Horse ATG/CsA in Aplastic Anemia Patients Unresponsive to or With a Suboptimal Response to Rabbit ATG/CsA Treatment

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Brief Title

Horse ATG/CsA in Aplastic Anemia Patients Unresponsive to or With a Suboptimal Response to Rabbit ATG/CsA Treatment

Official Title

Horse ATG/CsA in Aplastic Anemia Patients Unresponsive to or With a Suboptimal Response to Rabbit ATG/CsA Treatment

Brief Summary

      Background:

        -  Severe plastic anemia can lead to problems with bone marrow platelet production and
           result in low blood platelet counts, which require frequent platelet transfusions to
           improve blood clotting.

        -  A standard treatment for SAA involves injections of rabbit-antithymocyte globulin
           (r-ATG). r-ATG is developed by injecting horses with a type of human white blood cells
           called thymocytes. The horse's immune system reacts against these cells and makes
           antibodies that can destroy them. These antibodies are collected and purified to make
           r-ATG. Horses can also be used for this procedure to make horse-antithymocyte globulin
           (h-ATG).

        -  h-ATG is approved by the Food and Drug Administration for the treatment of aplastic
           anemia. h-ATG is a standard first-line method to treat aplastic anemia, but researchers
           do not know how effective it is in patients who were first treated unsuccessfully with
           r-ATG.

      Objectives:

      - To evaluate the effectiveness and safety of horse-ATG (with cyclosporine) in increasing
      blood counts and reducing the need for transfusions in aplastic anemia patients who have
      failed to respond to prior immunosuppressive treatment with rabbit-ATG and cyclosporine.

      Eligibility:

      - Patients 2 years of age and older who have consistently low blood platelet counts related
      to aplastic anemia that has not responded to conventional treatment with rabbit-ATG.

      Design:

        -  After initial screening, medical history, and blood tests, patients will be admitted to
           the inpatient unit at the National Institutes of Health Clinical Center. Researchers
           will perform a skin test with h-ATG to check for allergic or other adverse reaction.

        -  After the skin test, h-ATG will be given into a vein continuously over 4 days.

        -  Cyclosporine will also be given to improve the response rate of ATG treatment. Treatment
           with cyclosporine will start the same day as the h-ATG, either in liquid or capsule
           form, and continued for 6 months. The dose of cyclosporine will be monitored and
           adjusted based on blood levels and signs of side effects in the kidney and liver.

        -  To prevent or treat infections that may result from cyclosporine s effect on the immune
           system, patients will also take inhaled or capsule doses of pentamidine.

        -  After the study is completed, patients will have followup evaluations every 3 months, 6
           months, and annually for 5 years. Evaluations will include blood samples and periodic
           bone marrow biopsies.
    

Detailed Description

      Severe aplastic anemia (SAA), characterized by pancytopenia and a hypocellular bone marrow,
      is effectively treated by immunosuppressive therapy, usually a combination of antithymocyte
      globulin (ATG) and cyclosporine (CsA). Survival rates following this regimen are equivalent
      to those achieved with allogeneic stem cells transplantation. However, approximately 1/3 of
      patients will not show blood count improvement after ATG/CsA. General experience and small
      pilot studies have suggested that such patients benefit from further immunosuppression.
      Furthermore, analysis of our own clinical data suggests that patients with minimal blood
      count responses to a single course of ATG, even when transfusion independence is achieved,
      have a markedly worse prognosis than patients with robust hematologic improvement.

      The majority of the experience in the US and worldwide has been with horse ATG (h-ATG) plus
      CsA as initial therapy in SAA. Rabbit ATG (r-ATG) plus CsA has been employed successfully in
      about 1/3 of cases in those who are refractory to initial h-ATG/CsA (current NHLBI Protocol
      03-H-0249). In recent years, h-ATG and r-ATG have been used interchangeably in
      treatment-naive patients, and initial therapy with r-ATG/CsA is now frequent in the US and
      the only option in Europe and Japan, where h-ATG is no longer available. An active NHLBI
      randomized study is comparing the efficacy of h- and r-ATG as initial therapy in SAA, and the
      results from a recently completed interim analysis suggest that the hematologic response rate
      ultimately may not be comparable between these two agents (Protocol 06-H-0034). There is no
      published report on the outcome of repeat immunosuppressive therapy in those patients
      refractory to initial r-ATG/CsA, and thus the management of these patients is uncertain. We
      therefore propose this study of h-ATG/CsA in SAA patients who are refractory or have a
      suboptimal response to r-ATG.

      The primary endpoint will be the response rate at 3 months where response is defined as no
      longer meeting criteria for SAA.

      The primary objective is to evaluate the effectiveness (response rate) at 3 months of a
      second course of immunosuppression with h-ATG/CsA in subjects refractory to or with a
      suboptimal response to a course of r-ATG/CsA or cyclophosphamide at least 3 months post
      treatment.

      Secondary objectives include robustness of hematologic recovery, relapse, response rate at 6
      months, clonal evolution and overall survival.

      The primary endpoint will be changes in absolute neutrophil count, platelet count,
      reticulocyte count at 3 months.

      Secondary endpoints will include time to relapse, changes in cytogenetics, time to death.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of Participants With Complete Response at 3 Months.


Condition

Anemia, Aplastic

Intervention

h-ATG (ATGAM )

Study Arms / Comparison Groups

 Single Arm
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

Drug

Estimated Enrollment

23

Start Date

August 31, 2009

Completion Date

December 2016

Primary Completion Date

December 2015

Eligibility Criteria

        -  All patients 2 years old or over with SAA who have failed initial immunosuppression
             with r-ATG/CsA and are not candidates for a matched sibling marrow transplantation
             will be considered for enrollment. Patients who have a suitable matched sibling donor
             will be referred for consideration of allogeneic bone marrow transplantation. Patients
             not willing to undergo transplantation will be considered for enrollment. Eligibility
             will be determined on another screening Hematology Branch protocol (97-H-0041) or
             another active Hematology branch protocol. The time between determination of
             eligibility and signing consent to participate on this protocol and initiate treatment
             on this protocol will not exceed 90 days.

        INCLUSION CRITERIA:

          1. Diagnosed with SAA characterized by:

               1. Bone marrow cellularity < 30% (excluding lymphocytes)

               2. At least two of the following:

             i. Absolute neutrophil count <500/ microL

             ii. Platelet count <20,000/ microL

             iii. Reticulocyte count <60,000/ microL

          2. Failure to respond to an initial course of r-ATG/CsA or cyclophosphamide at least 3
             months post-treatment or a suboptimal response to initial therapy defined by both
             platelet and reticulocyte count < 50,000 /microL at 3 months post-treatment

          3. Age greater than or equal to 2 years of age

        EXCLUSION CRITERIA:

          1. Diagnosis of Fanconi anemia. Patients with very severe neutropenia (ANC < 200 /microL)
             will not be excluded initially if results of Fanconi anemia testing are not available
             or pending. If evidence of Fanconi anemia is later identified, the subject will go off
             study.

          2. Evidence of a clonal disorder on cytogenetics. Patients with very severe neutropenia
             (ANC < 200/uL) will not be excluded initially if results of cytogenetics are not
             available or pending. If evidence of a clonal disorder is later identified, the
             subject will go off study.

          3. Patients who received prior course(s) of alemtuzumab will not be excluded.

          4. Infection not adequately responding to appropriate therapy

          5. HIV seropositivity

          6. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary,
             infectious, or metabolic disease of such severity that it would preclude the patient s
             ability to tolerate protocol therapy or that death within 7-10 days is likely.

          7. Subjects with cancer who are on active chemotherapeutic treatment or who take drugs
             with hematological effects will not be eligible

          8. Serum creatinine > 2.5 mg/dL

          9. Current pregnancy, breast-feeding or unwillingness to refrain from pregnancy if of
             child bearing potential

         10. Inability to understand the investigational nature of the study or give informed
             consent
      

Gender

All

Ages

2 Years - 82 Years

Accepts Healthy Volunteers

No

Contacts

Danielle M Townsley, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00944749

Organization ID

090183

Secondary IDs

09-H-0183

Responsible Party

Sponsor

Study Sponsor

National Heart, Lung, and Blood Institute (NHLBI)


Study Sponsor

Danielle M Townsley, M.D., Principal Investigator, National Heart, Lung, and Blood Institute (NHLBI)


Verification Date

September 2020