Acute LeukaemiaPhase 2NCT01890746
A Safety and Efficacy Study of Eltrombopag in Subjects With AML
A Phase 2 study testing Daunorubicin, Cytarabine and Eltrombopag in people with Acute Leukaemia, run by Novartis Pharmaceuticals at 42 sites in 10 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Leukaemia
- What is being tested?
- Daunorubicin, Cytarabine and Eltrombopag
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 148 participants
- Where
- 42 sitesin 10 countries
- Study dates
- 5 Sep 2013to 25 Jan 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
Show all 12Show fewer
- 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.
Who cannot join
- 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.
Show all 9Show fewer
- 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 locations and contacts
42 sites in 10 countries.
42 sites in 10 countries
United States14 sites
Novartis Investigative Site
Ames, Iowa, 50010
Novartis Investigative Site
Atlanta, Georgia, 30322
Novartis Investigative Site
Burlington, Massachusetts, 01805
Novartis Investigative Site
Canton, Ohio, 44710
Novartis Investigative Site
Durham, North Carolina, 22713
Novartis Investigative Site
Farmington, Connecticut, 06030-1628
Novartis Investigative Site
Kansas City, Missouri, 64128
Novartis Investigative Site
Miami, Florida, 33136
Novartis Investigative Site
Nashville, Tennessee, 37232
Novartis Investigative Site
Orlando, Florida, 32806
Novartis Investigative Site
Philadelphia, Pennsylvania, 19104
Novartis Investigative Site
Providence, Rhode Island, 02903
Novartis Investigative Site
Rochester, New York, 14642
Novartis Investigative Site
Sioux City, Iowa, 51101-1733
Israel6 sites
Novartis Investigative Site
Haifa, 31096
Novartis Investigative Site
Holon, 58100
Novartis Investigative Site
Jerusalem, 91031
Novartis Investigative Site
Jerusalem, 91120
Novartis Investigative Site
Kfar Saba, 44281
Novartis Investigative Site
Tel Aviv, 64239
Russia6 sites
Novartis Investigative Site
Kaluga, 248007
Novartis Investigative Site
Moscow, 115478
Novartis Investigative Site
Nizhny Novgorod, 603126
Novartis Investigative Site
Penza, 440071
Novartis Investigative Site
St'Petersburg, 197341
Novartis Investigative Site
Tula, 300053
Australia3 sites
Novartis Investigative Site
Kogarah, New South Wales, 2217
Novartis Investigative Site
Melbourne, Victoria, 3004
Novartis Investigative Site
Parkville, Victoria, 3050
South Korea3 sites
Novartis Investigative Site
Seoul, 135-710
Novartis Investigative Site
Seoul, 138-736
Novartis Investigative Site
Seoul, Korea, 137-701
Belgium2 sites
Novartis Investigative Site
Brussels, 1070
Novartis Investigative Site
Leuven, 3000
Canada2 sites
Novartis Investigative Site
Montreal, Quebec, H2L 4M1
Novartis Investigative Site
Toronto, Ontario, M5G 2M9
Greece2 sites
Novartis Investigative Site
Athens, 11527
Novartis Investigative Site
Pátrai, 26500
Hungary2 sites
Novartis Investigative Site
Debrecen, 4012
Novartis Investigative Site
Szeged, 6720
Poland2 sites
Novartis Investigative Site
Słupsk, 76-200
Novartis Investigative Site
Wroclaw, 50-367
About this study
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
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.
- Conditions
- Acute Leukaemia
- Being tested
- Daunorubicin, Cytarabine, Eltrombopag, Placebo
- 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
- Medical subject headings
- Leukemia, Leukemia, Myeloid, Acute, Thrombocytopenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DaunorubicinDrug
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.
CytarabineDrug
100 mg/m2/day continuous IV infusion on Days 1 through 7.
EltrombopagDrug
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.
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Eltrombopag arm | Experimental | 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. Receives: Drug: Daunorubicin; Drug: Cytarabine; Drug: Eltrombopag |
| Placebo arm | Placebo comparator | 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. Receives: Drug: Daunorubicin; Drug: Cytarabine; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Any Adverse Events (AE) and Any Serious Adverse Events (SAE) as a Measure of Safety and Tolerability.
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.
Measured: 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
Change From Baseline in the Left Ventricular Ejection Fraction (LVEF).
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.
Measured: Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Number of Participants With Worst-case Grade Changes From Baseline in the Hematology Parameters
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.
Measured: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Number of Participants With Worst-case Grade Changes From Baseline in the Clinical Chemistry Parameters
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.
Measured: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Number of Participants With Liver Events.
The number of participants with liver enzyme (ALT, AST, ALP, Total bilirubin) abnormalities while receiving study treatment in each arm are presented.
Measured: 8 weeks
Number of Participants With Worst-case Changes From Baseline in Electrocardiogram (ECG) Values
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.
Measured: Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Number of Participants With Worst-case Changes From Baseline in the Eastern Cooperative Oncology Group (ECOG) Performance Status
The number of participants with worst case post-baseline changes (improved, no change, deteriorated) are presented.
Measured: Baseline and Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Worst-case Change From Baseline in Pulse Rate Values
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.
Measured: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Worst-case Post Baseline Change in Blood Pressure Values From Baseline
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.
Measured: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Worst-case Post Baseline Change in Temperature Values From Baseline
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.
Measured: Baseline and up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Secondary outcomes (30)
Plasma Pharmacokinetics (PK) Parameter of Daunorubicin: Half-life (t1/2)
Daunorubicin half-life. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Plasma Pharmacokinetics (PK) Parameter of Daunorubicinol: Half-life (t1/2)
Daunorubicinol half-life. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicin Dose-normalized Plasma: AUC(0-∞)
Daunorubicin AUC(0-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicinol Dose-normalized Plasma: AUC(0-∞)
Daunorubicinol AUC(0-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicin Dose-normalized Plasma: AUC(24-∞)
Daunorubicin AUC(24-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Daunorubicinol Dose-normalized Plasma: AUC(24-∞)
Daunorubicinol AUC(24-∞). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Daunorubicin Dose-normalized Plasma: AUC(0-t)
Daunorubicin AUC(0-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicinol Dose-normalized Plasma: AUC(0-t)
daunorubicinol AUC(0-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicin Dose-normalized Plasma: AUC(24-t)
Daunorubicin AUC(24-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Daunorubicinol Dose-normalized Plasma: AUC(24-t)
Daunorubicinol AUC(24-t). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Daunorubicin Dose-normalized Plasma: Cmax
Daunorubicin Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicinol Dose-normalized Plasma: Cmax
Daunorubicinol Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Cycle 2: Daunorubicin Dose-normalized Plasma: AUC(0-24)
Cycle 2 Daunorubicin AUC(0-24). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Cycle 2: Daunorubicinol Dose-normalized Plasma: AUC(0-24)
Cycle 2 Daunorubicinol AUC(0-24). PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Cycle 2: Daunorubicin Dose-normalized Plasma: Cmax
Cycle 2 Daunorubicin Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Cycle 2: Daunorubicinol Dose-normalized Plasma: Cmax
Cycle 2 Daunorubicinol Cmax. PK analyses used actual relative time and actual dosing information in mg/m2. All parameter values were divided by daunorubicin dose in mg/m2 except t1/2.
Measured: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Number of Platelet Transfusions Per Week Within Cycles
This was the average number of platelet transfusions per week within cycles.
Measured: Post-Base line up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Time to Platelet Count Recovery >=20 Gi/L
Time to Platelet counts >= 20 Gi/L for 3 consecutive days, unaided by transfusions in patients with < 20 Gi/L after chemotherapy. For this endpoint, the event required platelet count to be >= 20 Gi/L for 3 consecutive days. Hematology was assessed daily during hospital stay but only weekly after hospital discharge and thus, platelet count was not always available for 3 consecutive days to confirm the achievement of platelet count recovery.
Measured: From last dose of chemotherapy to up to end of study year 2 assessment
Time to Platelet Recovery >=100 Gi/L
Time to platelet counts >= 100 Gi/L unaided by transfusions in participants with < 100 Gi/L after chemotherapy.
Measured: From last dose of chemotherapy to up to end of study year 2 assessment
Number of Participants Who Achieved Platelet Count Recovery by Day 21
Number of participants with platelet counts 20 Gi/L for 3 consecutive days, unaided by transfusions, in patients with < 20 Gi/L after chemotherapy.
Measured: By Day 21
Summary of Platelet Counts Over Time
Platelet counts over time
Measured: Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
Maximum Duration (Days) of Platelet Transfusion Independence
Maximum time period (in days) during which the patient did not receive any platelet transfusion
Measured: At differnt time points from start of treatment and up to end of study year 2 assessment
Percentage of Patients Who Achieved Platelet Transfusion Independence ≥ 28 Days
Percentage of patients who achieved platelet transfusion independence ≥ 28 days.
Measured: From start of treatment and up to end of study year 2 assessment
Time to Neutrophil Engraftment
Time to absolute neutrophil count (ANC) >= 0.5 Gi/L for 3 consecutive days in participants with ANC < 0.5 Gi/L after chemotherapy
Measured: At different time points from last dose of chemotherapy up to end of study year 2 assessment
Summary of Absolute Neutrophil Counts (ANC)
Absolute neutrophil counts over time
Measured: Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
Summary of Hemoglobin
Hemoglobin level over time
Measured: Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
Incidence of Hemorrhagic Events
Incidence of bleeding events using WHO bleeding grade (G0=No bleeding, G1=Petechiae, G2=Mild blood loss, G3=Gross blood loss, G4=Debilitating blood loss) by week and cycle
Measured: Baseline, weekly within induction and re-induction cycles, end of therapy
Percentage of Participants With Disease Response Rate and Type of Response
Disease response as assessed by the investigator using the AML International Working Group Response Assessment at the end of therapy/remission assessment visit; Complete remission (CR): defined as transfusion independence, blood count recovery (Abs. neutrophil count > 1.0 Gi/L and Platelet count > 100.0 Gi/L), no leukemic blast in peripheral blood, Bone Marrow (BM) blasts < 5%, maturation of all cell lines, Auer rods not detectable, and no extramedullary disease.
Partial remission (PR): defined as CR except that for BM blasts where a decrease of at least 50% of BM blasts to 5-25% in BM aspirate is sufficient or BM blasts < 5% with Auer rods present.
Overall response (OR) = CR + PR.
Measured: Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Overall Survival (OS)
Overall survival defined as the time form randomization until the date of death due to any cause.
Measured: From randomization to end of 2-year follow-up
Number of Participants Who Required Medical Resource Utilization
Medical Resource Utilization pertained to unscheduled hospitalizations, unscheduled office visits, unscheduled laboratory tests, and unscheduled procedures.
Measured: At screening and from start of treatment to end of therapy/remission assessment visit (Day 42 of the latest chemotherapy cycle)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jul 2013 (estimated)
- Study start5 Sep 2013
- Primary completion13 Mar 2015
- Study completion25 Jan 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute LeukaemiaStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 148 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01890746
- Sponsor's protocol ID
- 117146
- Other IDs
- 2013-000642-20
- Status last verified
- Aug 2019
- First submitted
- 27 Jun 2013
- Last updated
- 11 Sep 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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.
PubMed 30704923
Study at a glance
From the registry record, last updated by the sponsor on 11 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01890746
- Acronym / sponsor ID
- 117146
- Conditions
- Acute Leukaemia
- Keywords
- AML, de novo AML, leukemia, sAML/MDS, acute myeloid leukemia, acute myelogenous leukemia (AML), secondary acute myeloid leukemia, ETB115
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 148 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 5 Sep 2013 (actual)
- Primary completion
- 13 Mar 2015 (actual)
- Study completion
- 25 Jan 2017 (actual)
- First posted
- 2 Jul 2013 (estimated)
- Results
- Posted 14 Jun 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Eltrombopag arm | Experimental | Drug: Daunorubicin, Drug: Cytarabine, Drug: EltrombopagSubjects 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 arm | Placebo comparator | Drug: Daunorubicin, Drug: Cytarabine, Drug: PlaceboSubject 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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:
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DaunorubicinFor 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. | Drug | Eltrombopag arm, Placebo arm |
| Cytarabine100 mg/m2/day continuous IV infusion on Days 1 through 7. | Drug | Eltrombopag arm, Placebo arm |
| Eltrombopag200 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. | Drug | Eltrombopag arm |
| PlaceboOrally, 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. | Drug | Placebo arm |
Primary outcome
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
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)
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)
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)
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
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)
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)
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)
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)
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)
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.
30 secondary outcomes
Plasma Pharmacokinetics (PK) Parameter of Daunorubicin: Half-life (t1/2)
Time frame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Plasma Pharmacokinetics (PK) Parameter of Daunorubicinol: Half-life (t1/2)
Time frame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicin Dose-normalized Plasma: AUC(0-∞)
Time frame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicinol Dose-normalized Plasma: AUC(0-∞)
Time frame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicin Dose-normalized Plasma: AUC(24-∞)
Time frame: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Daunorubicinol Dose-normalized Plasma: AUC(24-∞)
Time frame: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Daunorubicin Dose-normalized Plasma: AUC(0-t)
Time frame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicinol Dose-normalized Plasma: AUC(0-t)
Time frame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicin Dose-normalized Plasma: AUC(24-t)
Time frame: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Daunorubicinol Dose-normalized Plasma: AUC(24-t)
Time frame: Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)
Daunorubicin Dose-normalized Plasma: Cmax
Time frame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Daunorubicinol Dose-normalized Plasma: Cmax
Time frame: Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)
Cycle 2: Daunorubicin Dose-normalized Plasma: AUC(0-24)
Time frame: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Cycle 2: Daunorubicinol Dose-normalized Plasma: AUC(0-24)
Time frame: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Cycle 2: Daunorubicin Dose-normalized Plasma: Cmax
Time frame: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Cycle 2: Daunorubicinol Dose-normalized Plasma: Cmax
Time frame: Cycle 2 Day 1 to Day 2 (0 to 24 post-dose)
Number of Platelet Transfusions Per Week Within Cycles
Time frame: Post-Base line up to Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Time to Platelet Count Recovery >=20 Gi/L
Time frame: From last dose of chemotherapy to up to end of study year 2 assessment
Time to Platelet Recovery >=100 Gi/L
Time frame: From last dose of chemotherapy to up to end of study year 2 assessment
Number of Participants Who Achieved Platelet Count Recovery by Day 21
Time frame: By Day 21
Summary of Platelet Counts Over Time
Time frame: Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
Maximum Duration (Days) of Platelet Transfusion Independence
Time frame: At differnt time points from start of treatment and up to end of study year 2 assessment
Percentage of Patients Who Achieved Platelet Transfusion Independence ≥ 28 Days
Time frame: From start of treatment and up to end of study year 2 assessment
Time to Neutrophil Engraftment
Time frame: At different time points from last dose of chemotherapy up to end of study year 2 assessment
Summary of Absolute Neutrophil Counts (ANC)
Time frame: Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
Summary of Hemoglobin
Time frame: Baseline, daily then weekly within cycle up to 42 days after last chemotherapy dose, end of therapy /remission assessment visit
Incidence of Hemorrhagic Events
Time frame: Baseline, weekly within induction and re-induction cycles, end of therapy
Percentage of Participants With Disease Response Rate and Type of Response
Time frame: Day 42 of the latest chemotherapy cycle (Up to 8 weeks)
Overall Survival (OS)
Time frame: From randomization to end of 2-year follow-up
Number of Participants Who Required Medical Resource Utilization
Time frame: At screening and from start of treatment to end of therapy/remission assessment visit (Day 42 of the latest chemotherapy cycle)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Sep 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 30704923Frey 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.
- Individual participant dataSharing planned: Undecided. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Related trials for Acute Leukaemia
RecruitingPhase 1
A Study of CHM-029 in Participants With NPM1 Mutated, KMT2A or NUP98 Rearranged AML
AML (Acute Myeloid Leukemia)
RecruitingPhase 2
Testing New Therapies for Patients With Acute Myeloid Leukemia Who Are Newly Diagnosed and Have Not Yet Started Treatment (A MyeloMATCH Treatment Trial)
Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic/Myeloproliferative Neoplasm
Active, not recruitingPhase 2
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
RecruitingPhase 1/2
Venetoclax and CLAG-M for the Treatment of Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms
Acute Biphenotypic Leukemia, Acute Myeloid Leukemia
Not yet recruitingPhase 1
ATRN-119 in Combination With Decitabine in Patients With TP53-Mutated AML or Higher-Risk MDS
Acute Myeloid Leukemia, High-risk Myelodysplastic Syndrome
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
42 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Daunorubicin, Cytarabine and Eltrombopag in people with Acute Leukaemia, run by Novartis Pharmaceuticals at 42 sites in 10 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 42 sites in United States, Israel, Russia, Australia, South Korea and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Jun 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01890746, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2019.