Clinical trial NCT01890746: A Safety and Efficacy Study of Eltrombopag in Subjects With AML
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Leukaemia
Keywords: AML
de novo AML
leukemia
sAML/MDS
acute myeloid leukemia
acute myelogenous leukemia (AML)
secondary acute myeloid leukemia
ETB115
Eltrombopag
thrombocytopenia
oral thrombopoietin receptor agonist
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-07-02
Enrollment: 148
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: Number of Participants With Any Adverse Events (AE) and Any Serious Adverse Events (SAE) as a Measure of Safety and Tolerability.
timeFrame: 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
measure: Change From Baseline in the Left Ventricular Ejection Fraction (LVEF).
timeFrame: Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
measure: Number of Participants With Worst-case Grade Changes From Baseline in the Hematology Parameters
timeFrame: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
measure: Number of Participants With Worst-case Grade Changes From Baseline in the Clinical Chemistry Parameters
timeFrame: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
measure: Number of Participants With Liver Events.
timeFrame: 8 weeks
measure: Number of Participants With Worst-case Changes From Baseline in Electrocardiogram (ECG) Values
timeFrame: Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
measure: Number of Participants With Worst-case Changes From Baseline in the Eastern Cooperative Oncology Group (ECOG) Performance Status
timeFrame: Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
measure: Worst-case Change From Baseline in Pulse Rate Values
timeFrame: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
measure: Worst-case Post Baseline Change in Blood Pressure Values From Baseline
timeFrame: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
measure: Worst-case Post Baseline Change in Temperature Values From Baseline
timeFrame: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Secondary outcomes:
measure: Plasma Pharmacokinetics (PK) Parameter of Daunorubicin: Half-life (t1/2)
timeFrame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
measure: Plasma Pharmacokinetics (PK) Parameter of Daunorubicinol: Half-life (t1/2)
timeFrame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
measure: Daunorubicin Dose-normalized Plasma: AUC(0-∞)
timeFrame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
measure: Daunorubicinol Dose-normalized Plasma: AUC(0-∞)
timeFrame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
measure: Daunorubicin Dose-normalized Plasma: AUC(24-∞)
timeFrame: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
measure: Daunorubicinol Dose-normalized Plasma: AUC(24-∞)
timeFrame: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
measure: Daunorubicin Dose-normalized Plasma: AUC(0-t)
timeFrame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
measure: Daunorubicinol Dose-normalized Plasma: AUC(0-t)
timeFrame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
measure: Daunorubicin Dose-normalized Plasma: AUC(24-t)
timeFrame: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
measure: Daunorubicinol Dose-normalized Plasma: AUC(24-t)
timeFrame: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
measure: Daunorubicin Dose-normalized Plasma: Cmax
timeFrame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
measure: Daunorubicinol Dose-normalized Plasma: Cmax
timeFrame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
measure: Cycle 2: Daunorubicin Dose-normalized Plasma: AUC(0-24)
timeFrame: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
measure: Cycle 2: Daunorubicinol Dose-normalized Plasma: AUC(0-24)
timeFrame: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
measure: Cycle 2: Daunorubicin Dose-normalized Plasma: Cmax
timeFrame: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
measure: Cycle 2: Daunorubicinol Dose-normalized Plasma: Cmax
timeFrame: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
measure: Number of Platelet Transfusions Per Week Within Cycles
timeFrame: Post-Base line up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
measure: Time to Platelet Count Recovery >=20 Gi/L
timeFrame: From last dose of chemotherapy to up to end of study year 2 assessment
measure: Time to Platelet Recovery >=100 Gi/L
timeFrame: From last dose of chemotherapy to up to end of study year 2 assessment
measure: Number of Participants Who Achieved Platelet Count Recovery by Day 21
timeFrame: By Day 21
measure: Summary of Platelet Counts Over Time
timeFrame: Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
measure: Maximum Duration (Days) of Platelet Transfusion Independence
timeFrame: At differnt time points from start of treatment and up to end of study year 2 assessment
measure: Percentage of Patients Who Achieved Platelet Transfusion Independence ≥ 28 Days
timeFrame: From start of treatment and up to end of study year 2 assessment
measure: Time to Neutrophil Engraftment
timeFrame: At different time points from last dose of chemotherapy up to end of study year 2 assessment
measure: Summary of Absolute Neutrophil Counts (ANC)
timeFrame: Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
measure: Summary of Hemoglobin
timeFrame: Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
measure: Incidence of Hemorrhagic Events
timeFrame: Baseline, weekly within induction and re-induction cycles, end of therapy
measure: Percentage of Participants With Disease Response Rate and Type of Response
timeFrame: Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
measure: Overall Survival (OS)
timeFrame: From randomization to end of 2-year follow-up
measure: Number of Participants Who Required Medical Resource Utilization
timeFrame: At screening and from start of treatment to end of therapy/remission assessment visit (Day 42 of the latest chemotherapy cycle)
Other outcomes:
Locations:
city: Farmington
country: United States
facility: Novartis Investigative Site
state: Connecticut
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Orlando
country: United States
facility: Novartis Investigative Site
state: Florida
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Ames
country: United States
facility: Novartis Investigative Site
state: Iowa
city: Sioux City
country: United States
facility: Novartis Investigative Site
state: Iowa
city: Burlington
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Kansas City
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Rochester
country: United States
facility: Novartis Investigative Site
state: New York
city: Durham
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Canton
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Providence
country: United States
facility: Novartis Investigative Site
state: Rhode Island
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Kogarah
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Patra
country: Greece
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Holon
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Kfar Saba
country: Israel
facility: Novartis Investigative Site
city: Tel-Aviv
country: Israel
facility: Novartis Investigative Site
city: Seoul, Korea
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Slupsk
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Kaluga
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Nizhniy Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Penza
country: Russian Federation
facility: Novartis Investigative Site
city: St'Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Tula
country: Russian Federation
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Frey N, Jang JH, Szer J, Illes A, Kim HJ, Ram R, Chong BH, Rowe JM, Borisenkova E, Liesveld J, Winer ES, Cherfi A, Aslanis V, Ghaznawi F, Strickland S. Eltrombopag treatment during induction chemotherapy for acute myeloid leukaemia: a randomised, double-blind, phase 2 study. Lancet Haematol. 2019 Mar;6(3):e122-e131. doi: 10.1016/S2352-3026(18)30231-X. Epub 2019 Jan 29.