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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01890746




Registration number
NCT01890746
Ethics application status
Date submitted
27/06/2013
Date registered
2/07/2013
Date last updated
11/09/2019

Titles & IDs
Public title
A Safety and Efficacy Study of Eltrombopag in Subjects With AML
Scientific 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
Secondary ID [1] 0 0
2013-000642-20
Secondary ID [2] 0 0
117146
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Leukaemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Daunorubicin
Treatment: Drugs - Cytarabine
Treatment: Drugs - Eltrombopag
Treatment: Drugs - Placebo

Experimental: Eltrombopag arm - 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.

Placebo comparator: Placebo arm - 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: Drugs: 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 was adjusted to 60mg /m2.

Treatment: Drugs: Cytarabine
100 mg/m2/day continuous IV infusion on Days 1 through 7.

Treatment: Drugs: Eltrombopag
200 mg orally, once daily, beginning on Day 4 of the first cycle of induction. After 7 days, the dose of the Investigational Product (IP) was to be increased to 300 mg if platelet counts were \<100 Gi/L. IP continued 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) was used and after 7 days, the dose of IP was increased to 150 mg if platelet counts were \<100 Gi/L.

Treatment: Drugs: Placebo
Orally, once daily, beginning on Day 4 of the first cycle of induction. After 7 days, the dose given was matching 300 mg Eltrombopag if platelet counts were \<100 Gi/L. Placebo continued 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 was used and after 7 days, the placebo matching 150 mg Eltrombopag was given if platelet counts were \<100 Gi/L.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants With Any Adverse Events (AE) and Any Serious Adverse Events (SAE) as a Measure of Safety and Tolerability.
Timepoint [1] 0 0
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
Primary outcome [2] 0 0
Change From Baseline in the Left Ventricular Ejection Fraction (LVEF).
Timepoint [2] 0 0
Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Primary outcome [3] 0 0
Number of Participants With Worst-case Grade Changes From Baseline in the Hematology Parameters
Timepoint [3] 0 0
Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Primary outcome [4] 0 0
Number of Participants With Worst-case Grade Changes From Baseline in the Clinical Chemistry Parameters
Timepoint [4] 0 0
Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Primary outcome [5] 0 0
Number of Participants With Liver Events.
Timepoint [5] 0 0
8 weeks
Primary outcome [6] 0 0
Number of Participants With Worst-case Changes From Baseline in Electrocardiogram (ECG) Values
Timepoint [6] 0 0
Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Primary outcome [7] 0 0
Number of Participants With Worst-case Changes From Baseline in the Eastern Cooperative Oncology Group (ECOG) Performance Status
Timepoint [7] 0 0
Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Primary outcome [8] 0 0
Worst-case Change From Baseline in Pulse Rate Values
Timepoint [8] 0 0
Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Primary outcome [9] 0 0
Worst-case Post Baseline Change in Blood Pressure Values From Baseline
Timepoint [9] 0 0
Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Primary outcome [10] 0 0
Worst-case Post Baseline Change in Temperature Values From Baseline
Timepoint [10] 0 0
Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Secondary outcome [1] 0 0
Plasma Pharmacokinetics (PK) Parameter of Daunorubicin: Half-life (t1/2)
Timepoint [1] 0 0
Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Secondary outcome [2] 0 0
Plasma Pharmacokinetics (PK) Parameter of Daunorubicinol: Half-life (t1/2)
Timepoint [2] 0 0
Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Secondary outcome [3] 0 0
Daunorubicin Dose-normalized Plasma: AUC(0-8)
Timepoint [3] 0 0
Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Secondary outcome [4] 0 0
Daunorubicinol Dose-normalized Plasma: AUC(0-8)
Timepoint [4] 0 0
Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Secondary outcome [5] 0 0
Daunorubicin Dose-normalized Plasma: AUC(24-8)
Timepoint [5] 0 0
Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Secondary outcome [6] 0 0
Daunorubicinol Dose-normalized Plasma: AUC(24-8)
Timepoint [6] 0 0
Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Secondary outcome [7] 0 0
Daunorubicin Dose-normalized Plasma: AUC(0-t)
Timepoint [7] 0 0
Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Secondary outcome [8] 0 0
Daunorubicinol Dose-normalized Plasma: AUC(0-t)
Timepoint [8] 0 0
Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Secondary outcome [9] 0 0
Daunorubicin Dose-normalized Plasma: AUC(24-t)
Timepoint [9] 0 0
Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Secondary outcome [10] 0 0
Daunorubicinol Dose-normalized Plasma: AUC(24-t)
Timepoint [10] 0 0
Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Secondary outcome [11] 0 0
Daunorubicin Dose-normalized Plasma: Cmax
Timepoint [11] 0 0
Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Secondary outcome [12] 0 0
Daunorubicinol Dose-normalized Plasma: Cmax
Timepoint [12] 0 0
Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Secondary outcome [13] 0 0
Cycle 2: Daunorubicin Dose-normalized Plasma: AUC(0-24)
Timepoint [13] 0 0
Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Secondary outcome [14] 0 0
Cycle 2: Daunorubicinol Dose-normalized Plasma: AUC(0-24)
Timepoint [14] 0 0
Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Secondary outcome [15] 0 0
Cycle 2: Daunorubicin Dose-normalized Plasma: Cmax
Timepoint [15] 0 0
Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Secondary outcome [16] 0 0
Cycle 2: Daunorubicinol Dose-normalized Plasma: Cmax
Timepoint [16] 0 0
Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Secondary outcome [17] 0 0
Number of Platelet Transfusions Per Week Within Cycles
Timepoint [17] 0 0
Post-Base line up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Secondary outcome [18] 0 0
Time to Platelet Count Recovery >=20 Gi/L
Timepoint [18] 0 0
From last dose of chemotherapy to up to end of study year 2 assessment
Secondary outcome [19] 0 0
Time to Platelet Recovery >=100 Gi/L
Timepoint [19] 0 0
From last dose of chemotherapy to up to end of study year 2 assessment
Secondary outcome [20] 0 0
Number of Participants Who Achieved Platelet Count Recovery by Day 21
Timepoint [20] 0 0
By Day 21
Secondary outcome [21] 0 0
Summary of Platelet Counts Over Time
Timepoint [21] 0 0
Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
Secondary outcome [22] 0 0
Maximum Duration (Days) of Platelet Transfusion Independence
Timepoint [22] 0 0
At differnt time points from start of treatment and up to end of study year 2 assessment
Secondary outcome [23] 0 0
Percentage of Patients Who Achieved Platelet Transfusion Independence = 28 Days
Timepoint [23] 0 0
From start of treatment and up to end of study year 2 assessment
Secondary outcome [24] 0 0
Time to Neutrophil Engraftment
Timepoint [24] 0 0
At different time points from last dose of chemotherapy up to end of study year 2 assessment
Secondary outcome [25] 0 0
Summary of Absolute Neutrophil Counts (ANC)
Timepoint [25] 0 0
Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
Secondary outcome [26] 0 0
Summary of Hemoglobin
Timepoint [26] 0 0
Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
Secondary outcome [27] 0 0
Incidence of Hemorrhagic Events
Timepoint [27] 0 0
Baseline, weekly within induction and re-induction cycles, end of therapy
Secondary outcome [28] 0 0
Percentage of Participants With Disease Response Rate and Type of Response
Timepoint [28] 0 0
Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Secondary outcome [29] 0 0
Overall Survival (OS)
Timepoint [29] 0 0
From randomization to end of 2-year follow-up
Secondary outcome [30] 0 0
Number of Participants Who Required Medical Resource Utilization
Timepoint [30] 0 0
At screening and from start of treatment to end of therapy/remission assessment visit (Day 42 of the latest chemotherapy cycle)

Eligibility
Key inclusion 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
5/09/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
25/01/2017
Sample size
Target
Accrual to date
Final
148
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Kogarah
Recruitment hospital [2] 0 0
Novartis Investigative Site - Melbourne
Recruitment hospital [3] 0 0
Novartis Investigative Site - Parkville
Recruitment postcode(s) [1] 0 0
2217 - Kogarah
Recruitment postcode(s) [2] 0 0
3004 - Melbourne
Recruitment postcode(s) [3] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Connecticut
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Iowa
Country [5] 0 0
United States of America
State/province [5] 0 0
Massachusetts
Country [6] 0 0
United States of America
State/province [6] 0 0
Missouri
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
North Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
State/province [10] 0 0
Pennsylvania
Country [11] 0 0
United States of America
State/province [11] 0 0
Rhode Island
Country [12] 0 0
United States of America
State/province [12] 0 0
Tennessee
Country [13] 0 0
Belgium
State/province [13] 0 0
Bruxelles
Country [14] 0 0
Belgium
State/province [14] 0 0
Leuven
Country [15] 0 0
Canada
State/province [15] 0 0
Ontario
Country [16] 0 0
Canada
State/province [16] 0 0
Quebec
Country [17] 0 0
Greece
State/province [17] 0 0
Athens
Country [18] 0 0
Greece
State/province [18] 0 0
Patra
Country [19] 0 0
Hungary
State/province [19] 0 0
Debrecen
Country [20] 0 0
Hungary
State/province [20] 0 0
Szeged
Country [21] 0 0
Israel
State/province [21] 0 0
Haifa
Country [22] 0 0
Israel
State/province [22] 0 0
Holon
Country [23] 0 0
Israel
State/province [23] 0 0
Jerusalem
Country [24] 0 0
Israel
State/province [24] 0 0
Kfar Saba
Country [25] 0 0
Israel
State/province [25] 0 0
Tel-Aviv
Country [26] 0 0
Korea, Republic of
State/province [26] 0 0
Seoul, Korea
Country [27] 0 0
Korea, Republic of
State/province [27] 0 0
Seoul
Country [28] 0 0
Poland
State/province [28] 0 0
Slupsk
Country [29] 0 0
Poland
State/province [29] 0 0
Wroclaw
Country [30] 0 0
Russian Federation
State/province [30] 0 0
Kaluga
Country [31] 0 0
Russian Federation
State/province [31] 0 0
Moscow
Country [32] 0 0
Russian Federation
State/province [32] 0 0
Nizhniy Novgorod
Country [33] 0 0
Russian Federation
State/province [33] 0 0
Penza
Country [34] 0 0
Russian Federation
State/province [34] 0 0
St'Petersburg
Country [35] 0 0
Russian Federation
State/province [35] 0 0
Tula

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT01890746
Trial related presentations / publications
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.
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01890746