Safety and Efficacy of Patient’s Own AD-MSC and AD-HSC Transplantation in Patients With Severe Aplastic Anemia

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Brief Title

Safety and Efficacy of Patient's Own AD-MSC and AD-HSC Transplantation in Patients With Severe Aplastic Anemia

Official Title

A Multicenter, Randomized, Controlled Study of the Efficacy and Safety of the Combination of Adipose Tissue-derived Hematopoietic Stem Cells (AD-HSCs) and ATG in the Treatment of Severe Aplastic Anemia

Brief Summary

      RATIONALE: It has been shown that about 30% of patients do not respond to immunosuppressive
      therapy or experience recurrence, and graft rejection and graft-versus-host-disease (GVHD)
      decrease event-free survival to 30% to 50% in the alternative donor (matched unrelated,
      partially matched family member) transplantation. Although an overall and disease free
      survival of 85% to 100%, can be obtained in allogeneic blood or bone marrow stem cell
      transplantation using an human leukocyte antigen (HLA) matched sibling donor, only about 25%
      of patients have such a donor.

      PURPOSE: In an attempt to avoid GVHD, reduce earlier infection rate and decrease
      regimen-related toxicity while maintaining better engraftment, this study is to evaluate the
      effectiveness and safety of patient's own adipose-derived mesenchymal stem cell (AD-MSC) or
      AD-MSC transdifferentiated HSC (AD-HSC) transplant after an immunosuppressive regimen in
      treating patients who have severe aplastic anemia.

      The patient will be in the study for one year for observation and active monitoring. After
      treatment and active monitoring are over, the patient's medical condition will be followed
      indefinitely. The principle measures of safety and efficacy will be :

        1. Patient survival probability at 3 months, 6 months and 1 year.

        2. Engraftment at 3 months, 6 months and 1 year

        3. Incidence of graft versus host disease (GVHD), incidence of acute and chronic GVHD and
           Incidence of earlier infection rate as well as other complications within 6 months and 1
           years.
    

Detailed Description

      Severe aplastic anemia is characterized by severe deficiencies in peripheral-blood platelets,
      white cells, and red cells. These defects in mature cells occur because aplastic bone marrow
      contains severely reduced numbers of hematopoietic stem cells. To date, Hematopoietic stem
      cell (HSC) transplants are routinely used to treat patients with many different diseases,
      including various cancers and blood disorders, such as aplastic anemia. The main sources of
      HSCs are bone marrow, cord blood and peripheral blood. However, challenges include obtaining
      enough functional HSCs to ensure optimal engraftment, and avoiding immune rejection and other
      complications associated with allogeneic transplantations. Novel abundant sources of
      clinical-grade HSCs are therefore being sought.

      Our novel studies have demonstrated that adipose-derived mesenchymal stem cells (AD-MSCs) can
      be converted rapidly (in 4 days) into AD-HSCs on a large scale (2X108-9 cluster of
      differentiation 34(CD34)positive cells) by transfection of small RNAs to the the early region
      1A (E1A)-like inhibitor of differentiation 1 (EID1) in the presence of specific cytokines. In
      vitro, AD-HSCs expanded efficiently and resembled cord-blood HSCs in phenotype, genotype, and
      colony-forming ability. In a mouse model, primary and secondary transplantation analysis and
      repopulating assays showed that AD-HSCs homed to the bone marrow, differentiated into
      functional blood cells, and showed a long-term ability to self-renew. we show that
      adipose-derived mesenchymal stem cells (AD-MSCs) can be converted into AD-HSCs by
      transfection of small RNAs to the E1A-like inhibitor of differentiation 1 (EID1) in the
      presence of specific cytokines. In vitro, AD-HSCs expanded efficiently and resembled
      cord-blood HSCs in phenotype, genotype, and colony-forming ability. In a mouse model, primary
      and secondary transplantation analysis and repopulating assays showed that AD-HSCs homed to
      the bone marrow, differentiated into functional blood cells, and showed a long-term ability
      to self-renew. In the safety aspect, we saw no evidence of leukemia, teratoma and other
      cancers in the blood, testes and subcutaneous tissues of transplanted mice. More importantly,
      our preliminary data have shown that AD-HSCs can reconstitute hematopoietic function in five
      patients with severe aplastic anemia. Based on these premilitary studies,, we have determined
      to conduct a further clinical investigation in multiple medical centers. In this study we
      plan to enroll up to 90 patients, to make a comprehensive assessment for this new treatment
      regimen and to show it is equal or superior to the current immunosuppressive regimen.
      Patients will be in the study for one years for treatment and active monitoring. All patients
      will be followed until death.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Engraftment at 42 days post AD-HSC transplantation for patients with severe aplastic anemia.

Secondary Outcome

 To estimate the overall survival (OS) at 1 year following AD-HSC transplantation for Patients with Severe Aplastic Anemia

Condition

Severe Aplastic Anemia

Intervention

Rabbit antithymoglobulin (ATG)

Study Arms / Comparison Groups

 Rabbit antithymoglobulin (ATG)
Description:  Patient in this arm will receive rabbit ATG at 3.5 mg/kg/dose IV from day -6 to -2 with the goals of ablating host repressive T 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

Drug

Estimated Enrollment

90

Start Date

January 2015

Completion Date

July 2017

Primary Completion Date

January 2017

Eligibility Criteria

        Inclusion Criteria:

        Male or female recipients must have histopathologically confirmed diagnosis of SAA-I
        without or with more than 6 months after less than one treatment with ATG. Diagnostic
        Criteria for Server Aplastic Anemia will be based on the definitions set forth by the
        international Aplastic Anemia Study Group.

        At least two of the following:

        Absolute neutrophil count ≤ 0.5 X 109/l, Platelet count ≤ 20 X 109 /l, Anemia with
        corrected reticulocyte count ≤ 1%, and Bone marrow cellularity ≤ 25%, or bone marrow
        cellularity ≤ 50% with fewer than 30% hematopoietic cell, Hepatic: alanine aminotransferase
        (ALT)/ aspartate aminotransferase (AST) no greater than 4 times normal, Bilirubin: no
        greater than 2 mg/dl, Renal: Creatinine clearance at least 50 ml/min, Cardiovascular:
        Shortening fraction or ejection fraction at least 40% of normal for age by echocardiogram
        or radionuclide scan.

        No clinically significant comorbid illnesses (e.g., myocardial infarction or
        cerebrovascular accident).

        Exclusion Criteria:

        Active and uncontrolled infection, Active bleeding, Severe allergic history of ATG, HIV-1
        infection, Pregnancy or breastfeeding, Carbon monoxide lung diffusion capacity (DLCO) <40%
        predicted, SAA-II, Patients with severe psychological disorders, Recipients of other
        clinical trials.
      

Gender

All

Ages

14 Years - 70 Years

Accepts Healthy Volunteers

No

Contacts

james Q Yin, M.D.,Ph.D., 86-01-84008003, [email protected]

Location Countries

China

Location Countries

China

Administrative Informations


NCT ID

NCT02407470

Organization ID

Ginkgocell-ADHSC-AA-001


Responsible Party

Principal Investigator

Study Sponsor

Navy General Hospital, Beijing

Collaborators

 Peking Union Medical College Hospital

Study Sponsor

james Q Yin, M.D.,Ph.D., Principal Investigator, The military general hospital of Beijing


Verification Date

March 2015