A Safety and Efficacy Study of Eltrombopag in Subjects With AML

Phase 2

Completed

Conditions: Acute Leukaemia

Interventions: Drug: Daunorubicin
Drug: Cytarabine
Drug: Placebo
Drug: Eltrombopag

Registration Number: NCT01890746

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 148

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo arm	Placebo	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.
Eltrombopag arm	Cytarabine	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.
Eltrombopag arm	Daunorubicin	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.
Eltrombopag arm	Eltrombopag	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.
Placebo arm	Daunorubicin	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.
Placebo arm	Cytarabine	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Any Adverse Events (AE) and Any Serious Adverse Events (SAE) as a Measure of Safety and Tolerability.	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	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.
Number of Participants With Liver Events.	8 weeks	The number of participants with liver enzyme (ALT, AST, ALP, Total bilirubin) abnormalities while receiving study treatment in each arm are presented.
Number of Participants With Worst-case Changes From Baseline in Electrocardiogram (ECG) Values	Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)	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.
Worst-case Post Baseline Change in Blood Pressure Values From Baseline	Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)	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.
Number of Participants With Worst-case Grade Changes From Baseline in the Clinical Chemistry Parameters	Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)	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.
Worst-case Change From Baseline in Pulse Rate Values	Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)	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.
Worst-case Post Baseline Change in Temperature Values From Baseline	Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)	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.
Change From Baseline in the Left Ventricular Ejection Fraction (LVEF).	Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)	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.
Number of Participants With Worst-case Grade Changes From Baseline in the Hematology Parameters	Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)	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.
Number of Participants With Worst-case Changes From Baseline in the Eastern Cooperative Oncology Group (ECOG) Performance Status	Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)	The number of participants with worst case post-baseline changes (improved, no change, deteriorated) are presented.

Secondary Outcome Measures

Name	Time	Method
Daunorubicin Dose-normalized Plasma: AUC(24-t)	Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)	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.
Daunorubicinol Dose-normalized Plasma: AUC(24-t)	Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)	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.
Incidence of Hemorrhagic Events	Baseline, weekly within induction and re-induction cycles, end of therapy	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
Daunorubicin Dose-normalized Plasma: AUC(0-∞)	Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)	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.
Daunorubicinol Dose-normalized Plasma: AUC(0-∞)	Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)	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.
Daunorubicinol Dose-normalized Plasma: AUC(0-t)	Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)	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.
Plasma Pharmacokinetics (PK) Parameter of Daunorubicin: Half-life (t1/2)	Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)	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.
Plasma Pharmacokinetics (PK) Parameter of Daunorubicinol: Half-life (t1/2)	Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)	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 2: Daunorubicin Dose-normalized Plasma: AUC(0-24)	Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)	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: Daunorubicinol Dose-normalized Plasma: AUC(0-24)	Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)	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: Daunorubicin Dose-normalized Plasma: Cmax	Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)	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.
Number of Platelet Transfusions Per Week Within Cycles	Post-Base line up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)	This was the average number of platelet transfusions per week within cycles.
Daunorubicin Dose-normalized Plasma: AUC(24-∞)	Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)	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.
Daunorubicinol Dose-normalized Plasma: AUC(24-∞)	Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)	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.
Daunorubicinol Dose-normalized Plasma: Cmax	Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)	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.
Number of Participants Who Achieved Platelet Count Recovery by Day 21	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.
Summary of Platelet Counts Over Time	Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit	Platelet counts over time
Daunorubicin Dose-normalized Plasma: AUC(0-t)	Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)	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.
Daunorubicin Dose-normalized Plasma: Cmax	Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)	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.
Maximum Duration (Days) of Platelet Transfusion Independence	At differnt time points from start of treatment and up to end of study year 2 assessment	Maximum time period (in days) during which the patient did not receive any platelet transfusion
Percentage of Participants With Disease Response Rate and Type of Response	Day 42 of the latest chemotherapy cycle (Up to 8 weeks)	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.
Summary of Hemoglobin	Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit	Hemoglobin level over time
Overall Survival (OS)	From randomization to end of 2-year follow-up	Overall survival defined as the time form randomization until the date of death due to any cause.
Cycle 2: Daunorubicinol Dose-normalized Plasma: Cmax	Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)	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.
Time to Platelet Recovery >=100 Gi/L	From last dose of chemotherapy to up to end of study year 2 assessment	Time to platelet counts \>= 100 Gi/L unaided by transfusions in participants with \< 100 Gi/L after chemotherapy.
Time to Neutrophil Engraftment	At different time points from last dose of chemotherapy up to end of study year 2 assessment	Time to absolute neutrophil count (ANC) \>= 0.5 Gi/L for 3 consecutive days in participants with ANC \< 0.5 Gi/L after chemotherapy
Time to Platelet Count Recovery >=20 Gi/L	From last dose of chemotherapy to up to end of study year 2 assessment	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.
Percentage of Patients Who Achieved Platelet Transfusion Independence ≥ 28 Days	From start of treatment and up to end of study year 2 assessment	Percentage of patients who achieved platelet transfusion independence ≥ 28 days.
Summary of Absolute Neutrophil Counts (ANC)	Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit	Absolute neutrophil counts over time
Number of Participants Who Required Medical Resource Utilization	At screening and from start of treatment to end of therapy/remission assessment visit (Day 42 of the latest chemotherapy cycle)	Medical Resource Utilization pertained to unscheduled hospitalizations, unscheduled office visits, unscheduled laboratory tests, and unscheduled procedures.