A Safety and Efficacy Study of Eltrombopag in Subjects With AML

Study Overview
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Brief Summary
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The purpose of this randomized, blinded, placebo-controlled study was to provide clinical safety and exploratory efficacy data on the use of Eltrombopag in adult subjects with Acute Myeloid Leukemia (AML) receiving standard induction chemotherapy with daunorubicin plus cytarabine. A minimum of 120 evaluable subjects newly diagnosed with AML was stratified by antecedent malignant hematologic disorder and age.

Official Title
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A Randomized, Blinded, Placebo-Controlled, Dose Finding Study to Assess the Safety and Efficacy of the Oral Thrombopoietin Receptor Agonist, Eltrombopag, Administered to Subjects With Acute Myelogenous Leukaemia (AML) Receiving Induction Chemotherapy

Conditions
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Acute Leukaemia

Intervention / Treatment
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* Drug: Daunorubicin
* Drug: Cytarabine
* Drug: Eltrombopag
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age >=18 years Diagnosed with AML according to the WHO 2008 classification. Note: subjects with secondary AML following Myelodysplastic syndrome or secondary to previous leukemogenic therapy are allowed provided that a record of previous MDS history or leukemogenic therapy history is available. Eligible for induction by daunorubicin + cytarabine. Eligible to give informed consent to participate in the study. Have adequate baseline organ function defined by the following criteria: Total bilirubin <=1.5 x upper limit of normal (ULN) except for Gilbert's syndrome, or other conditions that are not indicative of inadequate liver function (i.e. elevation of indirect bilirubin (haemolytic) in the absence of alanine aminotransferase [ALT] abnormality). ALT <=3 x ULN. Serum Creatinine <=2.5 x ULN. Adequate cardiac function with LVEF >=50% as assessed by echocardiogram (ECHO) or Multi Gated Acquisition Scan (MUGA. Subjects with a QT interval corrected for heart rate according to Bazett's formula (QTcB) <450millisecond (msec) or <480msec for subjects with bundle branch block. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period. Women must be either of non-childbearing 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. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from time of randomization until 30 days after the last dose of investigational product. Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception during the study and for 30 days following the last dose of investigational product. Exclusion Criteria A diagnosis of acute promyelocytic (M3) or acute megakaryocytic leukaemia (M7). Previous history of exposure to an anthracycline compound. Previous AML treatment (other than hydroxyurea). Any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent. History of thromboembolic event or other condition requiring ongoing use of anticoagulation either with warfarin or low molecular-weight heparin. Note: Occlusion of a central line is not exclusion. Treatment with an investigational drug within 30 days or 5 half lives, whichever is longer, preceding the first dose of study medication. Current and continued use during study treatment period of known Breast cancer resistance protein (BCRP) inhibitors or known P-gp inhibitors. Known active hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV) infection. Known hypersensitivity to any of the study drugs or its excipients.

Ages Eligible for Study
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Minimum 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eltrombopag arm<br>Subjects received induction chemotherapy consisting of daunorubicin bolus intravenous (IV) infusion on Days 1-3 + cytarabine continuous IV infusion on Days 1-7 followed by Eltrombopag once daily orally starting on Day 4 of initial induction chemotherapy. If platelet count was not greater than 100 Gi/L after 7 days the dose was increased until a platelet count of at least 200 Gi/L was achieved/until remission was assessed/ maximum of 42 days from the start of the chemotherapy induction. Subjects who were not aplastic after first cycle of induction chemotherapy received second induction chemotherapy with a modified daunorubicin dose on Days 1-3 + cytarabine on Days 1-7. | Drug: Daunorubicin<br>* For subjects between the ages of 18 and 60 years, 90 mg/m2/day by bolus IV injection through a freshly established free-flowing IV line for 10-15 minutes on days 1, 2, and 3. For subjects > 60 years: daunorubicin dose was adjusted to 60mg /m2.<br>Drug: Cytarabine<br>* 100 mg/m2/day continuous IV infusion on Days 1 through 7.<br>Drug: Eltrombopag<br>* 200 mg orally, once daily, beginning on Day 4 of the first cycle of induction. After 7 days, the dose of the Investigational Product (IP) was to be increased to 300 mg if platelet counts were <100 Gi/L. IP continued until achievement of platelet count of at least 200 Gi/L or assessment of remission of bone marrow status or a maximum of 42 days after initiation of most recent induction. In subjects of East Asian heritage 100 mg orally once daily (a 50% dose reduction) was used and after 7 days, the dose of IP was increased to 150 mg if platelet counts were <100 Gi/L.<br>|
| Placebo Comparator: Placebo arm<br>Subject received induction chemotherapy consisting of daunorubicin bolus IV infusion on Days 1-3 + cytarabine continuous IV infusion on Days 1-7 followed by matching placebo once daily oral dose starting on Day 4 of initial induction chemotherapy. If platelet count was not greater than 100 Gi/L after 7 days the matching placebo was given until a platelet count of at least 200 Gi/L was achieved/ until remission was assessed/ maximum of 42 days from the start of the chemotherapy induction. Subjects who were not aplastic after first cycle of induction chemotherapy received a second induction chemotherapy with a modified daunorubicin dose on Days 1-3 + cytarabine on Days 1-7. | Drug: Daunorubicin<br>* For subjects between the ages of 18 and 60 years, 90 mg/m2/day by bolus IV injection through a freshly established free-flowing IV line for 10-15 minutes on days 1, 2, and 3. For subjects > 60 years: daunorubicin dose was adjusted to 60mg /m2.<br>Drug: Cytarabine<br>* 100 mg/m2/day continuous IV infusion on Days 1 through 7.<br>Drug: Placebo<br>* Orally, once daily, beginning on Day 4 of the first cycle of induction. After 7 days, the dose given was matching 300 mg Eltrombopag if platelet counts were <100 Gi/L. Placebo continued until achievement of platelet count of at least 200 Gi/L or assessment of remission of bone marrow status or a maximum of 42 days after initiation of most recent induction. In subjects of East Asian heritage placebo matching 100 mg Eltrombopag orally once daily was used and after 7 days, the placebo matching 150 mg Eltrombopag was given if platelet counts were <100 Gi/L.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Events (AE) and Any Serious Adverse Events (SAE) as a Measure of Safety and Tolerability. | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is an important medical event that jeopardizes the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or is associated with liver injury and impaired liver function. | From the time the first dose of study treatment was administered until 30 days following discontinuation of investigational product regardless of initiation of a new cancer therapy or transfer to hospice | 
| Change From Baseline in the Left Ventricular Ejection Fraction (LVEF). | LVEF is a measurement of the percentage of blood leaving heart each time it contracts. LVEF was assessed by an echocardiogram (ECHO) or Multiple Gated Acquisition scan (MUGA). Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was calculated as the Day 42 value minus the Baseline value. | Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks) | 
| Number of Participants With Worst-case Grade Changes From Baseline in the Hematology Parameters | The number of participants with a maximum post-baseline grade increase of Grade 3 (G3) or Grade 4 (G4) from their baseline grade are presented. Hematology parameters included only lab tests that are gradable by Common Terminology Criteria for Adverse Events (CTCAE) v4.0. | Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks) | 
| Number of Participants With Worst-case Grade Changes From Baseline in the Clinical Chemistry Parameters | The number of participants with a maximum post-baseline grade increase of Grade 3 or Grade 4 from their baseline grade are presented. Clinical Clinical Chemistry parameters included only lab tests that are gradable by CTCAE v4.0. | Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks) | 
| Number of Participants With Liver Events. | The number of participants with liver enzyme (ALT, AST, ALP, Total bilirubin) abnormalities while receiving study treatment in each arm are presented. | 8 weeks | 
| Number of Participants With Worst-case Changes From Baseline in Electrocardiogram (ECG) Values | The number of participants with worst case post-baseline changes (normal, abnormal - not clinically significant [NCS], abnormal - clinically significant [NS]) in ECG QT prolonged values are presented. The protocol does not define the criteria for normal, abnormal-NCS and abnormal CS ECG. The outcome was based solely on the investigator interpretation of ECG tracings. | Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks) | 
| Number of Participants With Worst-case Changes From Baseline in the Eastern Cooperative Oncology Group (ECOG) Performance Status | The number of participants with worst case post-baseline changes (improved, no change, deteriorated) are presented. | Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks) | 
| Worst-case Change From Baseline in Pulse Rate Values | The worst-case post Baseline high and low changes in pulse rate values from Baseline are presented. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Post Baseline is defined as the highest and lowest non-missing post Baseline value respectively. Change from Baseline was calculated as the post Baseline value minus the Baseline value. | Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks) | 
| Worst-case Post Baseline Change in Blood Pressure Values From Baseline | The worst-case post Baseline high changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) values from Baseline are presented. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Change from Baseline was calculated as the visit value minus the Baseline value. | Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks) | 
| Worst-case Post Baseline Change in Temperature Values From Baseline | The worst-case post Baseline high and low changes in temperature values from Baseline are presented. Baseline was defined as the most recent, non-missing value prior to or on the first study treatment dose date. Post Baseline was defined as the highest and lowest non-missing post Baseline value respectively. Change from Baseline was calculated as the post Baseline value minus the Baseline value. | Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Pharmacokinetics (PK) Parameter of Daunorubicin: Half-life (t1/2) | Daunorubicin half-life. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose) | 
| Plasma Pharmacokinetics (PK) Parameter of Daunorubicinol: Half-life (t1/2) | Daunorubicinol half-life. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose) | 
| Daunorubicin Dose-normalized Plasma: AUC(0-∞) | Daunorubicin AUC(0-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose) | 
| Daunorubicinol Dose-normalized Plasma: AUC(0-∞) | Daunorubicinol AUC(0-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose) | 
| Daunorubicin Dose-normalized Plasma: AUC(24-∞) | Daunorubicin AUC(24-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose) | 
| Daunorubicinol Dose-normalized Plasma: AUC(24-∞) | Daunorubicinol AUC(24-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose) | 
| Daunorubicin Dose-normalized Plasma: AUC(0-t) | Daunorubicin AUC(0-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose) | 
| Daunorubicinol Dose-normalized Plasma: AUC(0-t) | daunorubicinol AUC(0-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose) | 
| Daunorubicin Dose-normalized Plasma: AUC(24-t) | Daunorubicin AUC(24-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose) | 
| Daunorubicinol Dose-normalized Plasma: AUC(24-t) | Daunorubicinol AUC(24-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose) | 
| Daunorubicin Dose-normalized Plasma: Cmax | Daunorubicin Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose) | 
| Daunorubicinol Dose-normalized Plasma: Cmax | Daunorubicinol Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose) | 
| Cycle 2: Daunorubicin Dose-normalized Plasma: AUC(0-24) | Cycle 2 Daunorubicin AUC(0-24). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 2 Day 1 to Day 2 (0 to 24 post-dose) | 
| Cycle 2: Daunorubicinol Dose-normalized Plasma: AUC(0-24) | Cycle 2 Daunorubicinol AUC(0-24). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 2 Day 1 to Day 2 (0 to 24 post-dose) | 
| Cycle 2: Daunorubicin Dose-normalized Plasma: Cmax | Cycle 2 Daunorubicin Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 2 Day 1 to Day 2 (0 to 24 post-dose) | 
| Cycle 2: Daunorubicinol Dose-normalized Plasma: Cmax | Cycle 2 Daunorubicinol Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2. | Cycle 2 Day 1 to Day 2 (0 to 24 post-dose) | 
| Number of Platelet Transfusions Per Week Within Cycles | This was the average number of platelet transfusions per week within cycles. | Post-Base line up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks) | 
| Time to Platelet Count Recovery >=20 Gi/L | Time to Platelet counts >= 20 Gi/L for 3 consecutive days, unaided by transfusions in patients with < 20 Gi/L after chemotherapy. For this endpoint, the event required platelet count to be >= 20 Gi/L for 3 consecutive days. Hematology was assessed daily during hospital stay but only weekly after hospital discharge and thus, platelet count was not always available for 3 consecutive days to confirm the achievement of platelet count recovery. | From last dose of chemotherapy to up to end of study year 2 assessment | 
| Time to Platelet Recovery >=100 Gi/L | Time to platelet counts >= 100 Gi/L unaided by transfusions in participants with < 100 Gi/L after chemotherapy. | From last dose of chemotherapy to up to end of study year 2 assessment | 
| Number of Participants Who Achieved Platelet Count Recovery by Day 21 | Number of participants with platelet counts 20 Gi/L for 3 consecutive days, unaided by transfusions, in patients with < 20 Gi/L after chemotherapy. | By Day 21 | 
| Summary of Platelet Counts Over Time | Platelet counts over time | Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit | 
| Maximum Duration (Days) of Platelet Transfusion Independence | Maximum time period (in days) during which the patient did not receive any platelet transfusion | At differnt time points from start of treatment and up to end of study year 2 assessment | 
| Percentage of Patients Who Achieved Platelet Transfusion Independence ≥ 28 Days | Percentage of patients who achieved platelet transfusion independence ≥ 28 days. | From start of treatment and up to end of study year 2 assessment | 
| Time to Neutrophil Engraftment | Time to absolute neutrophil count (ANC) >= 0.5 Gi/L for 3 consecutive days in participants with ANC < 0.5 Gi/L after chemotherapy | At different time points from last dose of chemotherapy up to end of study year 2 assessment | 
| Summary of Absolute Neutrophil Counts (ANC) | Absolute neutrophil counts over time | Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit | 
| Summary of Hemoglobin | Hemoglobin level over time | Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit | 
| Incidence of Hemorrhagic Events | Incidence of bleeding events using WHO bleeding grade (G0=No bleeding, G1=Petechiae, G2=Mild blood loss, G3=Gross blood loss, G4=Debilitating blood loss) by week and cycle | Baseline, weekly within induction and re-induction cycles, end of therapy | 
| Percentage of Participants With Disease Response Rate and Type of Response | Disease response as assessed by the investigator using the AML International Working Group Response Assessment at the end of therapy/remission assessment visit; Complete remission (CR): defined as transfusion independence, blood count recovery (Abs. neutrophil count > 1.0 Gi/L and Platelet count > 100.0 Gi/L), no leukemic blast in peripheral blood, Bone Marrow (BM) blasts < 5%, maturation of all cell lines, Auer rods not detectable, and no extramedullary disease. Partial remission (PR): defined as CR except that for BM blasts where a decrease of at least 50% of BM blasts to 5-25% in BM aspirate is sufficient or BM blasts < 5% with Auer rods present. Overall response (OR) = CR + PR. | Day 42 of the latest chemotherapy cycle (Up to 8 weeks) | 
| Overall Survival (OS) | Overall survival defined as the time form randomization until the date of death due to any cause. | From randomization to end of 2-year follow-up | 
| Number of Participants Who Required Medical Resource Utilization | Medical Resource Utilization pertained to unscheduled hospitalizations, unscheduled office visits, unscheduled laboratory tests, and unscheduled procedures. | At screening and from start of treatment to end of therapy/remission assessment visit (Day 42 of the latest chemotherapy cycle) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, de novo AML, leukemia, sAML/MDS, acute myeloid leukemia, acute myelogenous leukemia (AML), secondary acute myeloid leukemia, ETB115, Eltrombopag, thrombocytopenia, oral thrombopoietin receptor agonist