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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Thomas Jefferson University
ClinicalTrials.gov Identifier:
NCT00429416
First received: January 29, 2007
Last updated: December 17, 2013
Last verified: December 2013
  Purpose

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


Condition Intervention Phase
Hematologic Malignancies
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)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Llme Treated Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematological Malignancies

Resource links provided by NLM:


Further study details as provided by Thomas Jefferson University:

Primary Outcome Measures:
  • Safety of CD34+ Stem Cell Infusions Followed by LLME as Measured by 100-Day Mortality [ Time Frame: Through 100 days post-transplant or death ] [ Designated as safety issue: Yes ]

    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:
  • Rate of Engraftment of Non-Myeloablative Transplants [ Time Frame: Through 30 days post-transplant ] [ Designated as safety issue: No ]
    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) [ Time Frame: Through 24 months post-treatment ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Through 3 months post-transplant ] [ Designated as safety issue: Yes ]

    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.


  • Number of Patients Who Achieve a CD4 Count > 200/Micro-liters [ Time Frame: Through 60 Days Post Transplant ] [ Designated as safety issue: No ]
    Determine the number of patients who achieve a CD4 count > 200/micro-liters by 60 days after transplant.


Enrollment: 14
Study Start Date: March 2004
Study Completion Date: May 2009
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LLME to Decrease GVHD Following HSC T
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)
Infusion of L-leucyl-L-leucine methyl ester (LLME) treated donor white blood cells
Other Name: LLME
Drug: Fludarabine
Fludarabine 30 mg/m2 prior to HSCT infusion
Other Names:
  • fludarabine phosphate
  • Fludara
Drug: Cytarabine
Cytarabine 2gm/m2 prior to HSCT infusion
Other Names:
  • Cytarabine
  • cytosine arabinoside
  • Ara-C
  • Arabinofuranosyl Cytidine
Drug: Cyclophosphamide
Cyclophosphamide 1gm/m2 prior to HSCT infusion
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • cytophosphane
Drug: Tacrolimus
Tacrolimus given before and after HSCT infusion
Other Names:
  • FK-506
  • Fujimycin
Drug: Mesna
Mesna 1gm/m2/day given prior to HSCT infusion.
Other Names:
  • Uromitexan
  • Mesnex
Biological: Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF)
GM-CSF given post HSCT infusion
Other Name: GM-CSF
Procedure: Hematopoietic stem cell transplantation (HSCT)
CD34 selected allogeneic stem cell infusion with 5x104/kg untreated T cells
Other Name: HSCT

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00429416

Locations
United States, Pennsylvania
Thomas Jefferson University`
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Thomas Jefferson University
Investigators
Principal Investigator: John Wagner, MD Thomas Jefferson University
  More Information

Additional Information:
No publications provided

Responsible Party: Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT00429416     History of Changes
Other Study ID Numbers: 04U.115, 2003-68
Study First Received: January 29, 2007
Results First Received: July 19, 2013
Last Updated: December 17, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Thomas Jefferson University:
Hematologic Malignancies
GVHD
Graft-Versus-Host-Disease
LLME
CD34+ stem cell infusions
CD34- fraction
Cyclosporine
Mycophenolate Mofetil
HSCT
Hematopoietic stem cell transplantation

Additional relevant MeSH terms:
Graft vs Host Disease
Neoplasms
Immune System Diseases
Cyclophosphamide
Cytarabine
Fludarabine
Fludarabine phosphate
Tacrolimus
Alkylating Agents
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Antiviral Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014