Overview

This trial is active, not recruiting.

Condition leukaemia, acute
Treatments daunorubicin, cytarabine, eltrombopag, placebo
Phase phase 2
Sponsor GlaxoSmithKline
Start date September 2013
End date March 2015
Trial size 148 participants
Trial identifier NCT01890746, 117146

Summary

The purpose of this randomized, blinded, placebo-controlled study is 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. These safety data are considered necessary to further development of Eltrombopag in both adult and paediatric patients suffering from malignant diseases with secondary thrombocytopenia. A minimum of 120 evaluable subjects with newly diagnosed with AML will be stratified by antecedent malignant hematologic disorder and age.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety study
Intervention model parallel assignment
Masking double blind (subject, investigator)
Primary purpose treatment
Arm
(Experimental)
Subject will receive 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 is not greater than 100 Gi/L after 7 days the dose will be increased until a platelet count of at least 200 Gi/L is achieved/until remission is assessed/ maximum of 42 days from the start of the chemotherapy induction. Subjects who are not aplastic after first cycle of induction chemotherapy will receive second induction chemotherapy with a modified daunorubicin dose on Days 1-3 + cytarabine on Days 1-7.
daunorubicin
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 is adjusted to 60mg /m2.
cytarabine
100 mg/m2/day continuous IV infusion on Days 1 through 7.
eltrombopag
200 mg orally, once daily, beginning on Day 4 of the first cycle of induction. After 7 days, the dose of IP will be increased to 300 mg if platelet counts are <100 Gi/L. IP continues 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) will be used and after 7 days, the dose of IP will be increased to 150 mg if platelet counts are <100 Gi/L
(Placebo Comparator)
Subject will receive 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 is not greater than 100 Gi/L after 7 days the matching placebo will be given until a platelet count of at least 200 Gi/L is achieved/ until remission is assessed/ maximum of 42 days from the start of the chemotherapy induction. Subjects who are not aplastic after first cycle of induction chemotherapy will receive a second induction chemotherapy with a modified daunorubicin dose on Days 1-3 + cytarabine on Days 1-7.
daunorubicin
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 is adjusted to 60mg /m2.
cytarabine
100 mg/m2/day continuous IV infusion on Days 1 through 7.
placebo
Orally, once daily, beginning on Day 4 of the first cycle of induction. After 7 days, the dose given will be matching 300 mg Eltrombopag if platelet counts are <100 Gi/L. Placebo continues 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 will be used and after 7 days, the placebo matching 150 mg Eltrombopag will be given if platelet counts are <100 Gi/L.

Primary Outcomes

Measure
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 (assessed up to 2 years)
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)
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)
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)
Number of participants with liver events.
time frame: 8 weeks
Number of participants with electrocardiogram (ECG) adverse events.
time frame: 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.
time frame: Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
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)
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)
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)

Secondary Outcomes

Measure
Number of platelet transfusions.
time frame: Up to 8 weeks
Time to platelet counts >=20 Giga units/liter (Gi/L) and >=100 Gi/L
time frame: Up to 8 weeks
Percentage of participants who achieved platelet count recovery by Day 21.
time frame: Day 21
Summary of platelet counts
time frame: Up to 8 weeks
Duration of platelet transfusion independence.
time frame: Up to 8 weeks
Time to absolute neutrophil count (ANC) engraftment defined as ANC recovery >=0.5 Gi/L sustained for 3 days.
time frame: Up to 8 weeks
Number of participants in each WHO Bleeding Grade.
time frame: Up to 8 weeks
Overall survival
time frame: Up to 2 years
Off-treatment Medical resource utilization (MRU)
time frame: Up to 8 weeks
Pharmacokinetic parameters of daunorubicin and daunorubicinol on Cycle 1 Day 3: half-life.
time frame: Cycle 1 Day 3 to Day 9
Pharmacokinetic parameters of daunorubicin and daunorubicinol on Cycle 1 Day 3: maximum plasma concentration (Cmax)
time frame: Cycle 1 Day 3 to Day 9
Pharmacokinetic parameters of daunorubicin and daunorubicinol on Cycle 1 Day 3: dose normalized plasma AUC(0-infinity), AUC(24-infinity), AUC(0-t), AUC(24-t)
time frame: Cycle 1 Day 3 to Day 9
Pharmacokinetic parameters of daunorubicin and daunorubicinol on Cycle 2 Day 1: Cmax.
time frame: Cycle 2 Day 1 to Day 2
Pharmacokinetic parameters of daunorubicin and daunorubicinol on Cycle 2 Day 1: dose-normalized plasma area under the concentration-time curve from time zero to 24 hours (AUC[0-24])
time frame: Cycle 2 Day 1 to Day 2
Changes in absolute neutrophil counts.
time frame: Up to 8 weeks
Changes in hemoglobin.
time frame: Up to 8 weeks
Number of participants in each disease response category.
time frame: Up to 8 weeks
Duration of response.
time frame: Up to 2 years

Eligibility Criteria

Male or female participants at least 18 years old.

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.

Additional Information

Official 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
Trial information was received from ClinicalTrials.gov and was last updated in February 2016.
Information provided to ClinicalTrials.gov by GlaxoSmithKline.
Location data was received from the National Cancer Institute and was last updated in May 2016.