A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This was a worldwide, three-part (Part 1: open-label, Part 2: randomized, double-blind, Part 3: extension), multi-center study to evaluate the effect of eltrombopag in subjects with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have thrombocytopenia due to bone marrow insufficiency from their underlying disease or prior chemotherapy. This objective was assessed by a composite primary endpoint that consists of the following: the proportion of ≥Grade 3 hemorrhagic adverse events, or platelet counts <10 Gi/L, or platelet transfusions. Patients with MDS or AML and Grade 4 thrombocytopenia due to bone marrow insufficiency from their underlying disease or prior chemotherapy were enrolled in the study. No low or intermediate-1 risk MDS subjects were enrolled in the study. Subjects must have had at least one of the following during the 4 weeks prior to enrolment: platelet count <10 Gi/L, platelet transfusion, or symptomatic hemorrhagic event. Supportive standard of care (SOC), including hydroxyurea, was allowed as indicated by local practice throughout the study. The study had 3 sequential parts. Subjects who were enrolled in Part 1 (open-label) cannot be enrolled in Part 2 of the study (randomized, double-blind); however, subjects who completed the treatment period for Part 1 or Part 2 (8 and 12 weeks, respectively) continued in Part 3 (extension) if the investigator determined that the subject was receiving clinical benefit on treatment.

Official Title
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A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia (Part 1: Open-label, Part 2: Randomized, Double-blind, Part 3: Extension)

Conditions
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Thrombocytopaenia

Intervention / Treatment
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* Drug: eltrombopag
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ≤50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded. Subjects must have Grade 4 thrombocytopenia (platelet counts <25 Gi/L) due to bone marrow insufficiency (or Grade 4 thrombocytopenia, but platelet count greater than or equal to 25 Gi/L due to platelet transfusion). In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count <10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible. Subjects must have platelet count, bleeding and platelet transfusion data available over a period of at least 4 weeks prior to randomization. Prior systemic treatment for malignancy, with the exception of hydroxyurea, must have been discontinued prior to entry into the study: at least 4 weeks before Day 1 for the following: chemotherapy, demethylating agents (azacitidine or decitabine), lenalidomide, thalidomide, clofarabine and IL-11(oprelvekin); at least 8 weeks before Day 1 for antithymocyte/antilymphocyte globulin. Subjects with a prior stem cell transplant (SCT) must have relapsed after the SCT. Subjects must be stable and, in the opinion of the investigator, be expected to complete a 12 week treatment period. ECOG Status 0-2. Subject must be able to understand and comply with protocol requirements and instructions. Subject has signed and dated an informed consent form. Adequate baseline organ function defined by the criteria below: total bilirubin ≤ 1.5xULN except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect (hemolytic) bilirubin in the absence of ALT abnormality), ALT ≤ 3xULN, creatinine ≤ 2.5xULN Women must be either of non-child bearing potential or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the first dose of study treatment. In France, a subject eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category. Exclusion Criteria: Subjects with MDS and an IPSS of low or intermediate-1 risk at screening. Subjects with a diagnosis of acute promyelocytic or megakaryocytic leukemia or AML secondary to a myeloproliferative neoplasm. History of treatment with romiplostim or other TPO-R agonists. Subjects with a QTc >480 msec (QTc >510 msec for subjects with Bundle Branch Block). Leukocytosis ≥25,000/uL on Day 1 of treatment with study medication. Subjects with known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator. Female subjects who are nursing or pregnant (positive serum or urine β-human chorionic gonadotropin [β-hCG] pregnancy test) at screening or pre-dose on Day 1. Current alcohol or drug abuse. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication. Active and uncontrolled infections (e.g. sepsis, hepatitis B, hepatitis C). Subjects infected with Human Immunodeficiency Virus (HIV). Subjects with liver cirrhosis (as determined by the investigator). Subjects receiving or planned to receive any prohibited medication. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or excipient (microcrystalline cellulose, mannitol, polyvinylpyrrolidone, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 400 and polysorbate 80) that contraindicates the subjects' participation. In France, subjects who have participated in any study using an investigational drug during the previous 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1, Open Label<br>100 mg daily (50 mg for subjects of East Asian heritage), intrasubject dose escalations to a maximum dose 300 mg (150 mg for subjects of East Asian heritage) are allowed. | Drug: eltrombopag<br>* 100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)<br>* Other names: Promacta;|
| Experimental: Part 2, eltrombopag arm<br>100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage) | Drug: eltrombopag<br>* 100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)<br>* Other names: Promacta;|
| Experimental: Part 2, placebo arm<br>100 mg matching placebo daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg matching placebo (150 mg for subjects of East Asian heritage) | Drug: placebo<br>* 100 mg matching placebo daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg matching placebo (150 mg for subjects of East Asian heritage)<br>|
| Experimental: part 3 extension<br>100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage) | Drug: eltrombopag<br>* 100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)<br>* Other names: Promacta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Platelet Response up to Week 8 During Part 1 | A participant was considered as a responder if he/she met the following response criteria: a Baseline platelet count <20 Giga cells per liter (Gi/L) and a post-Baseline increased to >20 Gi/L and at least 2 times the Baseline value; or a Baseline platelet count >=20 Gi/L and a post-Baseline absolute platelet count increased to >=50 Gi/L and at least 2 times the Baseline value. The response criteria was evaluated at each visit. Increase in platelet count observed up to 3 days after a platelet transfusion was not considered as a platelet response. The Part 1 Population was comprised of all participants enrolled into Part 1. | From Baseline up to Week 8 during Part 1 | 
| Clinically Relevant Thrombocytopenic Events (CRTE) From Week 5 up to Week 12 During Part 2 | A participant was considered to have a CRTE at a given assessment if he/she had platelet counts <10 Gi/L, or platelet transfusions, or >=Grade 3 hemorrhagic adverse events. CRTEs during Weeks 5 to 12 were compared between treatments using a generalized linear mixed model. Average of weekly proportion of subjects with CRTE during Week 5 to 12 was estimated for each treatment. Intent to Treat (ITT) Population was comprised of all randomized participants during Part 2. | From Week 5 up to Week 12 during Part 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 1 Subjects) |  | Day 1 to week 8 | 
| Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 2 Subjects) |  | Day 1 to week 12 | 
| Mean Number of Platelet Transfusions |  | Weeks 5 to 12 | 
| Hematologic Improvement | Definitions of hematologic improvement for platelets, neutrophils, and hemoglobin were based on modified International Working Group (IWG) consensus criteria. | Weeks 5 to 12 | 
| Change in Mean Platelet Count |  | Baseline to Week 12 | 
| Maximum Duration of Platelet Transfusion Independence |  | Weeks 5 to 12 | 
| Number of Participants With Maximum Bleeding Grade According to World Health Organization on Bleeding Scale | Occurrence and severity of bleeding, measured using the WHO Bleeding Scale Grade 0=no bleeding; Grade 1=petechiae; Grade 2=mild blood loss; Grade 3=gross blood loss; Grade 4=debilitating blood loss. | Weeks 5 to 12 | 
| Independent Reviewer-Assessed Best Response | Participants were evaluated in accordance with the modified International Working Group (Cheson, 2006). CR: Bone marrow blasts <5%, Hgb ≥11g/dL, Hematologic Improvement - Platelets (Baseline <20Gi/L: >20 Gi/L and 2x baseline; Baseline ≥20 Gi/L: ≥50 Gi/L and 2x baseline), Neutrophils ≥1.0 Gi/L, Peripheral blasts 0%. PR: Bone marrow blasts decreased by ≥50% but >5%, Peripheral blood as in CR. Marrow CR: Bone marrow blasts <5% and decrease by ≥50%, Note any Hematologic Improvements, Stable disease: Failure to achieve PR, but no evidence of progression for >8w, Cytogenetic response: Complete: disappearance of chromosomal abnormality; no new abnormalities Partial: ≥50% reduction of chromosomal abnormality. | up to week 12 | 
| Independent Reviewer Assessed Disease Progression |  | Up to week 12 | 
| Median Overall Survival |  | Up to 13 months | 
| Summary of Health Outcomes | The number of subject with medical resource utilization (MRU) data are reported in this table. MRU included number of emergency room visits, number of home healthcare visits, number of hospitalization days, number of medication or surgery specialist visits, number of procedures inpatient, number of procedures outpatient, number of non-study radiology visits, number of non-study laboratory visits, number of nurse practitioner/physician assistance/nurse visits, number of primary care physician visits, number of telephone consultations. | week 12 | 
| Functional Assessment of Cancer Therapy (FACT) | The FACT-Th-18 is the most widely used and accepted tool evaluating health-related quality-of-life outcomes in cancer patients with chronically low platelets (where Th designates thrombocytopenia). The entire FACT-Th-18 was used in this trial, which includes the 18-item thrombocytopenia subscale used to assess the impact of symptoms, signs, and functional consequences of thrombocytopenia in MDS and AML subjects. The FACT-Th-18 is a validated and reliable instrument with known psychometric properties. FACT-ThS is an 18 item questionnaire specific to assessing the impact of symptoms, signs, and functional consequences of Thrombocytopenia. ThS score ranges from 0 to 72 with higher the score, the better the QoL. FACT G total score moves from 0 to 108 where higher the score, the better the HRQL. FACT-Th Total Score is calculated by adding the FACT-ThS and FACT-G score. Total score ranges from 0 to 180 and again, higher the score, the better the HRQL. | Change from baseline, up to week 12 | 
| EQ-5D Utility Score Analysis | EuroQoL Five Dimensions Questionnaire (EQ-5D) is a standardized generic preference based health related quality of life instrument. It records how one's health is today and consists of a descriptive system. The Descriptive system is Comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension on the EQ-5D involves a 3-point response scale which indicates the level of impairment (level 1 = no problem; level 2 = some or moderate problem(s) and level 3 = unable, or extreme problems). Level of problem reported in each EQ-5D dimension determines a unique health state which is converted into a weighted health state index by applying scores from EQ-5D preference weights elicited from general population samples. This generates a unique description of the subjects' health status, which is valued between 0 (representing death) and 1 (representing perfect health). Higher the score, the better the quality of life. EQ-ED is a score. | Change from baseline, up to week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute myeloid leukemia (AML), acute myelogenous leukemia (AML), acute non lymphocytic leukemia (ANLL), myeloproliferative disease (MDS), myelodysplastic syndrome ( secondary acute myeloid leukemia), refractory acute myeloid leukemia