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

Phase 1

Completed

Conditions: Hematologic Malignancies

Interventions: 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)

Registration Number: NCT00429416

Lead Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
LLME to Decrease GVHD Following HSC T	Mesna	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).
LLME to Decrease GVHD Following HSC T	L-leucyl-L-leucine Methyl Ester (LLME)	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).
LLME to Decrease GVHD Following HSC T	Hematopoietic stem cell transplantation (HSCT)	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).
LLME to Decrease GVHD Following HSC T	Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF)	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).
LLME to Decrease GVHD Following HSC T	Cyclophosphamide	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).
LLME to Decrease GVHD Following HSC T	Fludarabine	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).
LLME to Decrease GVHD Following HSC T	Cytarabine	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).
LLME to Decrease GVHD Following HSC T	Tacrolimus	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).

Primary Outcome Measures

Name	Time	Method
Safety of CD34+ Stem Cell Infusions Followed by LLME as Measured by 100-Day Mortality	Through 100 days post-transplant or death	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.

Secondary Outcome Measures

Name	Time	Method
Number of Patients Who Achieve a CD4 Count > 200/Micro-liters	Through 60 Days Post Transplant	Determine the number of patients who achieve a CD4 count \> 200/micro-liters by 60 days after transplant.
Rate of Engraftment of Non-Myeloablative Transplants	Through 30 days post-transplant	Determine the engraftment rate of non-myeloablative transplants using CD34+ stem cells and LLME treated CD34- products.
Incidence of Grade II-IV Acute Graft-Versus-Host-Disease (GVHD)	Through 24 months post-treatment	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.
Rate of Serious Infectious Complications	Through 3 months post-transplant	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.