Partially HLA Mismatched (Haploidentical) Allogeneic Bone Marrow Transplantation

This study has been terminated.
(The protocol design is being reconfigured in order to open a new study.)
Sponsor:
Information provided by (Responsible Party):
Pritesh Patel, MD, University of Illinois at Chicago
ClinicalTrials.gov Identifier:
NCT01749293
First received: November 20, 2012
Last updated: June 3, 2014
Last verified: November 2013
  Purpose

Allogeneic stem cell transplantation is a potentially curative treatment for patients with many hematologic malignancies (e.g. leukemia, lymphoma, and myeloma with high risk of relapse). This process requires a suitable donor. The best case scenario involves an Human Leukocyte Antigen (HLA) matched sibling donor. However, this type of donor is not always available. Donor registries can provide another source for matched unrelated donors, but this may take valuable time delaying treatment for the transplant recipient. Donor availability remains a significant barrier to the use of allogeneic (from a donor) stem cell transplant. This issue disproportionately affects patients of minority backgrounds. Novel strategies to improve outcomes using alternative donors are desperately needed.

Haploidentical transplants are an alternative which provides a readily available donor in the form of a partially HLA matched family member. This provides for more potential donors and the donors can be selected based on other factors that can play a role in transplant success (e.g. age, gender, KIR alloreactivity). Recent advances in transplant techniques have greatly improved success rates with haploidentical transplants although disease relapse has remained as issue.

This trial aims to provide an alternative transplant option for patients with hematologic malignancies who require bone marrow transplantation but lack an HLA identical donor. The investigational component of this study is the combination of the Fludarabine/ Busulfan/ Total Body Irradiation conditioning regimen and the HLA Haploidentical Transplant with post-transplant Cyclophosphamide.


Condition Intervention Phase
Hematologic Malignancies
Procedure: Haploidentical Transplant
Drug: Fludarabine
Drug: Busulfan
Radiation: Total Body Irradiation
Drug: Cyclophosphamide
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: Partially HLA Mismatched (Haploidentical) Allogeneic Bone Marrow Transplantation for Patients With Hematologic Malignancies

Resource links provided by NLM:


Further study details as provided by University of Illinois at Chicago:

Primary Outcome Measures:
  • Engraftment Rate [ Time Frame: Up to Day 60 post-transplant. ] [ Designated as safety issue: No ]
    To estimate engraftment rates and incidence of full donor chimerism at Day 60 in patients undergoing an HLA haploidentical stem cell transplant with post transplant high dose cyclophosphamide.


Secondary Outcome Measures:
  • Overall & Event-Free Survival [ Time Frame: Up to one year post-transplant. ] [ Designated as safety issue: Yes ]
    To estimate the overall survival (OS), event free-survival (EFS) and incidence of progression or relapse at 1 year post transplant.

  • Toxicity [ Time Frame: Up to one year post-transplant. ] [ Designated as safety issue: Yes ]
    To determine the overall toxicity including rate of graft versus host disease.

  • HLA Disparity [ Time Frame: Up to one year post-transplant. ] [ Designated as safety issue: Yes ]
    Describe transplantation outcomes according to donor-recipient HLA disparity and models of natural killer cell alloreactivity.


Other Outcome Measures:
  • Immune Reconstitution [ Time Frame: Up to one year post-transplant. ] [ Designated as safety issue: Yes ]
    To assess immune reconstitution after transplant the patient's blood will be drawn and tested at baseline then 1, 3, 6, and 12 month. 10 ml of blood will be drawn for detection of lymphocyte subsets, monocytes, and dendritic cells by flow cytometry.


Enrollment: 2
Study Start Date: August 2012
Estimated Study Completion Date: June 2014
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Haploidentical Transplant
All subjects will be dosed with pre-transplant Fludarabine (180mg/m2)and Busulfan total AUC 2400 μmol*min/L or 6.4mg/kg. Subjects will then undergo total body irradiation 2Gy. Subjects will undergo haploidentical allogeneic bone marrow transplant, followed by Cyclophosphamide, Tacrolimus and MMF based GVHD prophylaxis.
Procedure: Haploidentical Transplant
Subjects will be dosed with pre-transplant Fludarabine (180mg/m2)and Busulfan total AUC 2400 μmol*min/L or 6.4mg/kg. Subjects will then undergo total body irradiation 2Gy. Subjects will undergo haploidentical allogeneic bone marrow transplant, followed by Cyclophosphamide, Tacrolimus and MMF based GVHD prophylaxis.
Other Name: Mismatched allogeneic bone marrow transplant
Drug: Fludarabine
Subjects in this trial will receive Fludarabine 30 mg/m2 IV QD, adjusted for CrCl from Days -8 through -3.
Other Name: Fludara
Drug: Busulfan
Subjects in this trial will receive Busulfan total AUC 2400 μmol*min/L or 6.4mg/kg in 4 doses with seizure prophylaxis from Days -6 through -3.
Other Names:
  • Busulfex
  • Myleran
Radiation: Total Body Irradiation
Subjects in this trial will receive total body irradiation (2Gy fractionated) from Day -2 or -1.
Drug: Cyclophosphamide
Subjects in this trial will receive Cyclophosphamide 50 mg/kg IV QD on Days 3 and 4 post-transplant.
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • cytophosphane

Detailed Description:

Allogeneic stem cell transplantation is a potentially curative treatment for patients with hematologic malignancies such as leukemia, lymphoma and myeloma who are at high risk of relapse. As well as the potential to deliver high doses of chemotherapy or radiation this procedure affords the benefit of an immunologic weapon against disease in the form of the graft versus tumor effect.

The major variables affecting the outcome of allogeneic transplant include: patient selection (age and comorbidities); disease status at the time of transplantation (remission vs. active disease); type of donor (HLA matched vs. mismatched or related vs. unrelated); type of conditioning regimen; source of stem cells (bone marrow vs. peripheral blood). Recent advances in the field of stem cell transplant have substantially lowered transplant related morbidity and mortality.

The availability of stem cell transplant as a treatment modality is dependent upon the availability of a suitable donor. Best outcomes are thought to occur in HLA matched sibling donors. The chance of a sibling being HLA matched is approximately 25%. Despite the development of large worldwide donor registries the likelihood of finding an HLA matched unrelated donor is 60-70% at best and drops to 10% in some ethnic minorities. In addition the process of identifying, confirming and harvesting an unrelated donor is cumbersome and time consuming at a time when the patient must proceed immediately to transplant (time from initiation of search to identification of an unrelated donor identification takes a median of 49 days). Therefore the development of alternative sources of hematopoietic stem cells is an area of immense interest to many investigators.

Alternative sources include cord blood and HLA haploidentical donors. Cord blood has been an attractive source permitting immediate availability and possibly a lower rate of graft versus host disease (GVHD). However delay in engraftment, particularly after myeloablative conditioning, remains a significant disadvantage. Haploidentical transplants carry some of the same advantages with virtually all patients having immediate access to a suitable and willing donor in the form of a partially HLA matched family member. Furthermore the number of potential donors allows for donor selection based upon factors such as age, gender, KIR alloreactivity. Finally the donor is readily available for future cellular therapies such as donor lymphocyte infusion.

Early attempts at haploidentical transplantation were hampered by high rates of graft failure and severe graft versus host disease. Recent advances in graft versus host disease prophylaxis with post transplant high dose cyclophosphamide (Cy) have overcome these barriers to a large degree. Published studies have shown that HLA-haploidentical bone marrow transplant (BMT) after non-myeloablative conditioning and using 2 doses of post-transplantation Cy followed by tacrolimus and mycophenolate mofetil (MMF) is a well-tolerated procedure. However, the major cause of treatment failure in this high-risk population was early relapse. As conditioning intensity has been clearly linked to rates of relapse in multiple diseases, it is postulated that utilizing conditioning with higher anti-tumor potential will lead to a lower relapse rate.

Given the advances in GVHD prophylaxis with post-transplantation Cy, reduced intensity conditioning with Fludarabine, Busulfan and total body irradiation combined with high-dose post-transplantation Cy is the platform for this study. The toxicities of this reduced intensity conditioning regimen are not expected to differ substantially from previous data incorporating post-transplantation Cy. However, this regimen may have higher anti-tumor potential resulting in a decreased relapse rate.

  Eligibility

Ages Eligible for Study:   10 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. First-degree related donor or half-sibling who is at minimum HLA haploidentical
  2. Lack of fully matched donor (related or unrelated). Patients with a matched unrelated donor may only be enrolled if they require an urgent transplant. Urgency of transplant will judged by PI and co-investigators.
  3. Eligible diagnoses are listed below:

    1. Low-grade non-Hodgkin's lymphoma or plasma cell neoplasm that has progressed during multiagent therapy including follicular lymphoma, Marginal zone (or MALT) lymphoma, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, Hairy cell leukemia, Small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), Prolymphocytic leukemia, Multiple myeloma and Plasma cell leukemia
    2. Poor-risk SLL or CLL
    3. Aggressive lymphoma that has failed at least one prior regimen of multiagent chemotherapy, and patient is either ineligible for autologous BMT or autologous BMT is not recommended including Hodgkin lymphoma, high grade Follicular lymphoma, Mantle cell lymphoma, Diffuse large B-cell lymphoma, Burkitt's lymphoma/leukemia, Anaplastic large cell lymphoma, Plasmablastic lymphoma, Peripheral T-cell lymphoma
    4. Relapsed or refractory acute leukemias.
    5. Poor-risk acute leukemia in first remission:

    i. Acute myeloid leukemia (AML) with at least one of the following:

    • AML arising from myelodysplastic syndrome (MDS) or a myeloproliferative disorder
    • Presence of FLT3 internal tandem duplications
    • Poor-risk cytogenetics

    ii. Acute lymphoblastic leukemia and/or lymphoma (ALL) with at least one of the following:

    • Poor risk cytogenetics
    • Primary refractory disease

    iii. Biphenotypic leukemia

    f. MDS with at least one of the following poor-risk features: i. Poor-risk cytogenetics ii. Int-2 or high IPSS score iii. Treatment-related MDS iv. MDS diagnosed before age 21 years v. Progression on or lack of response to standard hypomethylator therapy vi. Life-threatening cytopenias

    g. Imatinib-refractory chronic myelogenous leukemia (CML) in accelerated or chronic phase

    h. Philadelphia chromosome negative myeloproliferative neoplasm

    i. Chronic myelomonocytic leukemia

5. Adequate end-organ function as measured by:

  1. Left ventricular ejection fraction ≥ 35%
  2. Bilirubin ≤ 3.0 mg/dL and ALT and AST < 5 x ULN
  3. FEV1 and FVC > 40% of predicted

    6. Karnofsky score > 60

    7. Lack of recipient anti-donor HLA antibody

  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: NCT01749293

Locations
United States, Illinois
University of Illinois Cancer Center
Chicago, Illinois, United States, 60612
Sponsors and Collaborators
University of Illinois at Chicago
Investigators
Principal Investigator: Pritesh Patel, MD University of Illinois at Chicago
  More Information

No publications provided

Responsible Party: Pritesh Patel, MD, Faculty, Asst. Professor, University of Illinois at Chicago
ClinicalTrials.gov Identifier: NCT01749293     History of Changes
Other Study ID Numbers: 2012-0170
Study First Received: November 20, 2012
Last Updated: June 3, 2014
Health Authority: United States: Institutional Review Board
United States: University of Illinois Cancer Center Data Safety Monitoring Committee

Additional relevant MeSH terms:
Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Hematologic Diseases
Busulfan
Cyclophosphamide
Fludarabine monophosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Antirheumatic Agents
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on July 29, 2014