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Combined T Cell Depleted Haploidentical Peripheral Blood Stem Cell and Unrelated Umbilical Cord Blood Transplantation in Patients With Hematologic Malignancies Using a Total Lymphoid Irradiation Based Preparative Regimen

NCT02199041

Description:

In this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT), who do not have a suitable human leukocyte antigen (HLA)-matched related/sibling donor (MSD), matched unrelated donor (MURD) or killer-immunoglobulin receptors (KIR) ligand mismatched haploidentical donor identified, will receive a combined T cell depleted (TCD) haploidentical peripheral blood stem cell (PBSC) and unrelated umbilical cord blood transplantation (UCBT) using a total lymphoid irradiation (TLI) based preparative regimen. Primary objective: - To estimate the incidence of donor derived neutrophil engraftment by day +42 post-transplant for participants with high-risk hematologic malignancies undergoing a total lymphoid irradiation (TLI)-based hematopoietic cell transplantation (HCT) using a T cell depleted (TCI) haploidentical donor peripheral blood stem cell (PBSC) donor combined with an unrelated umbilical cord blood (UCB) donor. Secondary objectives: - Estimate the incidence of malignant relapse, event-free survival (EFS), and overall survival (OS) at one-year post-transplantation. - Estimate the incidence and severity of acute and chronic graft versus host disease (GVHD) in the first 100 days after transplantation. - Estimate the incidence of secondary graft failure transplant related mortality (TRM) and transplant related morbidity in the first 100 days after HCT.

Related Conditions:
  • Acute Biphenotypic Leukemia
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
  • Hodgkin Lymphoma
  • Juvenile Myelomonocytic Leukemia
  • Mature T-Cell and NK-Cell Lymphoma/Leukemia
  • Myelodysplastic Syndromes
  • Non-Hodgkin Lymphoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combined T Cell Depleted Haploidentical Peripheral Blood Stem Cell and Unrelated Umbilical Cord Blood Transplantation in Patients With Hematologic Malignancies Using a Total Lymphoid Irradiation Based Preparative Regimen
  • Official Title: Combined T Cell Depleted Haploidentical Peripheral Blood Stem Cell and Unrelated Umbilical Cord Blood Transplantation in Patients With Hematologic Malignancies Using a Total Lymphoid Irradiation Based Preparative Regimen

Clinical Trial IDs

  • ORG STUDY ID: HAPCORD
  • SECONDARY ID: NCI-2014-00526
  • NCT ID: NCT02199041

Conditions

  • Hematological Malignancies

Interventions

DrugSynonymsArms
CyclophosphamideCytoxanTreatment
ThiotepaThioplex(R), TESPA, TSPATreatment
FludarabineFludaraTreatment
MelphalanL-phenylalanine mustard, Phenylalanine mustard, L-PAM, L-sarcolysin, AlkeranTreatment
MesnaMesnexTreatment
G-CSFGranulocyte colony-stimulating factor (C-CSF), Filgrastim, Neupogen(R)Treatment
Mycophenolate mofetilMMF, CellCept(R)Treatment
TacrolimusFK506, Prograf(R), Protopic(R)Treatment
MethylprednisoloneMedrol(R), Solu-MedrolTreatment
Lymphocyte infusionsDonor lymphocyte infusions, DLITreatment

Purpose

In this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT), who do not have a suitable human leukocyte antigen (HLA)-matched related/sibling donor (MSD), matched unrelated donor (MURD) or killer-immunoglobulin receptors (KIR) ligand mismatched haploidentical donor identified, will receive a combined T cell depleted (TCD) haploidentical peripheral blood stem cell (PBSC) and unrelated umbilical cord blood transplantation (UCBT) using a total lymphoid irradiation (TLI) based preparative regimen. Primary objective: - To estimate the incidence of donor derived neutrophil engraftment by day +42 post-transplant for participants with high-risk hematologic malignancies undergoing a total lymphoid irradiation (TLI)-based hematopoietic cell transplantation (HCT) using a T cell depleted (TCI) haploidentical donor peripheral blood stem cell (PBSC) donor combined with an unrelated umbilical cord blood (UCB) donor. Secondary objectives: - Estimate the incidence of malignant relapse, event-free survival (EFS), and overall survival (OS) at one-year post-transplantation. - Estimate the incidence and severity of acute and chronic graft versus host disease (GVHD) in the first 100 days after transplantation. - Estimate the incidence of secondary graft failure transplant related mortality (TRM) and transplant related morbidity in the first 100 days after HCT.

Detailed Description

      Prior to stem cell infusion, participants will receive a preparative regimen of total
      lymphoid irradiation (TLI), fludarabine, cyclophosphamide, melphalan, and thiotepa to prepare
      their bone marrow. Thereafter, they will receive a hematopoietic cell graft from a
      haploidentical donor and an unrelated umbilical cord blood donor. Post-transplantation
      immunosuppressive treatment will include tacrolimus and mycophenolate mofetil.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalInterventions: cyclophosphamide, thiotepa, fludarabine, melphalan, mesna, granulocyte colony-stimulating factor (G-CSF), mycophenolate mofetil, tacrolimus, methylprednisolone, total lymphoid irradiation, and lymphocyte infusions. Cells for infusion are prepared using the CliniMACS System.
  • Cyclophosphamide
  • Thiotepa
  • Fludarabine
  • Melphalan
  • Mesna
  • Mycophenolate mofetil
  • Tacrolimus
  • Methylprednisolone

Eligibility Criteria

        Inclusion Criteria-Transplant Recipient:

          -  Age less than or equal to 21 years old.

          -  Does not have a suitable matched related/sibling donor (MSD) or volunteer matched
             unrelated donor (MUD) available in the necessary time for stem cell donation.

          -  Has a suitable partially human leukocyte antigen (HLA)-matched (≥ 3 of 6) family
             member donor.

          -  Has a partially HLA-matched single umbilical cord blood (UCB) unit (≥ 4 of 6) with
             adequate cell dose. UCB units must fulfill eligibility as outlined in 21 CFR 1271 and
             agency guidance.

          -  High-risk hematologic malignancy.

               -  High risk acute lymphocytic leukemia (ALL) in complete remission-1 (CR)1.
                  [Examples include, but not limited to t(9;22), hypodiploid,, M2 or greater marrow
                  at the end of induction, infants with mixed lineage leukemia (MLL) fusion or
                  t(4;11)].

               -  ALL in High risk CR2. [Examples include but not limited to t(9;22), bone marrow
                  (BM) relapse <36 mo CR1, T-ALL, very early (< 6mo CR1) isolated central nervous
                  system (CNS) relapse.]

               -  ALL in CR3 or subsequent.

               -  Acute myeloid leukemia (AML) in high risk CR1. [Examples include but not limited
                  to preceding MDS, 5q-, -5, -7, FAB M6, FAB M7 not t(1;22), minimal residual
                  disease (MRD) ≥ 5% on day 22 (AML08), M3 marrow after induction 1, M2 marrow
                  after two cycles of induction, FLT3-ITD.]

               -  AML in CR2 or subsequent.

               -  Therapy related AML, with prior malignancy in CR > 12mo

               -  Myelodysplastic syndrome (MDS), primary or secondary

               -  Natural killer (NK) cell, biphenotypic, or undifferentiated leukemia in CR1 or
                  subsequent.

               -  Chronic myeloid leukemia (CML) in accelerated phase, or in chronic phase with
                  persistent molecular positivity or intolerance to tyrosine kinase inhibitor.

               -  Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous
                  hematopoietic cell transplantation (HCT), or unable to mobilize stem cells for
                  autologous HCT.

               -  Non-Hodgkin lymphoma in CR2 or subsequent.

               -  Juvenile myelomonocytic leukemia (JMML).

               -  Refractory hematologic malignancies [ALL, AML, chronic myeloid leukemia (CML) in
                  blast crisis, Hodgkin or non-Hodgkin lymphoma] due to chemoresistant relapse or
                  primary induction failure.

               -  All patients with evidence of CNS leukemia must be treated and be in CNS CR to be
                  eligible for study.

          -  Patient must fulfill pre-transplant evaluation:

               -  Cardiac Function: Left ventricular ejection fraction (LVEF) ≥ 40% or shortening
                  fraction (SF) ≥ 25%.

               -  Creatinine clearance (CrCL) or glomerular filtration rate (GFR) ≥ 50
                  ml/min/1.73m2.

               -  Forced vital capacity (FVC) ≥ 50% of predicted value or pulse oximetry (Pox) ≥
                  92% on room air.

               -  Karnofsky or Lansky performance score ≥ 50.

               -  Bilirubin ≤ 3 times the upper limit of normal for age.

               -  Alanine aminotransferase (ALT) ≤ 5x the upper limit of normal for age.

               -  Aspartate aminotransferase (AST) ≤ 5x the upper limit of normal for age.

        Exclusion Criteria - Transplant Recipient:

          -  Patient has a suitable MSD, volunteer matched unrelated donor (MURD), or
             killer-immunoglobulin receptors (KIR) mismatched haploidentical donor available in the
             necessary time for stem cell donation.

          -  Patient has any other active malignancy other than the one for which HCT is indicated.

          -  Patient is pregnant as confirmed by positive serum or urine pregnancy test within 14
             days prior to enrollment.

          -  Patient is breast feeding.

          -  Patient has Down Syndrome.

          -  Patient has a current uncontrolled bacterial, fungal, or viral infection per the
             judgment of the principal investigator.

        Inclusion criteria - haploidentical donor

          -  At least single haplotype matched (≥ 3 of 6) family member

          -  At least 18 years of age.

          -  Human immunodeficiency virus (HIV) negative.

          -  Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days
             prior to enrollment (if female).

          -  Not breast feeding.

          -  Regarding eligibility, is identified as either:

               -  Completed the process of donor eligibility determination as outlined in 21 CFR
                  1271 and agency guidance; OR

               -  Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of
                  urgent medical need completed by the principal investigator or physician
                  sub-investigator per 21 CFR 1271.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants With Neutrophil Engraftment
Time Frame:Until day 42 post-transplant
Safety Issue:
Description:Neutrophil engraftment is defined as absolute neutrophil count (ANC) recovery of ≥ 0.5 x 10^9/L (500/mm^3) for three consecutive laboratory values obtained on different days (derived from either donor). Date of engraftment is the date of the first of the three consecutive laboratory values. The number of patients engrafted by day +42 post-transplant is provided.

Secondary Outcome Measures

Measure:Number of Participants With Malignant Relapse
Time Frame:One year after transplantation
Safety Issue:
Description:Relapse was evaluated using standard World Health Organization (WHO) criteria for each disease. The estimate of cumulative incidence of relapse will be estimated using Kalbfleisch-Prentice method. Relapse defined as the recurrence of original disease. Death is the competing risk event. The analysis will be implemented using Statistical Analysis System (SAS) macro (bmacro252-Excel2007\cin). Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who experienced malignant relapse is provided
Measure:Number of Participants With Event-free Survival (EFS)
Time Frame:One year after transplantation
Safety Issue:
Description:The Kaplan-Meier estimate of EFS with relapse, death due to any cause and graft failure as events along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\kme) available in the Department of Biostatistics at St. Jude, where EFS = min (date of last follow-up, date of relapse, date of graft failure, date of death due to any cause) - date of transplant, and all participants surviving at the time of analysis without events will be censored. The number of participants who did not experience any of these events through one year post-transplant is given. Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who did not experience any events defined above is provided.
Measure:Number of Participants With Overall Survival (OS)
Time Frame:One year after transplantation
Safety Issue:
Description:The Kaplan-Meier estimate of OS with relapse, death due to any cause and graft failure as events along with their standard errors will be calculated using the SAS macro (bmacro251-Excel2007\kme) available in the Department of Biostatistics at St. Jude, where OS = min (date of last follow-up, date of death) - date of hematopoietic cell transplantation (HCT) and all participants surviving after 1 year post-transplant will be considered as censored. Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who did not die at 1 year post-transplant is provided.
Measure:Number of Participants by Severity With Acute Graft Versus Host Disease (GVHD) in the First 100 Days After HCT
Time Frame:100 days after transplantation
Safety Issue:
Description:Cumulative incidence of acute GVHD was estimated using Kalbfleisch-Prentice method. Death is the competing risk event. SAS macro (bmacro252-Excel2007\cin) available at St. Jude was used for analysis. Severity of GVHD and stage were determined using the Clinical Oncology Group (COG) Stem Cell Committee Consensus Guidelines for establishing organ stage and overall grade of acute GVHD. Participants are graded on a scale from I to IV, with I being mild and IV being severe. Overall Clinical Grade (based on the highest stage obtained): Grade 0: No stage 1-4 of any organ. Grade I: Stage 1-2 skin and no liver or gut involvement. Grade II: Stage 3 skin, or Stage I liver involvement, or Stage 1 gastrointestinal (GI). Grade III: Stage 0-3 skin, with Stage 2-3 liver, or Stage 2-3 GI. Grade IV: Stage 4 skin, liver or GI involvement. Due to early close of study, a small number of patients were enrolled. The number of patients who experienced acute GVHD is provided.
Measure:Number of Participants by Severity With Chronic Graft Versus Host Disease (GVHD) in the First 100 Days After HCT
Time Frame:100 days after transplantation
Safety Issue:
Description:Cumulative incidence of acute and chronic GVHD was estimated using Kalbfleisch-Prentice method. Death is competing risk event. SAS macro (bmacro252-Excel2007\cin) available St. Jude was used for such analysis. Severity of chronic GVHD was evaluated using National Institutes of Health (NIH) Consensus Global Severity Scoring. Mild is considered a better outcome with severe being the worst. Criteria for grading chronic GVHD: Mild: 1-2 organs/sites, maximum organ score of 1, and lung score of 1. Moderate: 3 or more organs/sites and maximum organ score of 1 and lung score of 1, OR at least 1 organ/site and maximum organ score of 2 and lung score of 1. Severe: At least 1 organ/site and maximum organ score of 3 and lung score of 2-3. Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who experienced chronic GVHD is provided.
Measure:Number of Participants With Secondary Graft Failure
Time Frame:100 days after transplantation
Safety Issue:
Description:The cumulative incidence of secondary graft failure will be estimated using the Kalbfleisch-Prentice method. Deaths due to toxicity and relapse before day 100 are the competing events. Secondary graft failure or graft rejection will be defined as no evidence of donor chimerism by umbilical cord blood (UCB) and/or haploidentical donor (<10%), or too few cells to perform adequate chimerism analysis, in research participants with prior neutrophil engraftment. Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who experienced secondary graft failure is provided.
Measure:Number of Participants With Transplant-related Mortality (TRM)
Time Frame:100 days after transplantation
Safety Issue:
Description:TRM is any death in remission and related to protocol therapy. The cumulative incidence of TRM was estimated using the Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the completing events. Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who experienced TRM is provided.
Measure:Number of Participants With Transplant-related Morbidity
Time Frame:100 days after transplantation
Safety Issue:
Description:Any patient who had adverse events listed either as probable or definite in the first 100 days post-transplant are counted as transplant-related morbidity. The cumulative incidence of transplant-related morbidity will be estimated using the Kalbfleisch-Prentice method. Deaths before day 100 are the competing risk events. Due to the early close of the study, a small number of patients were enrolled. Subsequently, the number of patients who experienced at least one-transplant-related morbidity is provided.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:St. Jude Children's Research Hospital

Trial Keywords

  • Cord Blood
  • Haploidentical
  • Reduced Intensity Regimen

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