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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00145626
• Other study ID #: INFT2
• Secondary ID: NCI-2011-03671
• Status: Active, not recruiting
• Phase: Phase 2
• First received: September 1, 2005
• Last updated: January 20, 2016
• Start date: May 2004
• Est. completion date: June 2016

Study information

• Verified date: January 2016
• Source: St. Jude Children's Research Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 40
• Est. completion date: June 2016
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 24 Months

Eligibility

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

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lymphocytic Leukemia
• Acute Myeloid Leukemia
• Chronic Myeloid Leukemia
• Histiocytosis
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplasia
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia

Intervention

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.

Device:
• Miltenyi Biotec CliniMACS
Stem cell selection device

Procedure:
• Allogeneic stem cell transplantation
Allogeneic natural killer (NK)cell infusion

Locations

Country	Name	City	State
United States	St. Jude Children's Research Hospital	Memphis	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
St. Jude Children's Research Hospital	Assisi Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	One-year Survival	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.	One year after transplant	Yes
Secondary	Number of Transplant-Related Adverse Outcomes: Regimen-Related Mortality	The cumulative incidences of regimen-related mortality will be estimated using method of Kalbfleisch and Prentice.	100 days post-transplantation	Yes
Secondary	Number of Transplant-Related Adverse Outcomes: Engraftment Failure	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.	100 days post-transplantation	Yes
Secondary	Number of Transplant-Related Adverse Outcomes: Fatal Acute Graft-Versus Host Disease (GVHD)	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.	100 days post-transplantation	Yes
Secondary	Number of Transplant-related Adverse Outcomes	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.	5 Years	No
Secondary	Number of Incidences of Chronic GVHD.	The estimate of the incidence of chronic GVHD will be obtained using Binomial distribution.	Up to 5 years after transplant	Yes
Secondary	Factors Affecting One-year Survival: Median Age of Donor at HSCT	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).	Up to one year after transplant	No
Secondary	Factors Affecting One-year Survival: Median Dose of CD34	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).	Up to one year after transplant	No
Secondary	Factors Affecting One-year Survival: Median Dose of NK Cells	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).	Up to one year after transplant	No
Secondary	Factors Affecting One-year Survival: Disease Status at HSCT	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).	Up to one year after transplant	No
Secondary	Factors Affecting One-year Survival: Donor Type	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).	Up to one year after transplant	No
Secondary	Factors Affecting One-year Survival: Match N/6 HLA Loci	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).	Up to one year after transplant	No
Secondary	Factors Affecting One-year Survival: Minimal Residual Disease (MRD)	Detection of leukemia blasts in bone marrow by flow cytometry	Up to one year after transplant	No
Secondary	The Kinetics of Lymphohematopoietic Reconstitution.	The lymphohematopoietic reconstitution will be assessed in a longitudinal manner and analyzed accordingly.	Up to 5 years after transplant	No
Secondary	The Incidence of and Risk Factors for Organ Dysfunction.	The organ dysfunction will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.	Up to 5 Years after transplant	No
Secondary	The Incidence of and Risk Factors for Long-term Neurocognitive Deficit.	The long-term neurocognitive deficit will be summarized using summary statistics and assessed in a longitudinal manner and analyzed accordingly.	Up to 5 Years after transplant	No
Secondary	The Frequency of and Clinical Relevance of Minimal Residual Disease (MRD) Before and After Transplantation	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.	Baseline and up to 5 years after transplant	No

External Links

•   Clinical Trials Open at St. Jude
•   St. Jude Children's Research Hospital