A Pilot Study of the Thrombopoietin-Receptor Agonist Eltrombopag in Refractory Aplastic Anemia Patients
Condition: Anemia, Aplastic; Anemia, Hypoplastic; Thrombocytopenia
MeSH terms: Anemia; Thrombocytopenia; Anemia, Aplastic
Intervention: Eltrombopag
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 43.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Promacta; SAA; Aplastic Anemia; Thrombocytopenia

Summary:

      Severe aplastic anemia (SAA) is a life-threatening blood disease which can be effectively
      treated with immunosuppressive drug regimens or allogeneic stem cell transplantation.
      However, 20-40% of patients without transplant options do not respond to immunosuppressive
      therapies, and have persistent severe cytopenias, requiring regular platelet transfusions,
      which are expensive and inconvenient, and are a risk for further serious bleeding
      complications.

      Thrombopoietin (TPO) is the principal endogenous regulator of platelet production and also
      stimulates hematopoietic stem and progenitor cells. A small molecule oral TPO-agonist,
      eltrombopag has been shown to increase platelets in healthy subjects and in patients with
      immune thrombocytopenic purpura (ITP), and received FDA approval in 2008 for the treatment of
      thrombocytopenia in ITP. This Phase 2, non-randomized pilot study of eltrombopag in aplastic
      anemia patients with immunosuppressive therapy refractory thrombocytopenia will test the
      safety and potential efficacy of eltrombopag treatment patients with refractory
      thrombocytopenia following immunosuppression for aplastic anemia.

      Subjects will initiate study medication at an oral dose of 50 mg/day, which will be increased
      up to 150 mg/day as clinically indicated to the lowest dose that maintains a stable platelet
      count 20,000/(micro)L above baseline while maximizing tolerability. Response will be assessed
      at 3-4 months. Platelet response is defined as platelet count increases to 20,000/L above
      baseline at three months. or stable platelet counts with transfusion independence for a
      minimum of 8 weeks. Erythroid response for subjects with a pretreatment hemoglobin of less
      than 9 g/dL will be defined as an increase in hemoglobin by greater than or equal to 1.5g/dL
      without packed red blood cell (PRBC) transfusion support, or a reduction in the units of
      transfusions by an absolute number of at least 4 PRBC transfusions for eight consecutive
      weeks compared with the pretreatment transfusion number in the previous 8 weeks. Neutrophil
      response will be defined in those with a pretreatment absolute neutrophil count (ANC) of less
      than 0.5 times 10(9)/L as at least a 100 percent increase or an absolute increase greater
      than 0.5 times 10(9)/L. Subjects with response at 3-4 months may continue study medication
      (extended access) until they meet an off study criteria. The primary objective is to assess
      the safety and efficacy of the oral thrombopoietin receptor agonist (TPO-R agonist)
      eltrombopag in aplastic anemia patients with immunosuppressive-therapy refractory
      thrombocytopenia. Secondary objectives include the analysis of the incidence and severity of
      bleeding episodes, and the impact on quality of life.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Diagnosis of aplastic anemia, with refractory thrombocytopenia following at least
                  one treatment course of horse or rabbit ATG/cyclosporine.

               2. Platelet count less than or equal to 30,000/microL

               3. Age greater than or equal to 12 years old

        EXCLUSION CRITERIA:

          1. Diagnosis of Fanconi anemia

          2. Infection not adequately responding to appropriate therapy

          3. Patients with a PNH clone size in neutrophils of greater than or equal to 50%

          4. HIV positivity

          5. Creatinine > 2.5

          6. Bilirubin > 2.0

          7. SGOT or SGPT > 5 times the upper limit of normal

          8. Hypersensitivity to eltrombopag or its components

          9. Female subjects who are nursing or pregnant or are unwilling to take oral
             contraceptives or refrain from pregnancy if of childbearing potential

         10. History of malignancy other than localized tumors diagnosed more than one year
             previously and treated surgically with curative intent (for instance squamous cell or
             other skin cancers, stage 1 breast cancer, cervical carcinoma in situ, etc)

         11. Unable to understand the investigational nature of the study or give informed consent

         12. History of congestive heart failure arrhythmia requiring chronic treatment, arterial
             or venous thrombosis (not excluding line thrombosis) within the last 1 year, or
             myocardial infarction within 3 months before enrollment

         13. ECOG Performance Status of 3 or greater

         14. Treatment with horse or rabbit ATG or Campath within 6 months of study entry.
             Concurrent stable treatment with cyclosporine or G-CSF is permitted.