Bone Marrow Transplantation of Patients in Remission Using Partially Matched Relative Donor

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Thomas Jefferson University
ClinicalTrials.gov Identifier:
NCT01350245
First received: May 4, 2011
Last updated: July 7, 2014
Last verified: July 2014
  Purpose

The primary hypothesis of this research study is that patients in remission undergoing myeloablative haploidentical hematopoietic stem cell transplantation (HSCT) on the Thomas Jefferson University (TJU) 2 Step treatment regimen will have a disease-free survival (DFS) rate at 1 year that is the same or better than the historical DFS of patients with similar diagnoses and ages undergoing matched sibling HSCT. Based on a review of the literature a DFS rate of 50% or better at 1 year would meet the criterion for an effective alternative therapy. A DFS rate of 75% or better would imply superior efficacy of the TJU 2 Step approach over T-replete matched sibling HSCT.


Condition Intervention Phase
Acute Myeloid Leukemia
Myelodysplastic Syndromes
Biphenotypic Leukemia
Acute Lymphocytic Leukemia
Chronic Myeloid Leukemia
Chronic Lymphocytic Leukemia
Plasma Cell Neoplasms
Lymphoma
Hodgkin's Disease
Aplastic Anemia
Radiation: Total Body Irradiation (TBI)
Biological: Donor Lymphocyte Infusion (DLI)
Drug: Cyclophosphamide
Drug: Mycophenolate Mofetil (MMF)
Drug: Tacrolimus
Device: Hematopoietic stem cell transplantation (HSCT)
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematologic Malignancies in Remission From HLA Partially-Matched Related Donors

Resource links provided by NLM:


Further study details as provided by Thomas Jefferson University:

Primary Outcome Measures:
  • Disease-Free Survival (DFS) [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: No ]
    1-year post-transplant disease free survival (DFS), defined as success if a patient is alive and disease free at 1-year post-transplant.


Secondary Outcome Measures:
  • Time to Disease Progression [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: No ]
    Death or relapse will be considered events for this endpoint. The time to disease progression will be evaluated using the Kaplan-Meier survival curves. Median time to disease progression will be estimated with the corresponding confidence intervals.


Estimated Enrollment: 28
Study Start Date: July 2010
Estimated Study Completion Date: July 2015
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TJU 2 Step Regimen
All patients treated on this trial will have hematological malignancies that are in remission at the time of the transplant. Their diseases would be expected to relapse with standard therapy alone.
Radiation: Total Body Irradiation (TBI)
Total body irradiation is given in 8 fractions over 4 days (total dose of 12 Gy).
Biological: Donor Lymphocyte Infusion (DLI)
After TBI, the patients will receive a dose of 2 x 10e8 of their donor's T cells. After this infusion, the patients will have 2 rest days.
Drug: Cyclophosphamide
Cyclophosphamide is administered 2 days after the DLI to help tolerize the donor T cells. It is given at a dose of 60 mg/kg/d for 2 days
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • cytophosphane
Drug: Mycophenolate Mofetil (MMF)
Started the day before the transplant to prevent graft versus host disease (GVHD)
Other Name: CellCept
Drug: Tacrolimus
Started the day before the transplant to prevent graft-versus-host disease (GVHD)
Other Names:
  • FK-506
  • Fujimycin
Device: Hematopoietic stem cell transplantation (HSCT)

One day after the cyclophosphamide is finished, the patients will receive a CD34 selected-donor stem cell product. This is the day of transplant.

The CliniMACS® Plus Instrument will be used for the selection of human CD34+ hematopoietic stem and progenitor cells in human allogeneic hematopoietic stem cell transplantation.

Other Name: CliniMACS

Detailed Description:

The primary rationale for the development of this research study is to find out if the Thomas Jefferson University (TJU) 2 Step approach to stem cell transplant is an effective treatment for patients with blood cancers who require transplant for long-term survival but are without an available matched-sibling donor. Historically, survival rates for patients undergoing half-matched stem cell transplant have been much lower than those observed after matched sibling stem cell transplant. This may be due to the poor-risk disease features of the patients by the time they are referred for hematopoietic stem cell transplantation (HSCT). Survival post half-matched stem cell transplant has also been affected by the requirement to remove or soothe donor T cells resulting in higher rates of infection and relapse. Newer approaches to haploidentical HSCT, such as the TJU 2 Step approach, utilize cyclophosphamide (CY) to tolerize donor lymphocytes instead of removing them completely from the donor product. This has resulted in less infection without concomitant increase in severe graft-versus-host disease (GVHD) and has increased overall survival as compared to older haploidentical treatment approaches due to decreases in regimen-related morbidity.

Because of the historically low overall survival (OS) after haploidentical HSCT, it has become a procedure of last resort with most centers unwilling to consider it unless all other options are exhausted. With the recent development of regimens such as the TJU 2 Step approach which provide safe, alternative platforms for HSCT, it is now feasible, and ethically more acceptable, for patients without matched sibling donors to undergo HSCT prior to being heavily pretreated or developing resistant disease. In this setting, i.e. equivalent regimen safety profiles and more homogenous patient comparison groups, it is possible to more accurately compare antitumor effects between matched sibling donors and haploidentical donors. There is ample evidence in the literature that HLA mismatching causes GVHD. There is not a large body of evidence supporting the notion that HLA mismatching provides superior tumor control translating into greater relapse free survival. As compared to more common types of transplants where donor T cells are given to the recipient, the investigators would surmise that the T cell tolerization associated with the TJU 2 Step approach may decrease the anti-tumor effects of the donor immune system. Conversely, the greater degree of human leukocyte antigen (HLA) mismatch with exploitation of NK effects may mitigate some of the attenuated T cell alloreactivity.

Thus, in the context of comparable regimen-related toxicity, our major aim in this research study is to compare graft versus tumor effects as measured by disease-free survival (DFS) between matched sibling HSCT and the TJU 2 Step haploidentical HSCT. If DFS is similar despite T cell tolerization, than the TJU 2 Step haploidentical approach should be considered an effective alternative therapy for those patients in remission without a matched sibling donor. The widespread benefit of this outcome would be the enfranchisement of segments of the population who are without available matched donors resulting in a delay or a failure to receive this potentially life-saving therapy. If DFS survival after treatment on the TJU 2 Step haploidentical approach is superior to what would be expected after matched sibling HSCT, then one could conclude that haploidentical HSCT confers greater tumor control forming the basis for future studies regarding the potential benefits of utilizing haploidentical donors over matched sibling donors when both types of donors are available.

  Eligibility

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

Inclusion Criteria:

  1. Any patient with a hematologic or oncologic diagnosis without morphological evidence of disease in which allogeneic HSCT is thought to be beneficial.

    • Diagnoses include:

    Acute Myeloid Leukemia Myelodysplastic Syndromes Biphenotypic Leukemia Acute Lymphocytic Leukemia Chronic Myeloid Leukemia Chronic Lymphocytic Leukemia Plasma Cell Neoplasms Lymphoma Hodgkin Disease Aplastic Anemia

  2. Patients must have a related donor who is a two or more allele mismatch at the HLA-A; B; C; DR loci.
  3. Patients must adequate organ function:

    • LVEF of > or = 50%
    • DLCO > or = 50% of predicted corrected for hemoglobin
    • Adequate liver function as defined by a serum bilirubin < or = 1.8, AST or ALT < or = 2.5X upper limit of normal
    • Creatinine clearance of > or = 60 ml/min
  4. Performance status > or = 70% (TJU Karnofsky)
  5. HCT-CI Score < 5 Points
  6. Patients must be willing to use contraception if they have childbearing potential
  7. Able to give informed consent

Exclusion Criteria:

  1. Performance status < or = 70% (TJU Karnofsky)
  2. HCT-CI Score > 5 Points
  3. Combination of Performance status of < 80% (TJU Karnofsky) and an HCT-CI of 4 points or more.
  4. HIV positive
  5. Active involvement of the central nervous system with malignancy
  6. Psychiatric disorder that would preclude patients from signing an informed consent
  7. Pregnancy
  8. Patients with life expectancy of < or = 6 months for reasons other than their underlying hematologic/oncologic disorder
  9. Patients who have received alemtuzumab within 8 weeks of the transplant admission, or who have recently received horse or rabbit ant-thymocyte globulin and have an ATG level of > or = 2 ugm/ml
  10. Patients who cannot receive cyclophosphamide
  11. Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled 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: NCT01350245

Locations
United States, Pennsylvania
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Thomas Jefferson University
Investigators
Principal Investigator: Dolores Grosso, DNP, CRNP Thomas Jefferson University
Principal Investigator: Neal Flomenberg, MD Thomas Jefferson University
  More Information

Additional Information:
No publications provided

Responsible Party: Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT01350245     History of Changes
Other Study ID Numbers: 10D.219, 2010-10
Study First Received: May 4, 2011
Last Updated: July 7, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Thomas Jefferson University:
Acute Myeloid Leukemia
Myelodysplastic Syndromes
Biphenotypic Leukemia
Acute Lymphocytic Leukemia
Chronic Myeloid Leukemia
Chronic Lymphocytic Leukemia
Plasma Cell Neoplasms
Lymphoma
Hodgkin's Disease
Aplastic Anemia
Hematopoietic stem cell transplant (HSCT)
myeloablative haploidentical HSCT
graft versus host disease (GVHD)

Additional relevant MeSH terms:
Anemia
Anemia, Aplastic
Neoplasms
Hodgkin Disease
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Plasmacytoma
Myelodysplastic Syndromes
Preleukemia
Hematologic Diseases
Bone Marrow Diseases
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Myeloproliferative Disorders
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias

ClinicalTrials.gov processed this record on August 20, 2014