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NCT Number: NCT01890746

A Safety and Efficacy Study of Eltrombopag in Subjects With AML

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.

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Key information

Conditions

Acute Leukaemia Blood Platelet Disorders Cytopenia Hematologic Diseases Hemic and Lymphatic Diseases Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Neoplasms Neoplasms by Histologic Type Thrombocytopenia

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Novartis Investigative Site, Kogarah, New South Wales, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Daunorubicin

Drug

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.

Cytarabine

Drug

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

eltrombopag

Drug

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.

Placebo

Drug

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.

Primary outcomes

  1. Number of Participants With Any Adverse Events (AE) and Any Serious Adverse Events (SAE) as a Measure of Safety and Tolerability.

    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

    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.

  2. Change From Baseline in the Left Ventricular Ejection Fraction (LVEF).

    Time frame: 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.

  3. Number of Participants With Worst-case Grade Changes From Baseline in the Hematology Parameters

    Time frame: 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.

  4. Number of Participants With Worst-case Grade Changes From Baseline in the Clinical Chemistry Parameters

    Time frame: 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.

  5. Number of Participants With Liver Events.

    Time frame: 8 weeks

    The number of participants with liver enzyme (ALT, AST, ALP, Total bilirubin) abnormalities while receiving study treatment in each arm are presented.

  6. Number of Participants With Worst-case Changes From Baseline in Electrocardiogram (ECG) Values

    Time frame: 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.

  7. Number of Participants With Worst-case Changes From Baseline in the Eastern Cooperative Oncology Group (ECOG) Performance Status

    Time frame: 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.

  8. Worst-case Change From Baseline in Pulse Rate Values

    Time frame: 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.

  9. Worst-case Post Baseline Change in Blood Pressure Values From Baseline

    Time frame: 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.

  10. Worst-case Post Baseline Change in Temperature Values From Baseline

    Time frame: 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.

Secondary outcomes

  1. Plasma Pharmacokinetics (PK) Parameter of Daunorubicin: Half-life (t1/2)

    Time frame: 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.

  2. Plasma Pharmacokinetics (PK) Parameter of Daunorubicinol: Half-life (t1/2)

    Time frame: 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.

  3. Daunorubicin Dose-normalized Plasma: AUC(0-∞)

    Time frame: 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.

  4. Daunorubicinol Dose-normalized Plasma: AUC(0-∞)

    Time frame: 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.

  5. Daunorubicin Dose-normalized Plasma: AUC(24-∞)

    Time frame: 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.

  6. Daunorubicinol Dose-normalized Plasma: AUC(24-∞)

    Time frame: 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.

  7. Daunorubicin Dose-normalized Plasma: AUC(0-t)

    Time frame: 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.

  8. Daunorubicinol Dose-normalized Plasma: AUC(0-t)

    Time frame: 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.

  9. Daunorubicin Dose-normalized Plasma: AUC(24-t)

    Time frame: 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.

  10. Daunorubicinol Dose-normalized Plasma: AUC(24-t)

    Time frame: 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.

  11. Daunorubicin Dose-normalized Plasma: Cmax

    Time frame: 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.

  12. Daunorubicinol Dose-normalized Plasma: Cmax

    Time frame: 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.

  13. Cycle 2: Daunorubicin Dose-normalized Plasma: AUC(0-24)

    Time frame: 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.

  14. Cycle 2: Daunorubicinol Dose-normalized Plasma: AUC(0-24)

    Time frame: 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.

  15. Cycle 2: Daunorubicin Dose-normalized Plasma: Cmax

    Time frame: 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.

  16. Cycle 2: Daunorubicinol Dose-normalized Plasma: Cmax

    Time frame: 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.

  17. 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)

    This was the average number of platelet transfusions per week within cycles.

  18. Time to Platelet Count Recovery >=20 Gi/L

    Time frame: 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.

  19. Time to Platelet Recovery >=100 Gi/L

    Time frame: 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.

  20. Number of Participants Who Achieved Platelet Count Recovery by Day 21

    Time frame: 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.

  21. Summary of 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

    Platelet counts over time

  22. Maximum Duration (Days) of Platelet Transfusion Independence

    Time frame: 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

  23. 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

    Percentage of patients who achieved platelet transfusion independence ≥ 28 days.

  24. Time to Neutrophil Engraftment

    Time frame: 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

  25. Summary of Absolute Neutrophil Counts (ANC)

    Time frame: 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

  26. Summary of Hemoglobin

    Time frame: Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit

    Hemoglobin level over time

  27. Incidence of Hemorrhagic Events

    Time frame: 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

  28. Percentage of Participants With Disease Response Rate and Type of Response

    Time frame: 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.

  29. Overall Survival (OS)

    Time frame: 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.

  30. Number of Participants Who Required Medical Resource Utilization

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study title

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

Important dates

Study start
2013
Primary completion
2015
Study completion
2017
First posted
Jul 2, 2013
Registry last updated
Sep 11, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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