HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Assisi Foundation
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT00145626
First received: September 1, 2005
Last updated: January 20, 2016
Last verified: January 2016

September 1, 2005
January 20, 2016
May 2004
March 2015   (final data collection date for primary outcome measure)
One-year Survival [ Time Frame: One year after transplant ] [ Designated as safety issue: Yes ]

The one-year survival of infants with high-risk hematologic malignancies who receive a haploidentical transplant procedure using a total body irradiation (TBI)-excluding conditioning regimen followed by an HLA-nonidentical family donor hematopoietic stem cell (HSC) graft depleted of T cells ex vivo using the CliniMACS CD34+ selection system, with a subsequent infusion of donor NK cells purified ex vivo using the CliniMACS CD3+ depletion and CD56+ enrichment system.

The Kaplan-Meier estimate for one-year survival is reported.

  • To study the outcome of very young subjects treated with stem cell and NK cell transplant one year after treatment
  • To find out what factors affect the outcome of very young subjects treated with stem cell and NK cell transplant
  • To find out the effects (good and bad) of treatment with stem cell and NK cell transplant
  • To study the blood cells in the bone marrow before and after treatment with stem cell and NK cell transplant
Complete list of historical versions of study NCT00145626 on ClinicalTrials.gov Archive Site
  • Number of Transplant-Related Adverse Outcomes: Regimen-Related Mortality [ Time Frame: 100 days post-transplantation ] [ Designated as safety issue: Yes ]
    The cumulative incidences of regimen-related mortality will be estimated using method of Kalbfleisch and Prentice.
  • Number of Transplant-Related Adverse Outcomes: Engraftment Failure [ Time Frame: 100 days post-transplantation ] [ Designated as safety issue: Yes ]
    Engraftment failure is defined as <10% donor cell chimerism at any time point between 28 and 100 days after transplant with no evidence of disease relapse or requiring stem cell boost.
  • Number of Transplant-Related Adverse Outcomes: Fatal Acute Graft-Versus Host Disease (GVHD) [ Time Frame: 100 days post-transplantation ] [ Designated as safety issue: Yes ]
    The cumulative incidence estimate for occurrence of fatal acute GVHD by the end of the first 100 days post-transplant was calculated using method of Kalbfleisch and Prentice.
  • Number of Transplant-related Adverse Outcomes [ Time Frame: 5 Years ] [ Designated as safety issue: No ]

    Adverse outcomes include regimen-related mortality, engraftment failure, and fatal acute graft-versus-host-disease (GVHD).

    The cumulative incidences of regimen-related mortality will be estimated using method of Kalbfleisch and Prentice. The estimate of the incidence of engraftment failure and fatal acute GVHD will be obtained using Binomial distribution. Engraftment failure is defined as <10% donor cell chimerism at any time-point between 28-100 days after transplant with no evidence of disease relapse, or anyone requiring stem cell boost.

  • Number of Incidences of Chronic GVHD. [ Time Frame: Up to 5 years after transplant ] [ Designated as safety issue: Yes ]
    The estimate of the incidence of chronic GVHD will be obtained using Binomial distribution.
  • Factors Affecting One-year Survival: Median Age of Donor at HSCT [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: No ]
    Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
  • Factors Affecting One-year Survival: Median Dose of CD34 [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: No ]
    Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
  • Factors Affecting One-year Survival: Median Dose of NK Cells [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: No ]
    Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
  • Factors Affecting One-year Survival: Disease Status at HSCT [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: No ]
    Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
  • Factors Affecting One-year Survival: Donor Type [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: No ]
    Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
  • Factors Affecting One-year Survival: Match N/6 HLA Loci [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: No ]
    HLA typing determined the degree of match by looking at 6 different HLA loci. The results indicate the number of the 6 loci that matched for each participant. Due to small sample size (n=14) and total number of events (n=7), the analysis to check the various factors that affect the one-year survival was not performed (using logistic and cox model).
  • Factors Affecting One-year Survival: Minimal Residual Disease (MRD) [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: No ]
    Detection of leukemia blasts in bone marrow by flow cytometry
  • The Kinetics of Lymphohematopoietic Reconstitution. [ Time Frame: Up to 5 years after transplant ] [ Designated as safety issue: No ]
    The lymphohematopoietic reconstitution will be assessed in a longitudinal manner and analyzed accordingly.
  • The Incidence of and Risk Factors for Organ Dysfunction. [ Time Frame: Up to 5 Years after transplant ] [ Designated as safety issue: No ]
    The organ dysfunction will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.
  • The Incidence of and Risk Factors for Long-term Neurocognitive Deficit. [ Time Frame: Up to 5 Years after transplant ] [ Designated as safety issue: No ]
    The long-term neurocognitive deficit will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.
  • The Frequency of and Clinical Relevance of Minimal Residual Disease (MRD) Before and After Transplantation [ Time Frame: Baseline and up to 5 years after transplant ] [ Designated as safety issue: No ]
    The presence or absence of MRD before and after the bone marrow transplant (BMT) and its frequency distribution will be obtained for each time point separately. Their effect on overall survival will be evaluated using logistic regression and Cox's proportional hazard model if there is censoring.
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HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies
HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies

Recent studies of conventional chemotherapy for infants with high-risk hematologic malignancies show that the long-term disease-free survival is low. Although blood and marrow stem cell transplantation using an HLA identical sibling has improved the outcome for these children, less than 25% have this donor source available. Another option is haploidentical transplantation using a partially matched family member donor (i.e. parental donor).

Although haploidentical transplantation has proven curative for some patients, this procedure has been hindered by significant complications, primarily regimen-related toxicity including infection and graft versus host disease (GVHD). Building on prior institutional trials, this study will provide patients a haploidentical graft depleted of T lymphocytes using the investigational device, CliniMACS selection system. One week after the transplant procedure, patients will also receive an infusion of additional donor derived white blood cells called Natural Killer (NK) cells in an effort to decrease risks for rejection of the graft, disease relapse, and regimen related toxicity. The primary objective of the study is to evaluate 1 year survival in infants with high risk hematologic malignancies who receive this study treatment.

Secondary objectives for this study include the following:

  • To estimate the incidence of three transplant-related adverse outcomes (i.e., regimen-related mortality, engraftment failure, and fatal acute GVHD) in the first 100 days after transplantation.
  • To estimate the incidence of chronic graft-versus-host disease.
  • To evaluate those factors that affect one-year survival.
  • To assess the kinetics of lymphohematopoietic reconstitution.
  • To assess the frequency and clinical relevance of minimal residual disease (MRD) before and after transplantation.
  • To evaluate the incidence of and risk factors for long-term neurocognitive deficit and organ dysfunction.
Interventional
Phase 2
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Acute Myeloid Leukemia
  • Acute Lymphocytic Leukemia
  • Myelodysplasia
  • Chronic Myeloid Leukemia
  • Histiocytosis
  • Drug: Chemotherapy and antibodies
    Study participants will receive a non-TBI based preparative regimen consisting of Cyclophosphamide, fludarabine, thiotepa, melphalan, and muromonab-CD3 (OKT3) followed by an infusion of a T-lymphocyte depleted haploidentical hematopoietic stem cell graft. Seven days posttransplant, participants will receive an infusion of additional donor derived cells called NK cells.
    Other Names:
    • Cyclophosphamide
    • Fludarabine
    • Thiotepa
    • Melphalan
    • OKT3
  • Device: Miltenyi Biotec CliniMACS
    Stem cell selection device
  • Procedure: Allogeneic stem cell transplantation
    Allogeneic natural killer (NK)cell infusion
    Other Names:
    • Haploidentical stem cell transplantation
    • Allogeneic stem cell transplant
    • Immunotherapy
    • Mismatched family member donor transplant
    • NK cell infusions
Experimental: Study Participants

Participants who meet the eligibility criteria for this study. Donor cells will be obtained using the Miltenyi Biotec CliniMACS device.

Interventions: Chemotherapy and antibodies, allogeneic stem cell transplantation.

Interventions:
  • Drug: Chemotherapy and antibodies
  • Device: Miltenyi Biotec CliniMACS
  • Procedure: Allogeneic stem cell transplantation
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
40
June 2016
March 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

Must have one of the following diagnosis:

  • AML in remission or relapse (e.g., FAB M7 or biphenotypic leukemia)
  • High-risk ALL in first remission (e.g., poor responder to prednisone, Ph+ ALL)
  • ALL beyond first remission
  • Secondary leukemia
  • Primary myelodysplasia (including RAEB, RAEB-T, CMML, JCML, and JMML)
  • Chronic myeloid leukemia
  • Histiocytoses (including multi-system Langerhans' cell histiocytosis and hemophagocytic lymphohistiocytosis

Inclusion criteria Donor research participants

  • HIV negative (date).
  • Hepatitis B surface antigen negative (date).
  • Hepatitis C antibody negative (date).
  • Syphilis negative (date).
  • Donor is equal to or greater than 3 on 6 HLA match (date).
  • Not pregnant (negative pregnancy test).
  • Not lactating.
  • At least 18 years of age.

Exclusion Criteria

  • Patients greater than 24 months of age at the time of transplant.
  • HLA-identical sibling donor is available.
  • Cardiac function: shortening fraction <25%.
  • Pulse oximetry oxygen saturation <92% on room air.
  • Glomerular filtration rate less than 40 ml/min/1.73 m2 (may use Technetium-99 result for GFR).
  • Direct bilirubin > 3 mg/dl.
  • SGPT > 500 U/L.
  • Patients with previous allergy to mouse proteins.
  • Patients with previous allergy to rabbit serum products.
  • Patients with Down's syndrome
Both
up to 24 Months   (Child)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00145626
INFT2, NCI-2011-03671
No
Not Provided
Not Provided
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital
Assisi Foundation
Principal Investigator: Brandon Triplett, MD St. Jude Children's Research Hospital
St. Jude Children's Research Hospital
January 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP