A Safety and Efficacy Study of Eltrombopag in Subjects With AML

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01890746
First received: June 27, 2013
Last updated: October 16, 2014
Last verified: October 2014
  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 GlaxoSmithKline:

Primary Outcome Measures:
  • Number of subjects with adverse events (AE) as a measure of safety and tolerability [ Time Frame: Up to 2 years. ] [ Designated as safety issue: No ]
    AEs will be graded by the investigator according to the National Cancer Institute-Common terminology criteria for adverse events version 4 (NCI-CTCAE (version 4.0). AEs will be collected from the time the first dose of study treatment is administered until 30 days following discontinuation of investigational product (IP) regardless of initiation of a new cancer therapy or transfer to hospice.

  • Change from baseline in the left ventricular ejection fraction (LVEF). [ Time Frame: Day 42 of most recent chemotherapy cycle (up to 8 weeks). ] [ Designated as safety issue: No ]
    LVEF will be assessed by either an echocardiogram (ECHO) or Multiple Gated Acquisition scan (MUGA). The evaluation will be performed at baseline, during the screening evaluation period, and within 14 days of final disease response assessment.

  • Clinical laboratory assessment as measure of safety and tolerability. [ Time Frame: Day 42 of most recent chemotherapy cycle (up to 8 weeks). ] [ Designated as safety issue: No ]
    Clinical laboratory assessment includes hematology, clinical chemistry, and urinalysis.


Secondary Outcome Measures:
  • The number of platelet transfusions [ Time Frame: Day 42 of most recent chemotherapy cycle (up to 8 weeks). ] [ Designated as safety issue: No ]
    The number of platelet transfusion will be collected during the study until the response bone marrow biopsy or until the time of subject withdrawal from the study.

  • Time to platelet counts >=20 (Giga units per liter) Gi/L and >=100 Gi/L [ Time Frame: Day 42 of most recent chemotherapy cycle (up to 8 weeks). ] [ Designated as safety issue: No ]
    Platelet recovery is defined as platelet counts >=20 Gi/L for 3 consecutive days, unaided by transfusions.

  • Proportion of subjects who achieve platelet count recovery by Day 21 [ Time Frame: Day 21 ] [ Designated as safety issue: No ]
  • Summary of platelet counts [ Time Frame: Day 42 of most recent chemotherapy cycle (up to 8 weeks) ] [ Designated as safety issue: No ]
  • Duration of platelet transfusion independence [ Time Frame: Day 42 of most recent chemotherapy cycle (up to 8 weeks). ] [ Designated as safety issue: No ]
    Duration of platelet transfusion independence is defined as a time period where subjects do not receive any platelet transfusions during the treatment period and follow-up.

  • Time to absolute neutrophil count (ANC) engraftment defined as ANC recovery 0.5 Gi/L sustained for 3 days. [ Time Frame: Day 42 of most recent chemotherapy cycle (up to 8 weeks). ] [ Designated as safety issue: No ]
  • Number of bleeding events [ Time Frame: Day 42 of most recent chemotherapy cycle (up to 8 weeks). ] [ Designated as safety issue: No ]
    Assessment of bleeding using World Health Organization (WHO) scale will be performed throughout the study from screening until the response bone marrow biopsy assessment. Number of bleeding events will be recorded to assess the incidence and severity of haemorrhagic events.

  • Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Overall survival is defined as the time from randomization until death due to any cause. OS will be assessed to evaluate the effect on Acute Myeloid Leukemia (AML) disease control.

  • Off-treatment Medical resource utilization (MRU). [ Time Frame: Day 42 of most recent chemotherapy cycle (up 8 weeks) ] [ Designated as safety issue: No ]
    MRU information pertaining to unscheduled (not scheduled per protocol) hospitalizations (i.e., total hospital days), unscheduled office visits, unscheduled laboratory tests, and unscheduled procedures will be recorded during therapy and follow-up periods

  • Composite of pharmacokinetic (PK) parameters of daunorubicin and daunorubicinol on Cycle 1 Day 3. [ Time Frame: PK samples will be collected at pre-dose, 1 minute, 0.5, 1, 3, 7, 24, 48, 72, 96, 120, 144 hours post-Day 3 dose. ] [ Designated as safety issue: No ]
    PK parameters include: half-life and dose-normalized plasma area under the concentration-time curve from time zero extrapolated to infinite time (AUC[0-infinity]), area under the concentration-time curve from time zero to time of last quantifiable concentration (AUC[0-t]), area under the concentration-time curve from time 24 hours to time of last quantifiable concentration (AUC[24-t]), and maximum observed concentration (Cmax).

  • Composite of PK parameters of daunorubicin and daunorubicinol on Cycle 2 Day 1 [ Time Frame: PK samples will be collected at pre-dose, 1 minute, 0.5, 1, 3, 7, and 24 hours post-Day 1 dose. ] [ Designated as safety issue: No ]
    PK parameters include: dose-normalized plasma rea under the concentration-time curve from time zero to time 24 hours (AUC [0-24]) and Cmax.

  • Changes in absolute neutrophil counts [ Time Frame: Day 42 of most recent chemotherapy cycle (up to 8 weeks). ] [ Designated as safety issue: No ]
  • Changes in hemoglobin [ Time Frame: Day 42 of most recent chemotherapy cycle (up to 8 weeks) ] [ Designated as safety issue: No ]

Estimated Enrollment: 120
Study Start Date: September 2013
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: August 2016 (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
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

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

  Show 39 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01890746     History of Changes
Other Study ID Numbers: 117146
Study First Received: June 27, 2013
Last Updated: October 16, 2014
Health Authority: Russia: Roszdrav Nadzor
Russian Federation: Ministry of Health and social development of Russian Federation, Federal

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

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Cytarabine
Daunorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
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 October 19, 2014