Unrelated Cord Blood Transplant Plus a Haplo-Identical (Half-Matched), T-Cell Depleted Stem Transplant From a Related Donor for Subjects With High Risk Malignancies

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Brief Title

Unrelated Cord Blood Transplant Plus a Haplo-Identical (Half-Matched), T-Cell Depleted Stem Transplant From a Related Donor for Subjects With High Risk Malignancies

Official Title

A Prospective, Phase I/II Trial Determining the Efficacy and Safety of Allogeneic Hematopoietic Stem Cell Transplantation Using Banked Unrelated Umbilical Cord Blood Supplemented With Related, Haplo-Identical T-Cell Depleted Stem Cells in Subjects With High Risk Malignancies

Brief Summary

      Subjects will be diagnosed with a hematological malignancy (cancer of the blood), which is
      unlikely to be cured with conventional non-transplant therapy. The best results of bone
      marrow transplant are obtained with the donor is a relative that has identical tissue type
      (HLA-type). These subjects will not have such a donor available but they will have a
      appropriately matching unrelated umbilical cord blood unit (UCB). However, the cord blood
      unit does not contain a high enough number of cells and may take longer to engraft (or grow).
      The purpose of this study is to determine whether the addition of stem cells from a family
      member to supplement a standard unrelated cord blood transplant is safe and will increase the
      success of the cord blood transplantation procedure. Subjects enrolled in this study will
      receive an unrelated cord blood transplant plus a haplo-identical (half-matched), T-cell
      depleted stem transplant from a related donor. The goal of this study is to determine whether
      the addition of the related stem cells accelerates bone marrow recovery and improves
      long-term disease free survival.
    

Detailed Description

      Over the past decade, umbilical cord blood transplantation has been shown to be a viable
      alternative donor stem cell source for hematopoietic cell transplantation in subjects with
      catastrophic diseases treatable with transplantation therapy. UCB cells can cross partially
      mismatched HLA barriers without intolerable acute or chronic Graft-versus-Host Disease(GVHD).
      Thus, many subjects lacking a sufficiently matched, living related or unrelated bone marrow
      or adult stem cell donor, can use partially HLA-matched UCB cells for stem cell rescue after
      myeloablative irradiation and/or chemotherapy. UCB Cell dose, expressed per kilogram of
      recipient body weight, is the best predictor of outcomes after UCB transplantation. Cell dose
      thresholds strongly correlating with outcomes have been identified.

      In subjects receiving lower cell doses, while durable engraftment will ultimately occur,
      there are significant delays in myeloid and platelet engraftment which, at best, result in
      longer hospitalization and significant increases in resource utilization and in the worst
      cases, result in increased early deaths from infection and regimen-related toxicity.

      In infants and children weighing <40kg, it is possible to find a sufficiently matched UCB
      unit that will deliver a dose of cells critical for successful engraftment (defined as 5 x
      10^7 nucleated cells/kg) within a reasonable time frame in >90% of subjects. In teenagers and
      adults weighing >40kg, this is not always possible. Because UCB units contain a relatively
      fixed number of total nucleated cells, units delivering optimal cell dosing for subjects
      weighing >70kg will only be identified <10% of the time. Attempts to increase the dose of
      cells available for UCBT have included ex vivo expansion and combined unit transplantation.
      While expansion of UCB cells ex vivo is possible, infusion of these expanded cells have not
      resulted in shortening of engraftment times. Likewise, combinations of up to 5 UCB units for
      a single myeloablative transplant have not shortened time to neutrophil or platelet
      engraftment.

      In this study, we take an alternative approach to facilitating early myeloid engraftment in
      subjects undergoing UCB transplantation therapy. In subjects who cannot only identify a donor
      delivering a cell dose >2 x 10^7 nucleated cells/kg, we will augment the UCBT with a lower
      dose of haplo-identical, T-cell depleted stem cells from a related adult donor to facilitate
      early, short-term engraftment with the primary goal of minimizing early infections and other
      non-relapse mortality while the UCB cells engraft as the durable and permanent graft. As the
      immunocompetent UCB cells engraft, we expect that they will reject the immunologically
      incompetent haplo-identical adult stem cells. Thus, after approximately 100-180 days post
      transplant, the subject should convert to 100% donor chimerism with the UCB donor graft.

      In this study, we will investigate the use of unrelated UCB obtained from the umbilical cord
      blood banks supplements with related, haplo-identical, T-cell depleted stem cells in subjects
      with high risk refractory malignancies, myelodysplasia or severe aplastic anemia amenable to
      stem cell transplantation therapy but lacking conventional related or unrelated donors.

      OBJECTIVES:

        1. To determine the safety of co-transplantation of unrelated umbilical cord blood
           supplemented with related, haplo-identical, T-cell depleted stem cells in subjects with
           high risk malignancies.

        2. To describe the rates of neutrophil and platelet engraftment and immune reconstitution
           in these subjects.

        3. To determine whether short and long term lymphohematopoietic engraftment is derived from
           one or both donor sources.

      The primary endpoint of the study is number of days to ANC of 500/uL

      The secondary endpoints of the study are:

        1. 180 day survival

        2. Non-relapse mortality in the first 180 days post transplant

        3. Number of days to untransfused platelet count of 50K/uL

        4. Incidence of primary and secondary graft failure

        5. Incidence and severity of acute and chronic graft-versus-host disease (GVHD)

        6. Pace and quality of immune reconstitution

        7. Rates of leukemic relapse

        8. Donor chimerism
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

The Number of Participants Reaching Primary Endpoint of Absolute Neutrophil Count (ANC) of 500/uL (Engraftment).

Secondary Outcome

 180 Day Survival

Condition

Hematologic Malignancy

Intervention

haplo/cord transplant

Study Arms / Comparison Groups

 Transplant Recipients
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

3

Start Date

August 2007

Completion Date

April 2012

Primary Completion Date

April 2012

Eligibility Criteria

        Inclusion Criteria:

          -  Patient Selection Criteria: Patients with high risk or refractory malignancies,
             myelodysplasia (MDS) or severe aplastic anemia amenable to stem cell transplantation
             therapy but lacking conventional related or unrelated donors will be eligible for this
             trial.

          -  Have a consenting related haplo-identical (3/6 or 4/6) stem cell donor;

          -  Have an available 3, 4, 5, or 6/6 antigen matching unrelated UCB unit that will
             deliver a cell dose between 2.0-5.0 x 10e7cells/kg.

          -  Not have a consenting 6/6 or 5/6 antigen matched related bone marrow donor or
             genetically matched unrelated BM or adult stem cell donor.

          -  Patients must be <55 years of age at the time of study enrollment.

          -  Patients must have histologically confirmed diagnosis of a hematologic malignancy, MDS
             or severe aplastic anemia. Eligible patients include the following:

          -  Patients with high risk ALL in first complete remission, with high risk being defined
             by the presence of hypodiploidy, t(4;11; MLL. 11q23) or t(9;22), or patients
             presenting with extreme hyperleukocytosis (initial WBC >500,000/ml) or failure to
             achieve a complete remission after standard induction therapy.

          -  All patients with ALL or ANLL in second or subsequent remission.

          -  Patients with ALL or ANLL in relapse.

          -  Patients with MDS.

          -  Patients with CML in any chronic phase, accelerated phase or blast crisis.

          -  Patients with severe aplastic anemia refractory to medical therapy.

          -  Patients must not have active CNS disease at the time of study enrollment.

          -  Patients must have a good performance status (Lansky 80-100%, Karnofsky 50-100%).

          -  Patients must have adequate function of other organ systems as measured by:

          -  Creatinine < 2.0 mg/dl and creatinine clearance > 50 cc/min/m2.

          -  Hepatic transaminases (ALT/AST) < 4 x normal, bilirubin < 2.0 mg/dl.

          -  Normal cardiac function by echocardiogram or radionuclide scan, (ejection fraction or
             shortening fraction > 80% of normal value for age).

          -  Pulmonary function tests demonstrating FVC and FEV1 of >60% of predicted for age. For
             adult patients DLCO > 60% of predicted. If patient cannot perform PFTs, clearance by
             the pediatric or adult pulmonologist will be required.

          -  Patients must not have uncontrolled infections at the time of cytoreduction.

          -  Patient, parent, or legal guardian must have given written informed consent according
             to FDA guidelines.

          -  Patients may not be pregnant or lactating and must have a current negative pregnancy
             test.

          -  Patients must have a minimum life expectancy of at least 3 months.

          -  Patients must have an available related haplo-identical stem cell donor and an
             available unrelated cord blood donor delivering between 2 x10e7 cells/kg and 5 x 10e7
             cells/kg and matching at a minimum of 3/6 HLA loci.

          -  Patients must be HIV negative.

          -  Patients must not be concurrently involved in any other clinical trial that affects
             engraftment or immune reconstitution (e.g. other hematopoietic growth factors).

          -  Patients must not have any co-morbid condition which, in the view of the Principal
             Investigators, renders the patient at too high a risk from treatment complications and
             regimen related morbidity/mortality.
      

Gender

All

Ages

N/A - 55 Years

Accepts Healthy Volunteers

No

Contacts

Joanne Kurtzberg, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00673114

Organization ID

Pro00008292

Secondary IDs

8717

Responsible Party

Sponsor-Investigator

Study Sponsor

Joanne Kurtzberg, MD

Collaborators

 Miltenyi Biomedicine GmbH

Study Sponsor

Joanne Kurtzberg, MD, Principal Investigator, Duke University Medical Center Pediatric Blood and Marrow Transplant


Verification Date

March 2015