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

NCT00582816 | Terminated Phase 1 Results DMC

• 6 other identifiers: BMT06407H-2006-02972012-0661A536700SMPH\PEDIATRICS\PEDIATRICSNCI-2011-00687
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

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.

Conditions

Leukemia; Solid Tumors

Keywords

Recurrent or Refractory Leukemia or Solid Tumors in Pediatrics

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (3)

• NK Expression Levels

  Up to 12 months

• Association Between Parental KIR Genotypes and NK Cell Cytotoxicities

  Day 60

• Analysis of NK Cell KIR Expression Over Time

  Up to 12 months

Study Arms (1)

1

EXPERIMENTAL

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; Drug: conditioning chemotherapy; Other: DLI

Interventions

Clinimacs Cell Separation System DEVICE

Depletion of T-cells

1

conditioning chemotherapy DRUG

Methylprednisolone, Equine ATG, Cyclosporine, Fludarabine, Melphalan, Thiotepa and Rituximab.

1

DLI OTHER

NK Cell selected DLI

1

Eligibility Criteria

• Age: 6 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• Miltenyi Biomedicine GmbH: collaborator

Study Sites (1)

Kenneth DeSantes., MD

Madison, Wisconsin, 53972, United States

Location

Related Links

• University of Wisconsin Carbone Cancer Center

MeSH Terms

Conditions

Leukemia; Recurrence

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

This study involved a small patient cohort; blood samples were to be collected towards the secondary outcome measures. Unfortunately, participants whose blood samples were collected developed GVHD and the tests became uninterpretable.

Results Point of Contact

• Title: Dr. Ken DeSantes
• Organization: University of Wisconsin Carbone Cancer Center

kbdesantes@pediatrics.wisc.edu

608-263-8563

Study Officials

• Kenneth DeSantes, M.D.

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 19, 2007
• First Posted: December 28, 2007
• Study Start: August 1, 2008
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: December 9, 2019
• Results First Posted: July 19, 2017

Record last verified: 2017-07

Locations

US (1)