A Safety and Efficacy Study of Eltrombopag in Subjects With AML

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis
ClinicalTrials.gov Identifier:
NCT01890746
First received: June 27, 2013
Last updated: May 6, 2016
Last verified: May 2016
  Purpose
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.

Condition Intervention Phase
Leukaemia, Acute
Drug: Daunorubicin
Drug: Cytarabine
Drug: Eltrombopag
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks) ] [ Designated as safety issue: No ]
    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 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) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Liver Events. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    The number of participants with worst case post-baseline changes (improved, no change, deteriorated) are presented.

  • 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) ] [ Designated as safety issue: No ]
    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 Blood Pressure Values From Baseline [ Time Frame: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.


Enrollment: 148
Study Start Date: September 2013
Estimated Study Completion Date: March 2017
Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Eltrombopag arm
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.
Drug: 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.
Drug: Cytarabine
100 mg/m2/day continuous IV infusion on Days 1 through 7.
Drug: 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: Placebo arm
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.
Drug: 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.
Drug: Cytarabine
100 mg/m2/day continuous IV infusion on Days 1 through 7.
Drug: 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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01890746

  Show 43 Study Locations
Sponsors and Collaborators
Novartis
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis
ClinicalTrials.gov Identifier: NCT01890746     History of Changes
Other Study ID Numbers: 117146 
Study First Received: June 27, 2013
Results First Received: March 7, 2016
Last Updated: May 6, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
de novo AML
Eltrombopag
leukemia
sAML/MDS
acute myeloid leukemia
secondary acute myeloid
thrombocytopenia

Additional relevant MeSH terms:
Leukemia
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 28, 2016