Combination of Eltrombopag With Immunosuppressive Therapy in East-Asian Patients With Severe Aplastic Anemia

Study Overview
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Brief Summary
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This study is designed to evaluate the efficacy and safety of eltrombopag when added to r-ATG and CsA in treatment naive East-Asian adult and pediatric patients with SAA.

Official Title
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A Non-randomized, Open Label, Multi-center, Phase II Study to Assess the Safety and Efficacy of Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin (r-ATG) and Cyclosporine A (CsA) in East-Asian Patients With Treatment Naive Severe Aplastic Anemia (REACTS)

Conditions
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Severe Aplastic Anemia (SAA)

Intervention / Treatment
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* Drug: eltrombopag
* Drug: rabbit anti-thymocyte globulin (r-ATG)
* Drug: cyclosporine A (CsA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written study informed consent and (where applicable) assent from the subject, parent, or guardian must be obtained prior to participation in the study. Subjects of East Asian ethnicity aged ≥ 6 years old at the time of written informed consent and assent form (if applicable). SAA characterized by: Bone marrow cellularity < 25%, or 25-50% with < 30% residual hematopoietic cells and pancytopenia, with at least two of the following parameters in peripheral blood: Absolute neutrophil count < 0.5×109/L Platelet count < 20×109/L Absolute reticulocyte count < 20×109/L HSCT is not suitable or available as a treatment option (determined as per local practices or national guidelines), or has been refused by subject. Exclusion Criteria: Prior IST with any ATG/ALG , alemtuzumab, high dose cyclophosphamide (≥ 45 mg/kg/day), CsA within 6 months, or prior thrombopoietin receptor agonists. Eastern Cooperative Oncology Group (ECOG) performance status (age ≥ 16 years) >2, or Lansky performance status (age < 16 years) <50. Prior and/or active medical history of: Known underlying congenital/inherited bone marrow failure or aplastic anemia (e.g.,such as but not limited to Fanconi anemia, congenital dyskeratosis, congenital amegakaryocytic thrombocytopenia, or Shwachman-Diamond Syndrome) Symptomatic paroxysmal nocturnal hemoglobinuria (PNH) and/or PNH clones >50% of polymorphonuclear neutrophil (PMN) or RBC at time of enrollment Myelodysplastic syndrome (MDS) Any cytogenetic abnormalities on karyotyping or FISH within 30 days of study enrollment (an evaluable karyotyping with at least 10 metaphases is mandatory for eligibility) Other known or suspected underlying primary immunodeficiency Any concomitant malignancies that have not fully recovered from treatment or have not been disease-free for 5 years Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN). Creatinine ≥ 2.5×local ULN Past medical history of thromboembolism within 6 months, and/or prior or current antiphospholipid antibody syndrome (APS). Presence of clinically active uncontrolled significant (of such severity that it would preclude the subject's ability to consent, be compliant with study procedures, tolerate protocol therapy) infection, including bacterial, fungal, mycobacterial, parasitic or viral infection, or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the subject or compliance with the protocol Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks or compromise compliance with the protocol, such as: Known hepatocellular disease (e.g. active hepatitis or cirrhosis) Impairment of gastrointestinal (GI) function or gastrointestinal disease that may significantly alter the absorption of study treatment (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) Active skin, mucosa, ocular or GI disorders of Grade > 1 Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening. A positive serology for Hepatitis B (HB) is considered as a positive test for HBsAg. In addition, if serology is negative for HBsAg but hepatitis B core antibody (HBcAb) is positive (regardless of hepatitis B surface antibody (HBsAb) status), a hepatitis B virus (HBV) DNA test will be performed and if positive the patient will be excluded. Cardiac disorder (subjects with congestive heart disease of New York Heart Association (NYHA) functional classification Grade II/III/IV (for pediatric subjects, refer to the Grade II/III/IV of Modified ross heart failure classification for Children) should not be enrolled; subjects with NYHA Grade II due to cardiac disorder should not be enrolled but those with NYHA Grade II due to aplastic anemia (AA) may be enrolled.), arrhythmia with a risk of thrombosis (e.g. atrial fibrillation), pulmonary hypertension, or uncontrolled hypertension (>180/100 mmHg). Other protocol-defined Inclusion/Exclusion may apply.

Ages Eligible for Study
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Minimum Age: 6 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: eltrombopag<br>Participants will receive eltrombopag in combination with r-ATG and CsA. | Drug: eltrombopag<br>* Tablet 25mg and 12.5mg<br>* Other names: ETB115;Drug: rabbit anti-thymocyte globulin (r-ATG)<br>* r-ATG 25 mg sterile lyophilized powder in 10 mL vials for IV use<br>* Other names: r-ATG;Drug: cyclosporine A (CsA)<br>* CsA 25mg Capsule or CsA 5.0g/50mL solution for oral use<br>* Other names: CsA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate | A CR will be defined as (all 3 must be met): Absolute neutrophil count > 1.0 x10^9/L Platelet count > 100 x10^9/L Hemoglobin > 100 g/L | Week 26 (6 months after starting study treatment) | 
| PK Outcome: The AUC calculated to the end of a dosing interval (tau) at steady-state (AUCtau) | AUCtau will be calculated by the trapezoidal rule | Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR rate | A CR will be defined as (all 3 must be met): Absolute neutrophil count > 1.0 x10^9/L Platelet count > 100 x10^9/L Hemoglobin > 100 g/L | Week 13 (3 months), Week 52 (12 months) and yearly after until end of study up to approx. 3 years | 
| Overall response (ORR) rate | Overall response rate is patients achieving complete response (CR) or partial response (PR). A partial response (PR) will be defined as blood counts that do not meet criteria for SAA but are not sufficient for a CR. | Week 13 (3 months), 26 weeks (6 months), 52 weeks, yearly after until end of study up to approx. 3 years | 
| Time from the date of the start of response to the date of relapse or death, which ever occurs first at any time during the study. | Relapse: Clinical relapse is considered as the occurrence of any of the following event in a subject who had achieved a hematological response (CR or PR) but has subsequently lost response (not explained by any other independent concomitant medical conditions): meeting again the criteria for SAA requirement for transfusion again for subjects who had been transfusion independent decrease in any of the peripheral blood counts to: absolute neutrophil count < 0.5 x10^9/L or platelets < 20 x10^9/L. | from the date of the start of response to the date of relapse or death, whichever occurs first at any time during the study up to 3 years | 
| Time from the date of first dose of study treatment to the date of death | Overall Survival (OS) is defined as the time from the date of the first dose of study treatment to the date of death due to any cause. If a subject is not known to have died, survival will be censored at the date of last contact. The distribution function of OS will be estimated using the Kaplan- Meier method and will be plotted. | from date of first dose to date of death up to approx. 3 years | 
| Overall survival (OS) rate | Overall Survival is defined as the time from the date of the first dose of study treatment to the date of death due to any cause. If a subject is not known to have died, survival will be censored at the date of last contact. The distribution function of OS will be estimated using the Kaplan- Meier method and will be plotted. | Week 26, Wee 52 & yearly after up to 3 years | 
| Time from the most recent transfusion to week 13 and week 26 | Transfusion of packed RBC (Red blood cell(s)) units and platelet units | week 13, 26 | 
| Percentage of participants who become (platelet/RBC) transfusion independent | Transfusion independence at each assessment point is defined as follows: Platelet transfusion independence: The subjects who are transfusion dependent at baseline become transfusion free for a period of at least last 4 weeks. RBC transfusion independence: The subjects who are transfusion dependent at baseline become transfusion free for a period of at least last 8 weeks | From date of first dose to approx. 3 years | 
| Time from the date of first dose of investigational treatment to the date of first occurrence of any clonal evolution events | Cytogenetic abnormalities will be assessed by karyotyping (G-banding) and FISH (Fluorescence in situ hybridization) targeting abnormalities including, but not restricted to chromosome 3q del,5q del, monosomy 7, trisomy 8 and those associated with SAA (Severe aplastic anemia), MDS (Myelodysplastic syndrome), AML (Acute myeloid leukemia) etc | Week 13, Week 26, Week 52 and yearly after, and when clinically indicated till approximately 3 years | 
| Pharmacokinetics (PK) parameters: Area under the concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) | Blood samples (2 mL/sample) for eltrombopag PK evaluation will be collected. Full PK profile will be collected in a subset of patients. The plasma eltrombopag concentrations was determined using a validated LC-MS/MS approach. This PK parameter will be calculated by non-compartmental analysis. AUClast will be calculated by the trapezoidal rule | Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose | 
| Plasma trough concentration of eltrombopag | Blood samples (2 mL/sample) for eltrombopag PK evaluation will be collected. The plasma samples will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). 15th day of initial dose and each new dose has started | Baseline to week 26 | 
| PK Outcome: Observed maximum plasma concentration following administration (Cmax) | Full PK profile will be collected in a subset of patients. The plasma eltrombopag concentrations was determined using a validated LC-MS/MS approach. This PK parameter will be calculated by non-compartmental analysis. Cmax will be obtained directly from the concentration-time curve | Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose | 
| PK Outcome: The time to reach peak or maximum concentration (Tmax) | Full PK profile will be collected in a subset of patients. The plasma eltrombopag concentrations was determined using a validated LC-MS/MS approach. This PK parameter will be calculated by non-compartmental analysis. Tmax will be obtained directly from the concentration-time curve | Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose | 
| PK Outcome:Apparent systemic (or total body) clearance at steady state from plasma (CLss/F) | Full PK profile will be collected in a subset of patients. The plasma eltrombopag concentrations was determined using a validated LC-MS/MS approach. This PK parameter will be calculated by non-compartmental analysis. CLss/F will be calculated by dose/AUCtau | Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment naïve severe aplastic anemia, SAA, eltrombopag, ETB115, immunosuppressive therapy, rabbit anti-thymocyte globulin, r-ATG, cyclosporine A, CsA, East-Asian patients