Research Study to Determine if an Experimental Agent, LLME Can Decrease the Incidence and Severity of Graft-Versus-Host-Disease (GVHD) Following Blood (Hematopoietic) Stem Cell Transplantation

Study Overview
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Brief Summary
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The purpose of this research study is to determine if an experimental agent, LLME can decrease the incidence and severity of Graft-Versus-Host-Disease (GVHD) following blood (hematopoietic) stem cell transplantation

Detailed Description
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We believe that the risks of allogeneic transplant can be drastically reduced if the following criteria can be met: (1) consistent engraftment, (2) little or no GVHD with the ability to rapidly withdraw immune suppression, (3) rapid recovery of CD4 counts to levels greater than 200 cells/micro liter. Our prior (ongoing) trial attempts to address how LLME treated T cells given as donor lymphocyte infusion (DLI) can address points 2 and 3 above. The current study addresses how treatment of the CD34- fraction of the graft attempts to address points 1 and 2 (and to a lesser extent point 3) above. We believe that if these points can be consistently achieved that the mortality of allogeneic HSCT may be reduced to levels more akin to those of autologous HSCT. We propose to test the hypothesis that LLME-treated T cells will be safe with regard to reducing GVHD or other infusion related toxicities and that their administration as part of the transplant will facilitate engraftment. We believe that this approach will ultimately be an important step in a variety of transplant settings ranging from matched siblings to haplodisparate donors.

Official Title
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A Phase I/II Study of Llme Treated Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematological Malignancies

Conditions
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Hematologic Malignancies

Intervention / Treatment
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* Drug: L-leucyl-L-leucine Methyl Ester (LLME)
* Drug: Fludarabine
* Drug: Cytarabine
* Drug: Cyclophosphamide
* Drug: Tacrolimus
* Drug: Mesna
* Biological: Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF)
* Procedure: Hematopoietic stem cell transplantation (HSCT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be > 18 years of age, with no upper age limit. Patients must have an ECOG performance status of 0 or 1. Any patient with a hematologic malignancy which is unlikely to be cured by conventional treatment is eligible for this study. Patients for whom a disease specific protocol exists will be transplanted on those protocols as discussed in the introduction. Patients who have had prior autografts may be treated on this protocol. Patients must have adequate physical function as measured by the following criteria: Cardiac: Asymptomatic or, if symptomatic, then left ventricular ejection fraction at rest must be >40%. Hepatic: Aspartate transaminase (AST) micro 3x the upper limits of normal and total serum bilirubin < 2.5 mg/dL. Patients with a higher bilirubin from benign conditions such as Gilbert's disease may still be eligible for the study. Renal: Serum creatinine within the normal range or if creatinine outside normal range then creatinine clearance > 60 ml/min/1.73m2. Serum creatinine must be less than or equal to 2.0 mg/dl. Pulmonary: Asymptomatic or, if symptomatic, DLCO (diffusion capacity) > 45% of predicted (corrected for hemoglobin) The patient or guardian(s) must be able to give informed consent to the study. Patient must have a suitable donor who is identical for HLA (human leukocyte antigens) -A, -B, -C, -DR. Single antigen mismatches for HLA-A, -B, -C, -DR are also permitted. Donors obtained through the National Marrow Donor Program (NMDP) will follow NMDP guidelines. Exclusion Criteria: Patients who are eligible for a standard myeloablative transplant and for whom a standard myeloablative transplant is preferable will not be treated on this protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LLME to Decrease GVHD Following HSC T<br>To determine if an experimental agent, LLME, can decrease the incidence and severity of Graft-Versus-Host-Disease (GVHD) following hematopoietic stem cell transplantation (HSCT). | Drug: L-leucyl-L-leucine Methyl Ester (LLME)<br>* Infusion of L-leucyl-L-leucine methyl ester (LLME) treated donor white blood cells<br>* Other names: LLME;Drug: Fludarabine<br>* Fludarabine 30 mg/m2 prior to HSCT infusion<br>* Other names: Fludara;Drug: Cytarabine<br>* Cytarabine 2gm/m2 prior to HSCT infusion<br>* Other names: Arabinofuranosyl Cytidine;Drug: Cyclophosphamide<br>* Cyclophosphamide 1gm/m2 prior to HSCT infusion<br>* Other names: cytophosphane;Drug: Tacrolimus<br>* Tacrolimus given before and after HSCT infusion<br>* Other names: Fujimycin;Drug: Mesna<br>* Mesna 1gm/m2/day given prior to HSCT infusion.<br>* Other names: Mesnex;Biological: Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF)<br>* GM-CSF given post HSCT infusion<br>* Other names: GM-CSF;Procedure: Hematopoietic stem cell transplantation (HSCT)<br>* CD34 selected allogeneic stem cell infusion with 5x104/kg untreated T cells<br>* Other names: HSCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of CD34+ Stem Cell Infusions Followed by LLME as Measured by 100-Day Mortality | Determine the safety of CD34+ stem cell infusions followed by the LLME treated CD34- fraction. This includes monitoring the patients for any side effects associated with the LLME treated cell infusion or any other unexpected adverse events. This regimen will be gauged as to its safety using 100 day mortality as the measured endpoint. Deaths from all causes will be included. | Through 100 days post-transplant or death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Engraftment of Non-Myeloablative Transplants | Determine the engraftment rate of non-myeloablative transplants using CD34+ stem cells and LLME treated CD34- products. | Through 30 days post-transplant | 
| Incidence of Grade II-IV Acute Graft-Versus-Host-Disease (GVHD) | Determine the incidence of grade II-IV acute GVHD after administration of grafts when combined with Cyclosporine/Mycophenolate Mofetil for GVHD prophylaxis. GVHD assessments occur daily as an in patient and at each out patient visit. | Through 24 months post-treatment | 
| Rate of Serious Infectious Complications | Determine the rate of serious infectious complications. A serious infection will be defined as any requiring hospitalization or parenteral therapy. CD4 counts will be measured monthly for the first 3 months after transplant. | Through 3 months post-transplant | 
| Number of Patients Who Achieve a CD4 Count > 200/Micro-liters | Determine the number of patients who achieve a CD4 count > 200/micro-liters by 60 days after transplant. | Through 60 Days Post Transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematologic Malignancies, GVHD, Graft-Versus-Host-Disease, LLME, CD34+ stem cell infusions, CD34- fraction, Cyclosporine, Mycophenolate Mofetil, HSCT, Hematopoietic stem cell transplantation