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: May 19, 2015
Last verified: May 2015
  Purpose

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.


Condition Intervention Phase
Acute Myeloid Leukemia
Acute Lymphocytic Leukemia
Myelodysplasia
Chronic Myeloid Leukemia
Histiocytosis
Drug: Chemotherapy and antibodies
Device: Miltenyi Biotec CliniMACS
Procedure: Allogeneic stem cell transplantation
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: HLA-Nonidentical Stem Cell and Natural Killer Cell Transplantation for Children Less the Two Years of Age With Hematologic Malignancies

Resource links provided by NLM:


Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:
  • 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 non-TBI based preparative regimen and T-lymphocyte depleted graft with a subsequent infusion of donor NK cells will be reported.

    The estimates along with their 95% upper confidence bounds based on exact Binomial calculation will be reported. However, if there are censored observations, then Kaplan-Meier estimates along with its standard errors will be reported.



Secondary Outcome Measures:
  • 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.

  • The factors that affect the one-year survival. [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: No ]
    The impact on survival by factors will be evaluated using logistic regression and Cox's proportional hazard model if there is censoring.

  • 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 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.

  • 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 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.


Enrollment: 40
Study Start Date: May 2004
Estimated Study Completion Date: June 2016
Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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

Detailed Description:

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.
  Eligibility

Ages Eligible for Study:   up to 24 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00145626

Locations
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Sponsors and Collaborators
St. Jude Children's Research Hospital
Assisi Foundation
Investigators
Principal Investigator: Wing H. Leung, M.D., PhD St. Jude Children's Research Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00145626     History of Changes
Other Study ID Numbers: INFT2, NCI-2011-03671
Study First Received: September 1, 2005
Last Updated: May 19, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by St. Jude Children's Research Hospital:
Stem cell transplantation
Stem cell transplant
Haploidentical transplant

Additional relevant MeSH terms:
Histiocytosis
Leukemia
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Myeloproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Precancerous Conditions
Cyclophosphamide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on May 29, 2015