A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies

A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies
This study is currently recruiting participants.
Verified August 2012 by Thomas Jefferson University

First Received on June 27, 2011.  
Last Updated on August 7, 2012  
History of Changes
Sponsor: Thomas Jefferson University
Information provided by (Responsible Party): Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT01384513
  Purpose

This is a research study involving the treatment of patients with hematological cancers with reduced intensity conditioning (RIC) haploidentical hematopoietic stem cell transplant (HSCT) utilizing cyclophosphamide (CY) tolerization of T cells. HSCT is often referred to as bone marrow transplant. Patients who are not expected to have long term survival after conventional therapy will undergo HSCT as a curative therapy after receiving front line therapy for their disease. The aim of this study is to see if patients without matched related donors who have good risk disease do just as well in transplant with a half-matched donor than a fully matched related or unrelated donor now that the Thomas Jefferson University (TJU) Two Step approach has been developed. If so, many more patients could be treated with transplant because of the increased availability of donors. In addition, because the donor’s immune cells are half-matched, we would like to see if patients actually have better outcomes after haploidentical transplant as compared to matched transplant, because the donor cells recognize the disease easier (because it is only partially matched).

Condition Intervention Phase
Hematologic Malignancies
Acute Leukemia
Myelodysplastic Syndrome (MDS)
Specific Subtypes of Refractory Anemia (RA) or Refractory Anemia With Ringed Sideroblasts(RARS) Subtypes
Myeloproliferative Disorder (MPD)
Hodgkin’s Lymphoma
Non-Hodgkin’s Lymphoma
Myeloma
Aplastic Anemia
Drug: Fludarabine
Drug: Thiotepa
Radiation: Total Body Irradiation (TBI)
Biological: Donor Lymphocyte Infusion (DLI)
Drug: Cyclophosphamide (CY)
Drug: Tacrolimus
Drug: Mycophenolate mofetil
Device: Hematopoietic stem cell transplantation
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 Two Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematologic Malignancies

Resource links provided by NLM:

Further study details as provided by Thomas Jefferson University:

Primary Outcome Measures:

  • Overall Survival (OS) [ Time Frame: At 2 years post-treatment ] [ Designated as safety issue: No ]

    Compare OS rate using Two Step approach in patients with haploidentical family donors to reported historical OS rates in similar populations after reduced intensity conditioning (RIC) mated donor hematopoietic stem cell transplant (HSCT)

    • OS of < 35% at 2 years would demonstrate poor efficacy for the TJU 2 Step haploidentical regimen as compared to regimens using matched related and unrelated donors
    • OS of ≥60% at 2 years would demonstrate that the TJU 2 Step haploidentical RIC regimen is equal or superior to those using matched related or unrelated donors

Secondary Outcome Measures:

  • Treatment Related Mortality (TRM) [ Time Frame: At 2 years ] [ Designated as safety issue: Yes ]
    To compare the treatment related mortality rate (TRM) for patients treated on this study to the historical TRM rates of patients undergoing reduced intensity conditioning (RIC) matched-sibling hematopoietic stem cell transplant (HSCT) as reported in the literature

  • Graft versus Host Disease (GVHD) [ Time Frame: At 1 and 3 years ] [ Designated as safety issue: Yes ]
    To determine the incidence and severity of graft-versus-host disease (GVHD) in patients undergoing treated on the TJU Two Step approach

  • Relapse Rates [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
    To compare the relapse rates of patients with myeloid diseases to that of patients with lymphoid diseases who are treated on this Two Step approach

  • Engraftment Rates [ Time Frame: 100 days post-transplant ] [ Designated as safety issue: Yes ]
    To evaluate engraftment rates in patients treated on the Two Step approach

  • Incidence of Treatment Related Mortality (TRM) [ Time Frame: At 100 days ] [ Designated as safety issue: Yes ]
    To evaluate the incidence of TRM at 100 days in patients treated on the Two Step approach

  • Relapse Related Mortality [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
    To compare the relapse related mortality of patients with myeloid diseases to that of patients with lymphoid diseases who are treated on this Two Step approach

  • Lymphoid Reconstitution [ Time Frame: 100 days post-transplant ] [ Designated as safety issue: No ]
    To evaluate lymphoid reconstitution in patients treated on the Two Step approach

Estimated Enrollment: 30
Study Start Date: August 2011
Estimated Study Completion Date: July 2017
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)

Arms

Assigned Interventions
Experimental: Transplant Treatment Group

All patients treated on this research study
Drug: Fludarabine

Part of the conditioning regimen
Other Names:
  • fludarabine phosphate
  • Fludara

Drug: Thiotepa

Part of the conditioning regimen
Other Names:
  • N,N’N’-triethylenethiophosphoramide
  • ThioTEPA

Radiation: Total Body Irradiation (TBI)

2 Gy administered as part of the conditioning regimen
Other Name: radiotherapy

Biological: Donor Lymphocyte Infusion (DLI)

Immediately following the conditioning regimen of fludarabine, thiotepa, and TBI, the patient receives a set dose of their donor’s T cells (DLI), After the DLI, the donor’s T cells will react with the remaining parts of the recipients immune system.
Other Name: buffy coat fusion

Drug: Cyclophosphamide (CY)

Two days after the DLI, CY will be given to help the donor T cells become tolerant to the recipient to help prevent graft versus host disease (GVHD). Should GVHD occur, CY will also help treat it.
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • cytophosphane

Drug: Tacrolimus

Administered one day prior to transplant to help facilitate the recipient’s body’s acceptance of the donor cells.
Other Names:
  • FK-506
  • Fujimycin

Drug: Mycophenolate mofetil

Administered one day prior to transplant to help facilitate the recipient’s body’s acceptance of the donor cells.
Other Names:
  • MMF
  • CellCept

Device: Hematopoietic stem cell transplantation

One day after the Cyclophosphamide ends, the patient will receive their donor’s stem cells. This is the actual 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:

Haploidentical (using a donor who is half-matched to the patient) hematopoietic stem cell transplantation (HSCT) is a life-saving therapy for patients with hematological malignancies who do not have a fully Human Leukocyte Antigen (HLA)-matched donor. This type of approach has been characterized by lower survival rates as compared to matched related HSCT. These poorer outcomes are at least in part due to the attenuation of the donor graft necessary to avoid catastrophic graft versus host effects (or graft versus host disease/GVHD) and the late stage disease status of the patients undergoing haploidentical HSCT. Graft versus host disease is a condition where the donor immune cells attack the tissues of the recipient and can lead to death. The risk of GVHD is higher in haploidentical HSCT because the donor’s immune cells are better able to recognize and potentially attack the tissues of the recipient because they are only half-matched.

Recently, approaches to haploidentical HSCT utilizing less intensive therapy (reduced intensity regimen or RIC) with the drug cyclophosphamide (CY) have resulted in less GVHD and less treatment-related mortality (TRM) as compared to historical approaches using haploidentical donors. At our institution, the RIC HSCT regimen utilizing CY is called the TJU 2 Step approach because patients receive their graft in two separate steps. This transplant methodology has greatly improved overall survival rates for patients undergoing haploidentical HSCT at Jefferson.

A major problem in the transplant field is that many patients do not have available matched donors. Almost every patient will have a haploidentical donor though, because children, parents and siblings can be used as half matched donors. Therefore, successful transplantation using half matched donors extends the therapy to many more patients especially minorities who have less success in finding a fully matched donor.

The aim of this study is to see if patients without matched related donors who have good risk disease do just as well in transplant with a half-matched donor than a fully matched related or unrelated donor now that the Thomas Jefferson University (TJU) 2 step approach has been developed. If so, many more patients could be treated with transplant because of the increased availability of donors. In addition, because the donor’s immune cells are half-matched, we would like to see if patients actually have better outcomes after haploidentical transplant as compared to matched transplant, because the donor cells recognize the disease easier (because it is only partially matched).

  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 hematologic or oncologic diagnosis in which allogeneic HSCT is thought to be beneficial, and in whom front-line therapy has already been applied. Patients treated on this protocol will be without morphological evidence of disease (complete remission or "CR"), or if the patient has evidence of disease, the patient must have had at least a good partial response (PR) to the most recent therapy and the disease must be chemoresponsive.
  2. Patients treated on this study will have:

    • Acute leukemia in 1st or 2nd CR
    • MDS (myelodysplastic syndrome), specific subtypes of RA (refractory anemia) or RARS (refractory anemia with ringed sideroblasts) subtypes.
    • Hodgkin or Indolent Non-Hodgkin’s lymphoma with chemosensitive disease
    • Myeloma without morphological evidence of disease, or a deep PR to the most recent therapy
    • Myeloproliferative disorders with at least a PR to current therapy
    • Aplastic Anemia
    • A hematological or oncological disease (not listed) that meets the criteria reviewed above (in CR or with a good PR).
  3. Patients must have a related donor who is HLA mismatched at 2, 3, or 4 antigens at the HLA-A; B; C; DR loci in the GVHD direction. (Patients with related donors who are HLA identical or are a 1-antigen mismatch may be treated on this therapeutic approach, but will have their outcomes will not be part of the statistical aims of the study (see Summary section).
  4. Patients must adequate organ function:

    • LVEF (Left ventricular end diastolic function) of >50%
    • DLCO (Diffusing Capacity of the Lung for Carbon Monoxide ) ≥50% of predicted corrected for hemoglobin
    • Adequate liver function as defined by a serum bilirubin <1.8, AST or ALT < 2.5X upper limit of normal
    • Creatinine Clearance of ≥ 60 mL/min
  5. Performance status ≥ 80% (TJU Karnofsky) for patients ≥ 60 years old or ≥70% for patients < 60 years old.
  6. HCT-CI Score ≤ 4 points for patients ≥ 60 years old or ≤ 5 points for patients < 60 years old.
  7. Patients must be willing to use contraception if they have childbearing potential
  8. Able to give informed consent

Exclusion Criteria:

  1. Performance status < 80% (TJU Karnofsky) for patients ≥ 60 years old or <70% for patients < 60.
  2. Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) Score > 4 points for patients ≥ 60 years old or > 5 points for patients < 60.
  3. HIV positive
  4. Active involvement of the central nervous system with malignancy
  5. Inability to obtain informed consent
  6. Pregnancy
  7. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder
  8. Patients who have received alemtuzumab within 8 weeks of the transplant admission, or who have recently received horse or rabbit anti-thymocyte globulin and have an anti-thymocyte globulin level of > 2 ugm/ml
  9. 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

Please refer to this study by its ClinicalTrials.gov identifier: NCT01384513

Contacts
Contact: Dolores Grosso, DNP, CRNP 215-955-8874
Contact: Donna Zuccarello 215-955-6612

Locations
United States, Pennsylvania
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Dolores Grosso, DNP, CRNP     215-955-8874        
Contact: Donna Zuccarello     215-955-6612        
Principal Investigator: Dolores Grosso, DNP, CRNP            
Principal Investigator: Neal Flomenberg, MD            
Sub-Investigator: S. Onder Alpdogan, MD            
Sub-Investigator: Matthew Carabasi, MD            
Sub-Investigator: Joanne Filicko-O’Hara, MD            
Sub-Investigator: Elena Gitelson, MD, PhD            
Sub-Investigator: Margaret Kasner, MD            
Sub-Investigator: Ubaldo Martinez-Outschoorn, MD            
Sub-Investigator: John L Wagner, MD            
Sub-Investigator: Mark Weiss, MD            
Sub-Investigator: Maria Werner-Wasik, MD            
Sub-Investigator: Wenyin Shi, MD, PhD            
Sub-Investigator: William O’Hara, PharmD            
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: NCT01384513    
History of Changes
Other Study ID Numbers: 11D.247, 2011-31
Study First Received: June 27, 2011
Last Updated: August 7, 2012
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Thomas Jefferson University:

Allogeneic HSCT
Hematopoietic stem cell transplantation

Additional relevant MeSH terms:

Anemia
Anemia, Aplastic
Anemia, Refractory
Neoplasms
Hodgkin Disease
Leukemia
Lymphoma
Lymphoma, Non-Hodgkin
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Acute Disease
Hematologic Neoplasms
Hematologic Diseases
Bone Marrow Diseases
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Precancerous Conditions
Disease Attributes
Pathologic Processes
Neoplasms by Site
Cyclophosphamide
Mycophenolate mofetil
Thiotepa
Fludarabine monophosphate
Tacrolimus
Fludarabine

ClinicalTrials.gov processed this record on August 21, 2012

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