-00687 ( Registry Identifier: NCI Trial ID )
• First Posted: December 28, 2007
• Results First Posted: July 19, 2017
• Last Update Posted: December 9, 2019
• Last Verified: July 2017

Keywords provided by University of Wisconsin, Madison:

Recurrent or Refractory Leukemia or Solid Tumors in Pediatrics

Additional relevant MeSH terms:

Leukemia; Neoplasms; Neoplasms by Histologic Type