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

Study Overview
=================
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.

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

Conditions
-----------------
Hematological Malignancies

Intervention / Treatment
-----------------
* 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


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>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. | Drug: Cyclophosphamide<br>* Given by intravenous infusion as part of the preparative regimen.<br>* Other names: Cytoxan;Drug: Thiotepa<br>* Given by intravenous infusion as part of the preparative regimen.<br>* Other names: TSPA;Drug: Fludarabine<br>* Given by intravenous infusion as part of the preparative regimen.<br>* Other names: Fludara;Drug: Melphalan<br>* Given by intravenous infusion as part of the preparative regimen.<br>* Other names: Alkeran;Drug: Mesna<br>* 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.<br>* Other names: Mesnex;Biological: G-CSF<br>* Given either by intravenous infusion or subcutaneously daily until absolute neutrophil count (ANC) >2000 for 3 consecutive days.<br>* Other names: Neupogen(R);Drug: Mycophenolate mofetil<br>* Given either orally or by intravenous infusion as part of the post-transplantation immunosuppression.<br>* Other names: CellCept(R);Drug: Tacrolimus<br>* Given either orally or by intravenous infusion as part of the post-transplantation immunosuppression.<br>* Other names: Protopic(R);Drug: Methylprednisolone<br>* Given either intravenously or orally, if needed to treat graft-versus-host-disease (GVHD).<br>* Other names: Solu-Medrol;Radiation: Total lymphoid irradiation<br>* TLI will be administered in divided fractions given at a minimum of 6 hours apart.<br>* Other names: TLI;Biological: Lymphocyte infusions<br>* 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.<br>* Other names: DLI;Device: CliniMACS<br>* 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.<br>* Other names: Cell Selection System;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Neutrophil Engraftment | 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. | Until day 42 post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Malignant Relapse | 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 | One year after transplantation | 
| Number of Participants With Event-free Survival (EFS) | 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. | One year after transplantation | 
| Number of Participants With Overall Survival (OS) | 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. | One year after transplantation | 
| Number of Participants by Severity With Acute Graft Versus Host Disease (GVHD) in the First 100 Days After HCT | 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. | 100 days after transplantation | 
| Number of Participants by Severity With Chronic Graft Versus Host Disease (GVHD) in the First 100 Days After HCT | 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. | 100 days after transplantation | 
| Number of Participants With Secondary Graft Failure | 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. | 100 days after transplantation | 
| Number of Participants With Transplant-related Mortality (TRM) | 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. | 100 days after transplantation | 
| Number of Participants With Transplant-related Morbidity | 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. | 100 days after transplantation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cord Blood, Haploidentical, Reduced Intensity Regimen