Unrelated Umbilical Cord Blood Transplantation for Severe Aplastic Anemia and Hypo-plastic MDS Using CordIn(TM), Umbilical Cord Blood-Derived Ex Vivo Expanded Stem and Progenitor Cells to Expedite Engraftment and Improve Transplant Outcome

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Brief Title

Unrelated Umbilical Cord Blood Transplantation for Severe Aplastic Anemia and Hypo-plastic MDS Using CordIn(TM), Umbilical Cord Blood-Derived Ex Vivo Expanded Stem and Progenitor Cells to Expedite Engraftment and Improve Transplant Outcome

Official Title

Unrelated Umbilical Cord Blood Transplantation for Severe Aplastic Anemia and Hypo-plastic MDS Using CordIn, Umbilical Cord Blood-Derived Ex Vivo Expanded Stem and Progenitor Cells, to Expedite Engraftment and Improve Transplant Outcome

Brief Summary

      Background:

      Severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS) are bone marrow diseases.
      People with these diseases usually need a bone marrow transplant. Researchers are testing
      ways to make stem cell transplant safer and more effective.

      Objective:

      To test if treating people with SAA or MDS with a co-infusion of blood stem cells from a
      family member and cord blood stem cells from an unrelated donor is safe and effective.

      Eligibility:

      Recipients ages 4-55 with SAA or MDS

      Donors ages 4-75

      Design:

      Recipients will be screened with:

        -  Blood, lung, and heart tests

        -  Bone marrow biopsy

        -  CT scan

      Recipients will have an IV line placed into a vein in the neck. Starting 11 days before the
      transplant they will have several chemotherapy infusions and 1 30-minute radiation dose.

      Recipients will get the donor cells through the IV line. They will stay in the hospital 3-4
      weeks. After discharge, they will have visits:

        -  First 3-4 months: 1-2 times weekly

        -  Then every 6 months for 5 years

      Donors will be screened with:

        -  Physical exam

        -  Medical history

        -  Blood tests

      Donors veins will be checked for suitability for stem cell collection. They may need an IV
      line to be placed in a thigh vein.

      Donors will get filgrastim injections daily for 5-7 days. On the last day, they will have
      apheresis: Blood drawn from one arm or leg runs through a machine and into the other arm or
      leg. This may be repeated 2 days or 2-4 weeks later.
    

Detailed Description

      Severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS) are life-threatening bone
      marrow disorders. For SAA patients, long term survival can be achieved with immunosuppressive
      treatment. However, of those patients treated with immunosuppressive therapy, one quarter to
      one third will not respond, and about 50% of responders will relapse.

      Combined haplo-cord transplant as an alternative to cord or haploidentical donor alone
      transplantation has recently been shown to be a viable transplant option for SAA patients
      lacking an HLA matched donor. In our ongoing protocol 08-H-0046, we have utilized this
      approach in 25 patients with SAA with 23/25 patients having sustained engraftment and
      long-term disease free/transfusion free survival. However, engraftment patterns have varied
      substantially and in some patients, cord engraftment was profoundly delayed or never
      occurred. A number of strategies to expand hematopoietic progenitor cells (HPC) in vitro to
      improve engraftment and prevent graft rejection have recently been studied. Nicotimanide
      (NAM) expanded umbilical cord blood/unrelated cord blood (UCB) can be successfully engrafted
      in NOD/SCID mice (1) and humans (2) where they appear to have long-term repopulating
      potential. CordIn(TM) is a cryopreserved stem/progenitor cell-based product of purified
      CD133+ cells composed of ex vivo expanded allogeneic UCB cells. CordIn(TM) comprises: 1) Ex
      vivo expanded, umbilical cord blood-derived hematopoietic CD34+ progenitor cellsU (
      (CordIn(TM) cultured fraction (CF)); and 2) the non-cultured cell fraction of the same CBU
      (CordIn(TM) Non-cultured Fraction (NF)) consisting of mature myeloid and lymphoid cellsU.
      Both fractions, i.e. CordIn(TM) CF and CordIn(TM) NF are kept frozen until they are infused
      on the day of transplantation.

      This research protocol is therefore designed to evaluate the safety and effectiveness of
      transplantation with ex vivo expanded UCB (CordIn(TM)) to overcome the high incidence of
      graft rejection associated with conventional UCB for aplastic anemia, where graft rejection
      occurs in up to 50% of subjects. We believe, based on preliminary data, that transplantation
      of CordIn(TM) will not only lead to rapid engraftment, but will also lead to sustained
      hematopoiesis, expedited immune recovery, and will reduce the chance of cord graft failure in
      this setting, potentially obviating the need for co-transplanting haploidentical CD34+ cells
      as a stem cell back-up. This phase II study is designed to have two cohorts: cohort 1 is
      intended to establish (in as safe a manner as possible) preliminary pilot data to support the
      capacity for the CordIn unit to engraft in patients with SAA in the presence of haplo CD34+
      cells. For cohort 1, three to six subjects will be conditioned then will be transplanted with
      the thawed CordIn(TM) unit (consisting of the cultured fraction and the non-cultured fraction
      of the same CBU) and approximately 3 x 106 CD34+ cells/kg from a haploidentical donor which
      will serve as a backup stem cell source should cord graft failure occur. If 3 of the first 3
      to 4 subjects or 4 of 6 subjects achieve early and sustained engraftment (defined as ANC >500
      cells/ul by day 26 and a calculated cord ANC >500 cells /ul by day 42 sustained at day 100),
      the study will move to cohort 2 where up to 23 subsequent subjects will be transplanted with
      the CordIn(TM) unit alone.

      The primary objective of the Phase II study is to evaluate the ability of the CordIn(TM) unit
      to achieve sustained early engraftment. Secondary endpoints will include 100 day and 200 day
      treatment related mortality (TRM), and standard transplant outcome variables such as
      non-hematologic toxicity, incidence and severity of acute and chronic GVHD, and relapse of
      disease. Health related quality of life will also be assessed as secondary outcome measure.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Cord engraftment

Secondary Outcome

 Treatment related mortality (TRM), and standard transplant outcome variables such as non-hematologic toxicity, incidence and severity of acute and chronic GVHD, and relapse of disease

Condition

Severe Aplastic Anemia

Intervention

CordIn

Study Arms / Comparison Groups

 1
Description:  CordIn is a cryopreserved stem/progenitor cell-based product of purified CD133+ cells composed of ex vivo expanded allogeneic UCB cells.

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

37

Start Date

June 13, 2017

Completion Date

December 31, 2023

Primary Completion Date

April 4, 2022

Eligibility Criteria

        -  INCLUSION CRITERIA - RECIPIENT:

               1. Diagnosed with severe aplastic anemia with bone marrow cellularity <30%
                  (excluding lymphocytes) associated with RBC or platelet transfusion dependence
                  and/or neutropenia (absolute neutrophil count <=1000 cells/ uL or for patients
                  receiving granulocyte transfusions, absolute neutrophil count <=1000 cells/ uL
                  before beginning granulocyte transfusions).

                  OR

                  History of severe aplastic anemia transformed to MDS that meet the following
                  criteria: a) International Prognostic Scoring System (IPSS) risk category of
                  INT-1 or greater, b) < 5% myeloblasts and < 30% of cellularity in the bone marrow
                  on screening morphologic analysis.

               2. Intolerance of or failure to respond to standard immunosuppressive therapy.

               3. Identification of either a) at least one alternative donor (i.e. HLA-
                  haploidentical related donor (i.e. greater than or equal to 5/10 HLA match:
                  HLA-A, B, C, DR, and DQ loci) or greater than or equal to 9/10 HLA matched
                  unrelated donor) who is available to serve as a stem cell donor for a salvage
                  allogeneic transplant in the event that the CordIn unit has been rejected or b)
                  umbilical cord blood unit/s that can be used for a salvage cord blood transplant
                  in the event that the CordIn unit has been rejected.

               4. Availability of at least one greater than or equal to 4/8 HLA-matched (HLA-A, B,
                  C, and DR loci) cord blood unit from the National Marrow Donor Program (NMDP).

               5. The cord blood unit must contain a minimum TNC of at least 1.8 x 10^9 and at
                  least 1.8x10^7/kg TNC and at least 8 x 10^6 CD34+ cells (all doses prior to
                  thawing). The CBU will have undergone volume reduction (both plasma and red blood
                  cell depletion) prior to cryopreservation. All CBUs should be procured from
                  public banks that meet local applicable regulations.

               6. Ages 4-55 years inclusive.

               7. Ability to comprehend the investigational nature of the study and provide
                  informed consent. The procedure will be explained to subjects aged 4-17 years
                  with formal consent being obtained from parents or legal guardian.

        EXCLUSION CRITERIA - RECIPIENT (ANY OF THE FOLLOWING):

          1. Availability of an HLA identical or 9/10 HLA matched (HLA A, B, C, DR, and DQ loci) -
             relative to serve as a stem cell donor.

          2. The patient is deemed to be a candidate for a 10/10 HLA matched unrelated stem cell
             transplant (availability of a donor and resources required for such a transplant).

          3. ECOG performance status of 2 or more.

          4. Major anticipated illness or organ failure incompatible with survival from transplant.

          5. Current pregnancy, or unwillingness to take oral contraceptives or use a barrier
             method of birth control or practice abstinence to refrain from pregnancy, if of
             childbearing potential for one year.

          6. HIV positive.

          7. Diagnosis of Fanconi s anemia (by chromosome breakage study)

          8. Diffusion capacity of carbon monoxide (DLCO) <40% predicted using DLCO corrected for
             Hgb or lung volumes (patients under the age of 10 may be excluded from this criterion
             if they have difficulty performing the test correctly and thus are unable to have
             their DLCO assessed).

          9. Left ventricular ejection fraction < 40% (evaluated by ECHO).

         10. Transaminases > 5x upper limit of normal.

         11. Serum bilirubin >4 mg/dl.

         12. Creatinine clearance < 50 cc/min/BSAm^2 by 24-hour urine collection adjusted by body
             surface area..

         13. Serum creatinine > 2.5 mg/dl

         14. Presence of an active infection not adequately responding to appropriate therapy.

         15. History of a malignant disease liable to relapse or progress within 5 years.

         16. Allergy to bovine, Gentamicin, or to any product which may interfere with the
             treatment.

         17. Presence of donor-specific antibodies (DSA) to the umbilical cord blood unit and for
             cohort 1, to the haplo-identical donor.
      

Gender

All

Ages

4 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Richard W Childs, M.D., (240) 760-6101, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03173937

Organization ID

170091

Secondary IDs

17-H-0091

Responsible Party

Sponsor

Study Sponsor

National Heart, Lung, and Blood Institute (NHLBI)


Study Sponsor

Richard W Childs, M.D., Principal Investigator, National Heart, Lung, and Blood Institute (NHLBI)


Verification Date

September 20, 2021