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

Study Overview
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Brief Summary
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This is a phase II, open label, multi-center, intra-patient dose escalation study to characterize the pharmacokinetics (PK) after oral administration of eltrombopag in combination with immunosuppressive therapy in pediatric patients with previously untreated or relapsed/refractory severe aplastic anemia or recurrent aplastic anemia.

Detailed Description
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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 SAA or recurrent AA 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. There are four separate periods of this study: Screening (signing of written informed consent through Day -1), Treatment (for 26 weeks), Follow-up (additional 52 weeks), and Long-term Follow-up (for additional 3 years). The first 3 periods will be considered the Core phase of the study. Study completion (Core) will occur when the last patient completes the 26-week treatment and 52-week Follow-up Period [at Week 78].

Official Title
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A Phase II, Open-label, Non-controlled, Intra-patient Dose-escalation Study to Characterize the Pharmacokinetics After Oral Administration of Eltrombopag in Pediatric Patients With Refractory, Relapsed or Treatment Naive Severe Aplastic Anemia or Recurrent Aplastic Anemia

Conditions
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Aplastic Anemia

Intervention / Treatment
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* Drug: Eltrombopag
* Drug: hATG
* Drug: CsA


Participation Criteria
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Eligibility Criteria
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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 Immunosuppressive therapy (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 White blood cell (WBC) or Red blood cell (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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A (Option 1)<br>Regimen 1: hATG (ATGAM®), CsA and eltrombopag begin on Day 1. | Drug: Eltrombopag<br>* Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily<br>* Other names: ETB115;Drug: hATG<br>* Horse ATG (ATGAM) (hATG) is not considered an investigational medicinal product (IMP)<br>Drug: CsA<br>* Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day<br>|
| Experimental: Cohort A (option 2)<br>CsA and eltrombopag begin on Day 1. | Drug: Eltrombopag<br>* Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily<br>* Other names: ETB115;Drug: CsA<br>* Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day<br>|
| Experimental: Cohort B<br>previously untreated SAA), hATG (ATGAM®), CsA and eltrombopag begin on Day 1 and all patients will be treated with the same regimen | Drug: Eltrombopag<br>* Tablet for oral use, once daily or Powder for oral suspension (PfOS), once daily<br>* Other names: ETB115;Drug: hATG<br>* Horse ATG (ATGAM) (hATG) is not considered an investigational medicinal product (IMP)<br>Drug: CsA<br>* Cyclosporine (CsA) will be by supplied as either oral capsules or oral solution, administered twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Eltrombopag PK parameter: AUCtau | Area under the curve calculated to the end of the dosing interval (tau). | 2 weeks and 11 weeks after dose initiation | 
| Eltrombopag PK parameter: Cmax | Peak concentration of drug | 2 weeks and 11 weeks after dose initiation | 
| Eltrombopag PK parameter: Ctrough | Pre-dose drug concentration in a repeated dose setting. | 2 weeks and 11 weeks after dose initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants who have achieved a complete (CR) or partial response (PR) | Percentage of participants who have achieved a complete (CR) or partial response (PR) | Week 12, Week 26, Week 52, and Week 78. | 
| Percentage of participants with a platelet response | Percentage of participants who have achieved a complete or partial platelet response | Week 12, Week 26, Week 52, and Week 78. | 
| Hematologic counts | Platelet (PLT), Hgb, and neutrophil counts | Week 12, Week 26, Week 52, Week 78, and then annually up to 3 years | 
| Red Blood Cell (RBC) transfusion independence | Number and frequency of participants with RBC transfusion independence defined as a period of time of at least 56 days without RBC transfusion. | From date of first dose to approx. 3 years | 
| Platelet transfusion independence | Number and frequency of participants with platelet transfusion independence defined as a period of time of at least 28 days without PLT transfusion. | From date of first dose to approx. 3 years | 
| Bone marrow cellularity | Percentage of hematopoietic cells in bone marrow biopsy. | Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years | 
| Bone marrow morphology | Percentage of hematopoietic cells in bone marrow aspirate | Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years | 
| Bone marrow cytogenetics | Chromosomal structure by karyotyping and Fluorescence in situ hybridization (FISH) | Screening, Week 12, Week, 26, Week 52, Week 78 and then annually up to 3 years | 
| Acceptability and palatability for both tablets and powder for oral suspension | Standardized (total) summary score, ranged from 0-100 will be derived from all items from the questionnaire based on a scoring matrix. | Week 1, Week 2, Week 3, Week 4, Week, 12, Week 26, Week 78 | 
| Clonal evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH) | Percentage of participants with PNH clones | Baseline, Week 12, 26, 52, 78 and annually for up to 3 years to at time of disease progression. | 
| Exposure-response relationship of eltrombopag and overall response and platelet response | Pharmacokinetic parameters of eltrombopag at the highest dose by the best overall response and platelet response | Week 12 or up to Week 26 when the PK highest dose has been achieved | 
| Alternate Overall response (aOR) | Percentage of participants with alternate overall response rate (aORR) defined as the proportion of patients who have achieved an alternate complete response (aCR) or an alternate partial response (aPR) | Week 12, Week 26, Week 52, and Week 78. | 
| PK of eltrombopag at the starting dose (AUCtau) | Pharmacokinetic parameters of eltrombopag (AUCtau) | Week 3 Day 1 | 
| PK of eltrombopag at the starting dose (Cmax) | Pharmacokinetic parameters of eltrombopag (Cmax) | Week 3 Day 1 | 
| PK of eltrombopag at the starting dose (Ctrough) | Pharmacokinetic parameters of eltrombopag (Ctrough) | Week 3 Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cyclosporine, Eltrombopag, Horse anti-thymocyte globulin, previously untreated or relapsed severe aplastic anemia, recurrent aplastic anemia, Severe aplastic anemia, Pharmacokinetics, Immunosuppressive therapy, ETB115, Refractory