A Phase II Dose-escalation Study Characterizing the PK of Eltrombopag in Pediatric Patients With Previously Untreated or Relapsed Severe Aplastic Anemia or Recurrent Aplastic Anemia

Inclusion Criteria:

For Cohort A patients:

History of prior diagnosis of SAA,
Diagnosis of relapsed/refractory SAA or recurrent AA following treatment for SAA, as per Section 5.1. Patients with recurrent AA (e.g., losing their response) are exempt from meeting the diagnostic criteria for SAA relapse at the time of study enrollment, but must have been previously diagnosed with SAA.

Agree to concurrent eltrombopag treatment with appropriate, investigator-selected IST with either hATG + CsA or CsA.

For Cohort B patients:

Diagnosis of SAA at time of enrollment.
Patients must not have been previously treated with IST, and must meet all criteria as described in Table 5-1.

Patients must agree to treatment with hATG + CsA concurrent with eltrombopag.

All patients eligible for inclusion in this study must meet all of the following criteria:

Age 1 to <18 years.
Assessments to rule out congenital/inherited bone marrow failure syndromes and other causes of immune-mediated pancytopenia, which may be treated with transplant, must be completed prior to enrollment.
Hematopoietic stem cell transplantation (HSCT) is not suitable or available as a treatment option or has been refused by the patient. (Candidacy for HSCT will be determined as per local practices or national guidelines.)
Bone marrow aspirate and biopsy at any time during the 4 weeks prior to first dose of eltrombopag.

12. Performance status score: Karnofsky ≥50 for patients 16 years of age and older or Lansky ≥50 for patients below 16 years of age.

15. Written informed consent must be signed by a parent or legal guardian prior to initiation of any study specific procedure.

16. Normal karyotype within 4 weeks prior to first dose of eltrombopag. If there are insufficient metaphases (< 10) to determine karyotype, a repeat marrow aspirate is required. If upon repeat bone marrow aspirate, the number of metaphases is insufficient (< 10), then FISH probes performed in marrow aspirate as per protocol must be normal.

Exclusion Criteria:

2. Prior and/or active medical history of:

Fanconi anemia (via chromosome breakage test or growth arrest by flow cytometry)
Other known underlying inherited marrow failure syndrome (such as but not limited to Dyskeratosis Congenita, Congenital Amegakaryocytic Thrombocytopenia, or Shwachman-Diamond Syndrome).
Symptomatic Paroxysmal Nocturnal Hemoglobinuria (PNH) and/or PNH clones >50% of WBC or RBC at time of enrollment.
Any cytogenetic abnormalities by karyotyping or FISH.
Myelodysplastic syndrome (MDS)
Other known or suspected underlying primary immunodeficiency

Any malignancy 3. Active infection not responding to appropriate therapy. 4. Prior eltrombopag or other thrombopoietin receptor (TPO-R) agonist treatment for at least 2 months and a lack of response.

5. Have any of the following out-of-range laboratory values:

Serum Creatinine >2.5 × upper limit of normal (ULN),
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × ULN. 6. Concurrent participation in an investigational study within 30 days prior to enrollment or within 5-half-lives of the investigational product, whichever is longer. Note: a parallel enrollment in a registry for patients with SAA or AA is acceptable.