Study of Efficacy and Safety of Eltrombopag in Lower-risk MDS Patients With Platelet Transfusion Dependence

Study Overview
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Brief Summary
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This study is designed to evaluate the efficacy and safety of eltrombopag monotherapy in Japanese adult patients with platelet transfusion-dependent lower-risk Myelodysplastic syndromes (LR-MDS).

Detailed Description
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This is a randomized, double-blind, placebo-controlled, Japanese local phase II study to evaluate the efficacy and safety of eltrombopag monotherapy in Japanese adult patients with platelet transfusion-dependent lower-risk MDS (IPSS-R very low, low, intermediate risk with bone marrow blast count < 5% and cytogenetic very good, good or intermediate risk). Platelet transfusion dependence at baseline is defined as receiving platelet transfusion regularly with a frequency of 2 or more times within 4 weeks prior to randomization. Platelet transfusion should be performed for a patient with platelet counts < 20 X 10^9/L, or with hemorrhagic symptoms and platelet counts < 30 X 10^9/L. The primary objective is to demonstrate superiority of eltrombopag versus placebo in terms of the proportion of participants who achieve platelet transfusion independence at Week 24.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Japan Local Phase II Clinical Study Comparing Eltrombopag Monotherapy Versus Placebo in Adult Lower-risk Myelodysplastic Syndromes (MDS) Patients With Platelet Transfusion Dependence

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Eltrombopag
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with MDS according to the WHO classification revised 4th edition by investigator assessment with one of the following prognostic risk categories, based on the International Prognostic Scoring System (IPSS-R): very low (0-1.5) low (2-3) intermediate risks (3.5-4.5) All following criteria for prognostic variables per IPSS-R should be met. Bone marrow blast < 5% (per both investigator's assessment and central review) Cytogenetic very good, good or intermediate risk corresponding to IPSS-R Platelet transfusion dependence Refractory, intolerant to, or ineligible for MDS treatments Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 0 or 1 Exclusion Criteria: Patients with a history of prior administration of eltrombopag, romiplostim, or other TPO-RA Therapy-related MDS per WHO classification revised 4th edition MDS/myeloproliferative neoplasms including chronic myelomonocytic leukaemia per the WHO classification revised 4th edition MDS with excess blasts (EB) per WHO classification revised 4th edition Known history of IPSS-R high or very high risk MDS Currently receiving treatments for MDS (e.g., HMA, cyclosporine A (CsA) or lenalidomide). Supportive treatment with erythropoiesis-stimulating agents (ESAs) in anemic patients or granulocyte-colony stimulating factor (G-CSF) in patients with severe neutropenia and recurrent infections is allowed if at stable dosage for 3 months prior to screening and continued at the same dosing/schedule until the optimal dose of eltrombopag has been established. Patients scheduled for hematopoietic stem cell transplantation Bone marrow fibrosis that leads to an inability to aspirate adequate bone marrow sample Known thrombophilic risk factors (except in cases where potential benefits of participating in the study outweighed potential risks of thromboembolic events(TEE), as determined by the investigator) Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 99 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eltrombopag Arm<br>Participants randomized to a 1: 1 ratio will take eltrombopag. | Drug: Eltrombopag<br>* Eltrombopag comes in 12.5 mg & 25 mg tablets and is taken orally once per day (QD)<br>* Other names: ETB115;|
| Placebo Comparator: Placebo Arm<br>Participants randomized to a 1: 1 ratio will take Placebo. | Drug: Placebo<br>* Placebo comes in 12.5 mg & 25 mg tablets and is taken orally once per day (QD)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants who achieve platelet transfusion independence at Week 24 | Platelet transfusion independence is defined as the absence of platelet transfusion for at least 8 weeks. Platelet count should be higher than the baseline count. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to platelet transfusion independence | This is defined as time from the date of randomization to the first day of a platelet transfusion-free period lasting at least 8 weeks. | Year 1, Year 2 | 
| Duration of platelet transfusion independence | This is defined for participants who have achieved platelet transfusion independence only and will be calculated from the first date of platelet transfusion-free resulting in achievement of transfusion independence to the date before becoming platelet transfusion dependent. | Year 1, Year 2 | 
| Percentage of participants with platelet transfusion independence | Platelet transfusion independence is defined as the absence of platelet transfusion for at least 8 weeks. Platelet count should be higher than the baseline count. | Year 1, Year 2 | 
| Percentage of participants with platelet transfusion frequency reduction at Week 24 | This is defined as a reduction by at least 50 percent during the 4 prior weeks as compared to the 4 weeks prior to randomization. | Week 24 | 
| Percentage of participants with platelet response (Hematologic improvement (HI) - platelet)) | Platelet response is defined as HI-platelet per International Working Group criteria. | Week 24, Year 1, Year 2 | 
| Time to platelet response | This is defined as time from the date of randomization to the first date of achieving the platelet response criteria per modified IWG criteria. | Week 24, Year 1, Year 2 | 
| Duration of platelet response | This is defined for participants who have achieved platelet response and will be calculated from the first date of achieving the platelet response criteria to the date before loss of platelet response per modified IWG criteria. | Week 24, Year 1, Year 2 | 
| Percentage of hematologic improvement-erythroid and -neutrophil | per modified IWG criteria at 24 weeks, Year 1 and 2 | Week 24, Year 1, Year 2 | 
| Percentage of participants with disease progression excluding relapse after HI | This is with regards to blast counts for both investigator assessment and central review per modified IWG criteria. | Week 24, Year 1, Year 2 | 
| Percentage of participants with relapse after HI and transfusion independence | The percentage of participants with relapse after HI and transfusion independence at Week 24, Year 1 and 2. | Week 24, Year 1, Year 2 | 
| Percentage of participants with progression to Acute myeloid leukemia (AML) | This is defined as ≥ 20% blasts at Week 24, Year 1 and 2 for both investigator assessment and central review per WHO classification revised 4th edition. | Week 24, Year 1, Year 2 | 
| Leukemia free survival (LFS) | This is defined as time from the date of randomization to progression to AML per WHO classification revised 4th edition of ≥ 20 percent blasts or death due to any cause for both investigator assessment and central review. | Week 24, Year 1, Year 2 | 
| Clinically significant bleeding events | This is defined as ≥ grade 2 events as per WHO bleeding scale. | Week 24, Year 1, Year 2 | 
| Overall survival (OS) | OS is defined as time from randomization to death due to any cause. | Week 24, Year 1, Year 2 | 
| Quality of Life measured using QLQ-C30 | The changes from baseline to each visit where measured using QLQ-C30. EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Subject's responses to 28 questions about their physical functioning, disease symptoms, global health status and utilities are scored on a 4-point scale (1=Not at all to 4=Very much), a low score indicates a high / healthy level of functioning. And the responses to 2 questions about health-related QoL are scored on a 7-point scale (1=Very poor to 7=Excellent), a high score indicates a high / healthy level of functioning. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. | Baseline, every 4 weeks until week 52, every 8 weeks after week 52 up to end of treatment or end of post-treatment follow-up, approximately 3.5 years. | 
| Pharmacokinetics (PK): Cmax | Full PK profile of eltrombopag over 24 hours at steady state at the initial dose, and at 125 mg and 150 mg when applicable, in subset of participants. | Intensive: pre-dose, 1, 2, 4, 6, 8, and 24 hours post-dose. Trough: 15th days after starting the initial dose or each dose modification until reaching the maximum dose. | 
| PK: Tmax | Full PK profile of eltrombopag over 24 hours at steady state at the initial dose, and at 125 mg and 150 mg when applicable, in subset of participants. | Intensive: pre-dose, 1, 2, 4, 6, 8, and 24 hours post-dose. Trough: 15th days after starting the initial dose or each dose modification until reaching the maximum dose. | 
| PK: AUC | Full PK profile of eltrombopag over 24 hours at steady state at the initial dose, and at 125 mg and 150 mg when applicable, in subset of participants. | Intensive: pre-dose, 1, 2, 4, 6, 8, and 24 hours post-dose. Trough: 15th days after starting the initial dose or each dose modification until reaching the maximum dose. | 
| Trough concentrations of eltrombopag at steady state | at each dose level in all the participants | Intensive: pre-dose, 1, 2, 4, 6, 8, and 24 hours post-dose. Trough: 15th days after starting the initial dose or each dose modification until reaching the maximum dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TPO-RA, placebo, myelodysplastic syndromes (MDS), Phase II, eltrombopag, ETB115, platelet transfusion dependence, lower-risk MDS patients with platelet transfusion dependence