| City: |
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Bethesda |
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State:
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MD |
| Zip Code: |
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20892 |
| Conditions: |
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Anemia, Aplastic - Anemia, Hypoplastic - Thrombocytopenia |
| Purpose: |
|
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(Registered Trademark)) 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 20,000/(micro)L above baseline while maximizing
tolerability. Treatment response is defined as platelet count increases to 20,000/(micro)L
above baseline at three ...
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| Study 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 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(Registered Trademark)) 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 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
teh units of PRBC 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 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. |
| 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 18 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. |
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| Study is available at: |
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National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, MD 20892
United States
Primary Contact:
Patient Recruitment and Public Liaison Office
Email: prpl@mail.cc.nih.gov
Phone: (800) 411-1222 |
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If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
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| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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March 23, 2011 |
Modifications to
this listing: |
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above to view all information about this clinical trial. |
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