A Pilot Study of the Thrombopoietin-Receptor Agonist Eltrombopag in Refractory Aplastic Anemia Patients
A Pilot Study of the Thrombopoietin-Receptor Agonist Eltrombopag in Refractory Aplastic Anemia Patients
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.
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 thrombocytopenia. Even patients that respond to
 immunosuppressive therapies with an improvement in their life-threatening neutropenia
 sometimes have persistent thrombocytopenia. Both groups of patients (i.e. nonresponders to
 immunosuppressive therapy and responders with persistent thrombocytopenia) require 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. On binding
 to the megakaryocyte progenitor TPO receptor, TPO initiates a number of signal transduction
 events to increase the production of mature megakaryocytes and platelets. Thrombopoietin also
 has stimulatory effects on more primitive multilineage progenitors and stem cells in vitro
 and in animal models. A 2nd generation small molecule TPO-agonist, eltrombopag (Promacta )
 has been shown to increase platelets in healthy subjects and in thrombocytopenic patients
 with chronic immune thrombocytopenic purpura (ITP) and hepatitis C virus (HCV) infection.
 Eltrombopag is administered orally and has been well-tolerated in clinical trials. Unlike
 recombinant TPO, it has not been found to induce autoantibodies. Eltrombopag received FDA
 accelerated approval on Nov 20, 2008 for the treatment of thrombocytopenia in patients with
 chronic immune (idiopathic) thrombocytopenic purpura who have had an insufficient response to
 corticosteroids, immunoglobulins, or splenectomy.

 Because a paucity of megakaryocytes and decreased platelet production is responsible for
 thrombocytopenia in aplastic anemia patients, we now propose this Phase 2, non-randomized
 pilot study of eltrombopag in aplastic anemia patients with immunosuppressive therapy
 refractory thrombocytopenia.

 Subjects will initiate study medication at an oral dose of 50 mg/day (25 mg/day for East
 Asians), which will be increased or decreased as clinically indicated to the lowest dose that
 maintains a stable platelet count greater than or equal to 20,000/microL above baseline while
 maximizing tolerability. Platelet treatment response is defined as platelet count increases
 to 20,000/microL 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 a platelet, erythroid, and/or
 neutrophil response at 12 weeks may continue study medication (extended access) until they
 meet an off study criteria. Subjects with platelet, erythroid, or neutrophil response at 12
 weeks may continue study medication for an additional 4 weeks (to ensure eligibility) prior
 to being consented for entry into the extended access part of the trial. Patients may remain
 on the extended access trial until they met 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.

 The primary endpoint will be the portion of drug responders as defined by changes in the
 platelet count and/or platelet transfusion requirements, hemoglobin levels, number of red
 blood cell transfusions, or neutrophil counts as measured by International Working Group
 criteria and the toxicity profile as measured using the CTCAE criteria. Platelet treatment
 response is defined as platelet count increases to 20,000/microL 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 9g/dL will be
 defined as an increase in hemoglobin by greater than or equal to 1.5g/dL or a reduction in
 the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to
 response assessment compared with the pretreatment transfusion number in the previous 8
 weeks. Neutrophil response will be defined in those with pretreatment absolute neutrophil
 count (ANC) of less than 0.5 times 10(9)/L as at least a 100 percent increase in ANC, or an
 ANC increase greater than 0.5 times 10(9)/L.

 Secondary endpoints will include incidence of bleeding; changes in serum thrombopoietin level
 (as measured by enzyme-linked immunosorbent assay, R&D Systems), and health related quality
 of life (as measured by the Medical Outcomes Study 36-Item Short Form General Health Survey,
 version 2 [SF36v2J]; Quality-Metric) measured at 12 weeks.
-  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.