Study of Efficacy and Safety of Eltrombopag in Patients With Poor Graft Function

Study Overview
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Brief Summary
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The purpose of this phase II open-label, single-arm 36-week clinical trial is to evaluate the effect of eltrombopag in patients with poor graft function (PGF) after allogeneic-hematopoietic stem cells transplantation (allo-HSCT).

Detailed Description
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The primary objective of this study is to evaluate the efficacy of eltrombopag for poor graft function on overall hematologic response (partial and complete), as determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the initiation of eltrombopag.

Official Title
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The ELTION Study - A Multicenter Open-label Interventional Study of Eltrombopag in Patients With Poor Graft Function After Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Poor Graft Function

Intervention / Treatment
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* Drug: Eltrombopag


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be able to understand and communicate with the investigator and comply with the requirements of the study and must provide written, signed and dated informed consent form before any study assessment is performed Male of female patients ≥ 18 years of age Patients diagnosed with primary or secondary poor graft function (PGF) defined as two or more cytopenias after day +30 post-transplant (re-tested in a peripheral blood analysis at screening): Platelet count <20,000/ µL (mandatory) Absolute neutrophil count (ANC) <1,000/µL Hemoglobin <100 g/L Presence of donor chimerism >90% in screening visit Karnofsky status ≥90% (Karnofsky assessment must be performed within 7 days prior to Day 1) Exclusion Criteria: Pregnant or nursing (lactating women). Evidence of active acute or chronic graft versus host disease (GVHD). Evidence of any active malignancy. Subjects who are human immune deficiency virus (HIV), hepatitis C virus (HCV), hepatitis B surface antigen (HBsAg) positive in screening visit. Cytogenetic abnormality in chromosome 7 present before the allo-HSC. Evidence of any clonal abnormality on cytogenetics (in bone marrow analysis). A local post-transplant conventional cytogenetic assessment should be available within 8 weeks before Day 1. If the cytogenetics is not valuable, i.e, it does not show metaphases, a FISH for MDS-related most frequent abnormalities including chromosome 7 is accepted. As a consequence, patients with dry tap bone marrow aspiration are NOT eligible. Evidence of bone marrow involvement or progression of the underlying disease assessed by the applicable methods in each case. Evidence of thrombotic microangiopathy. Evidence of possible causes of cytopenia other than PGF (active infections, myelotoxic drugs, hypersplenism…). Prior use of any thrombopoietin receptor (TPO-R) agonists for PGF. AST or ALT levels >3 x ULN. Creatinine level ≥1.5 x ULN. Total bilirubin level ≥1.5 x ULN. Previous thromboembolic event (other than line-related upper extremity thrombosis) Hypersensitivity to eltrombopag or its components. Clinically significant ECG abnormality history or current diagnosis of cardiac disease indicating significant risk of safety for subjects participating in the study such as uncontrolled or significant cardiac disease or impaired cardiac function including any of the following: . Corrected QTc > 450 msec (male subjects), > 460 msec (female subjects) using Fredericia correction (QTcF) on the screening ECG . Myocardial infarction . Uncontrolled congestive heart failure . Unstable angina . Congenital long QT syndrome. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment. Patient with liver cirrhosis. Risk factors for Torsade de Pointes including uncorrected hypokalemia or hypomagnesemia. Subjects with any serious and/ or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with patient´s safety, obtaining informed consent or compliance with the study procedures as per investigator discretion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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>Patients will receive eltrombopag orally once daily up to 36 weeks. | Drug: Eltrombopag<br>* 50mg Film-coated tablet and 25mg Film-coated tablet for oral use administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with hematologic response (partial and complete) | Evaluate the efficacy of eltrombopag on overall hematologic response (partial (PR) and complete (CR). A PR is defined when any of the following: Platelet count ≥20,000/μL (with platelet transfusion independence), confirmed in two consecutive blood tests separated a minimum of 7 days. Absolute neutrophil count (ANC) ≥1,000/μL (when pretreatment ANC was <1,000/μL), confirmed in two blood tests separated a minimum of 7 days. Hemoglobin (Hb) ≥100g/L (when pretreatment Hb was <100g/L) (with Red Blood Cells transfusion independence), confirmed in two blood tests separated a minimum of 7 days. A CR is defined when all three of the following: Platelet count ≥100,000/μL, confirmed in two blood tests separated a minimum of 7 days. ANC ≥1,500/μL (when pretreatment ANC was <1,000/μL), confirmed in two blood tests separated a minimum of 7 days. Hb ≥110 g/L (when pretreatment Hb was <100g/L), confirmed in two blood tests separated a minimum of 7 days. | Baseline up to approximately 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients who have a response in the neutrophil lineage | ANC ≥1,000/ µL or ≥ 1500/ µL in hematological results before week 16, confirmed in two consecutive blood tests separated a minimum of 7 days. | Baseline up to approximately 16 weeks | 
| Percentage of patients who have a response in the platelet lineage | Platelet count ≥20,000/µL or ≥ 100000/µL in hematological results until week 16, confirmed in two consecutive blood tests separated a minimum of 7 days. | Baseline up to approximately 16 weeks | 
| Percentage of patients who have a response in the hemoglobin lineage | Hb ≥100 g/L or ≥ 110 g/L in hematological results obtained before week 16, confirmed in two consecutive blood tests separated a minimum of 7 days | Baseline up to approximately 16 weeks | 
| Percentage of participants that mantain hematologic response (partial and complete) | Evaluate if overall hematologic response (partial and complete) at week 16 is mantained at 24 and 36 weeks after treatment. Same values of 3 lineages separately (netrophil, platelet and hemoglobin) will be used to assess this endpoint. | Baseline up to approximately 24 and 36 weeks | 
| Percentage of participants who were previously transfusion-dependent and do no longer require transfusions | Patients previously transfusion-dependent who do no longer require platelets and/or RBC transfusion before and after the first 16 weeks of treatment. | Baseline up to approximately 16 weeks and after week 16 to week 36 | 
| Discontinuation of G-CSF and/or EPO therapy | Number of patients who discontinue or reduce by ≥50% the use of concomitant G-CSF and/or EPO therapy. | Baseline up to approximately 36 weeks | 
| Overall survival | Time from the date of inclusion until the date of death due to any cause. All patients who discontinue from the study, regardless the reason of discontinuation, will be followed for survival for 24 and 36 weeks, unless they withdraw their consent, die or are lost-to follow-up, in which case will be censored at the last contact. | Baseline up to approximately 36 weeks | 
| Percentage of participants surviving at 24 and 36 weeks | Percentage of patients still alive at 24 weeks and 36 weeks. | Baseline up to approximately 24 and 36 weeks | 
| Duration of transfusion independence | Analyze the time period where patients did not receive any platelet or RBC transfusions | Baseline up to approximately 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eltrombopag, hematological response; poor graft function, stem cell transplantation. CETB115EES03, adult, ELTION, phase II