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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

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ClinicalTrials.gov Identifier: NCT02199041
Recruitment Status : Terminated (The study was halted early due to slow accrual.)
First Posted : July 24, 2014
Results First Posted : February 7, 2018
Last Update Posted : February 7, 2018
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Tracking Information
First Submitted Date  ICMJE July 9, 2014
First Posted Date  ICMJE July 24, 2014
Results First Submitted Date  ICMJE August 1, 2017
Results First Posted Date  ICMJE February 7, 2018
Last Update Posted Date February 7, 2018
Actual Study Start Date  ICMJE July 11, 2014
Actual Primary Completion Date May 23, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 10, 2018)
Number of Participants With Neutrophil Engraftment [ Time Frame: Until day 42 post-transplant ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 21, 2014)
Rate of engraftment [ Time Frame: Until day 42 post-transplant ]
The rate of engraftment by day +42 will be approximated using a Binomial distribution. Neutrophil engraftment is defined as absolute neutrophil count (ANC) recovery of ≥ 0.5 x 109/L (500/mm3) for three consecutive laboratory values obtained on different days. Date of engraftment is the date of the first of the three consecutive laboratory values.
Change History Complete list of historical versions of study NCT02199041 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 10, 2018)
  • Number of Participants With Malignant Relapse [ Time Frame: One year after transplantation ]
    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
  • Number of Participants With Event-free Survival (EFS) [ Time Frame: One year after transplantation ]
    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.
  • Number of Participants With Overall Survival (OS) [ Time Frame: One year after transplantation ]
    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.
  • 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 ]
    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.
  • 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 ]
    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.
  • Number of Participants With Secondary Graft Failure [ Time Frame: 100 days after transplantation ]
    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.
  • Number of Participants With Transplant-related Mortality (TRM) [ Time Frame: 100 days after transplantation ]
    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.
  • Number of Participants With Transplant-related Morbidity [ Time Frame: 100 days after transplantation ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 21, 2014)
  • Incidence of malignant relapse [ Time Frame: One year after transplantation ]
    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 SAS macro (bmacro252-Excel2007\cin).
  • Event-free survival [ Time Frame: One year after transplantation ]
    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.
  • Overall survival [ Time Frame: One year after transplantation ]
    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 HCT and all participants surviving after 1 year post-transplant will be considered as censored.
  • Incidence by severity of acute and chronic graft versus host disease (GVHD) [ Time Frame: 100 days after transplantation ]
    The cumulative incidence of acute and chronic GVHD will be estimated using Kalbfleisch-Prentice method. Death is the competing risk event. The SAS macro (bmacro252-Excel2007\cin) available in the Department of Biostatistics at St. Jude will be used for such analysis. The severity of acute GVHD and chronic GVHD will be described. GVHD grade and stage (acute and chronic) will be determined by pre-defined criteria per protocol.
  • Incidence of transplant-related mortality (TRM) [ Time Frame: 100 days after transplantation ]
    The cumulative incidence of TRM will be estimated using the Kalbfleisch-Prentice method. Deaths before day 100 because of other reasons are the competing risk events.
  • Incidence of transplant-related morbidity [ Time Frame: 100 days after transplantation ]
    The cumulative incidence of transplant-related morbidity will be estimated using the Kalbfleisch-Prentice method. Morbidity before day 100 because of other reasons are the competing risk events.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief Summary

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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hematological Malignancies
Intervention  ICMJE
  • Drug: Cyclophosphamide
    Given by intravenous infusion as part of the preparative regimen.
    Other Name: Cytoxan
  • Drug: Thiotepa
    Given by intravenous infusion as part of the preparative regimen.
    Other Names:
    • Thioplex(R)
    • TESPA
    • TSPA
  • Drug: Fludarabine
    Given by intravenous infusion as part of the preparative regimen.
    Other Name: Fludara
  • Drug: Melphalan
    Given by intravenous infusion as part of the preparative regimen.
    Other Names:
    • L-phenylalanine mustard
    • Phenylalanine mustard
    • L-PAM
    • L-sarcolysin
    • Alkeran
  • Drug: Mesna
    Mesna is generally dosed at approximately 25% of the cyclophosphamide dose. It is generally given intravenously prior to and again at 3, 6 and 9 hours following each dose of cyclophosphamide.
    Other Name: Mesnex
  • Biological: G-CSF
    Given either by intravenous infusion or subcutaneously daily until absolute neutrophil count (ANC) >2000 for 3 consecutive days.
    Other Names:
    • Granulocyte colony-stimulating factor (C-CSF)
    • Filgrastim
    • Neupogen(R)
  • Drug: Mycophenolate mofetil
    Given either orally or by intravenous infusion as part of the post-transplantation immunosuppression.
    Other Names:
    • MMF
    • CellCept(R)
  • Drug: Tacrolimus
    Given either orally or by intravenous infusion as part of the post-transplantation immunosuppression.
    Other Names:
    • FK506
    • Prograf(R)
    • Protopic(R)
  • Drug: Methylprednisolone
    Given either intravenously or orally, if needed to treat graft-versus-host-disease (GVHD).
    Other Names:
    • Medrol(R)
    • Solu-Medrol
  • Radiation: Total lymphoid irradiation
    TLI will be administered in divided fractions given at a minimum of 6 hours apart.
    Other Name: TLI
  • Biological: Lymphocyte infusions
    Donors will undergo haploidentical mobilization with G-CSF. Cells will be collected by leukapheresis over two days, then processed using the investigational CliniMACS device and CD34 Microbead reagent as directed by the manufacturer.
    Other Names:
    • Donor lymphocyte infusions
    • DLI
  • Device: CliniMACS
    The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.
    Other Name: Cell Selection System
Study Arms  ICMJE Experimental: Treatment

Interventions: 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.

Interventions:
  • Drug: Cyclophosphamide
  • Drug: Thiotepa
  • Drug: Fludarabine
  • Drug: Melphalan
  • Drug: Mesna
  • Biological: G-CSF
  • Drug: Mycophenolate mofetil
  • Drug: Tacrolimus
  • Drug: Methylprednisolone
  • Radiation: Total lymphoid irradiation
  • Biological: Lymphocyte infusions
  • Device: CliniMACS
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 26, 2017)
24
Original Estimated Enrollment  ICMJE
 (submitted: July 21, 2014)
49
Actual Study Completion Date  ICMJE May 23, 2017
Actual Primary Completion Date May 23, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02199041
Other Study ID Numbers  ICMJE HAPCORD
NCI-2014-00526 ( Registry Identifier: NCI Clinical Trial Registration Program )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Pediatric Postmarket Surveillance of a Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party St. Jude Children's Research Hospital
Study Sponsor  ICMJE St. Jude Children's Research Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Brandon Triplett, MD St. Jude Children's Research Hospital
PRS Account St. Jude Children's Research Hospital
Verification Date August 2017

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