A Safety and Efficacy Study of Eltrombopag in Subjects With AML

Novartis Pharmaceuticals148 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

148

Conditions

Acute Leukaemia

Interventions

DaunorubicinDRUG

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.

CytarabineDRUG

100 mg/m2/day continuous IV infusion on Days 1 through 7.

EltrombopagDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (42)

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)

Data from ClinicalTrials.gov

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Novartis Investigative Site

Farmington, Connecticut, United States

Novartis Investigative Site

Miami, Florida, United States

Novartis Investigative Site

Orlando, Florida, United States

Novartis Investigative Site

Atlanta, Georgia, United States

Novartis Investigative Site

Ames, Iowa, United States

Novartis Investigative Site

Sioux City, Iowa, United States

Novartis Investigative Site

Burlington, Massachusetts, United States

Novartis Investigative Site

Kansas City, Missouri, United States

Novartis Investigative Site

Rochester, New York, United States

Novartis Investigative Site

Durham, North Carolina, United States

...and 32 more locations

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: By Day 21

Summary of Platelet Counts Over Time

Platelet counts over time

Time frame: 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

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: At screening and from start of treatment to end of therapy/remission assessment visit (Day 42 of the latest chemotherapy cycle)