Study Overview

This is a phase II, multi-center, study with eltrombopag in combination with immunosuppressive therapy in pediatric patients with previously untreated or relapsed/refractory severe aplastic anemia or recurrent aplastic anemia.

All patients will be treated with eltrombopag for the 26-week Treatment Period, followed by a 52-week Follow-Up Period. Patients who have been previously untreated with immunosuppressive therapy will be treated according to the standard of care, hATG/cyclosporine, in addition to eltrombopag. Patients with relapsed/refractory severe aplastic anema or recurrent aplastic anemia will be enrolled into one of two treatment options: hATG/cyclosporine plus eltrombopag or cyclosporine plus eltrombopag, depending on prior treatment with immunosuppressive therapy.

After initiating treatment with eltrombopag, patients will have their dose assessed and modified as tolerated, until the targeted platelet count or maximum dose is achieved. Pharmacokinetic assessments will be performed at time points intended to capture steady state PK of the starting dose and highest dose achieved. 

Upon completion of the Treatment and Follow-Up Periods, all patients will be offered the opportunity to enroll in an additional 3 year Long Term Follow-Up Period. 

Study Eligibility

For Cohort A:

1. Prior history of diagnosis of SAA

2. Diagnosis of relapsed/refractory SAA or recurrent AA following IST for SAA at the time of enrollment. Patients with recurrent AA (e.g., losing their response) are exempt from meeting the diagnostic criteria for relapsed SAA at the time of enrollment, but must have been previously diagnosed with SAA.

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

For Cohort B:

4. Diagnosis of SAA at the time of enrollment

5. Patients must not have been previously treated for SAA

6. Patients must agree to treatment with hATG + CsA concurrent with eltrombopag. For all patients, regardless of cohort:

7. Age 1 to <18 years

8. Where appropriate, 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.

9. Hematopoietic stem cell transplantation (HSCT) is not available or suitable as a treatment option or has been refused by the patient. (Candidacy for HSCT will be determined as per local practice.)

10. Bone marrow aspirate and biopsy at any time during the 4 weeks prior to first dose of eltrombopag

11. Normal karyotype with FISH for chromosomes 7 and 8

12. Performance status score: Karnofsky ≥50 or Lansky ≥50 (depending on age)

13. Serum creatinine ≤2.5 × ULN

14. Total bilirubin ≤1.5 × ULN

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

Exclusion Criteria:

1. Prior and/or active medical history of:

• Fanconi anemia (via chromosomal breakage test or growth arrest by flow cytometry)
• Other known underlying congenital/inherited marrow failure syndromes
• Symptomatic Paroxysmal Nocturnal Hemoglobinuria (PNH) and/or PNH clones >50% of PMN or RBC at time of enrollment
• Any cytogenetic abnormalities, including but not limited to chromosome 7 or myelodysplasia, in bone marrow within 4 weeks of study enrollment
• Myelodysplastic syndrome (MDS) Updated 01/23/2019
• Other known or suspected underlying primary immunodeficiency
• Any malignancy 

2. Active infection not responding to appropriate therapy

3. Prior eltrombopag or other thrombopoietin receptor (TPO-R) agonist treatment for at least 2 months and a lack of response.

4. Any out of range lab values Creatinine >2.5 × upper limit of normal (ULN), Total bilirubin >1.5 × ULN Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × ULN