A Safety and Efficacy Study of Eltrombopag in Subjects With AML

Novartis

Status and phase: Completed; Phase 2

Conditions: Acute Leukaemia

Treatments: Drug: Placebo; Drug: Daunorubicin; Drug: Cytarabine; Drug: Eltrombopag

Study type: Interventional

Funder types: Industry

Identifiers

NCT01890746

117146

2013-000642-20 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 148 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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148 participants in 2 patient groups, including a placebo group

Eltrombopag arm

Experimental group

Description:

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.

Treatment:

Drug: Eltrombopag

Drug: Daunorubicin

Drug: Cytarabine

Placebo arm

Placebo Comparator group

Description:

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.

Treatment:

Drug: Daunorubicin

Drug: Placebo

Drug: Cytarabine