A Safety and Efficacy Study of Eltrombopag in Subjects With AML

NCT01890746 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 1171462013-000642-20
• Study Type: interventional
• Target: 148
• Locations: 10 countries
• Sites: 42

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.

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

Outcome Measures

Primary Outcomes (10)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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)

  Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)

• Plasma Pharmacokinetics (PK) Parameter of Daunorubicinol: Half-life (t1/2)

  Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)

• Daunorubicin Dose-normalized Plasma: AUC(0-∞)

  Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)

• Daunorubicinol Dose-normalized Plasma: AUC(0-∞)

  Cycle 1 Day 3 to Day 9 (0 to 144 hrs post-dose)

• Daunorubicin Dose-normalized Plasma: AUC(24-∞)

  Cycle 1 Day 4 to Day 9 (24 to 144 hrs post-dose)

Study Arms (2)

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.

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.

Drug: Daunorubicin; Drug: Cytarabine; Drug: Placebo

Interventions

Daunorubicin DRUG

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.

Eltrombopag arm; Placebo arm

Cytarabine DRUG

100 mg/m2/day continuous IV infusion on Days 1 through 7.

Eltrombopag arm; Placebo arm

Eltrombopag DRUG

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.

Eltrombopag arm

Placebo DRUG

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.

Placebo arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (42)

Novartis Investigative Site

Farmington, Connecticut, 06030-1628, United States

Location

Novartis Investigative Site

Miami, Florida, 33136, United States

Location

Novartis Investigative Site

Orlando, Florida, 32806, United States

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Novartis Investigative Site

Atlanta, Georgia, 30322, United States

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Novartis Investigative Site

Ames, Iowa, 50010, United States

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Novartis Investigative Site

Sioux City, Iowa, 51101-1733, United States

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Novartis Investigative Site

Burlington, Massachusetts, 01805, United States

Location

Novartis Investigative Site

Kansas City, Missouri, 64128, United States

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Novartis Investigative Site

Rochester, New York, 14642, United States

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Novartis Investigative Site

Durham, North Carolina, 22713, United States

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Novartis Investigative Site

Canton, Ohio, 44710, United States

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Novartis Investigative Site

Philadelphia, Pennsylvania, 19104, United States

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Novartis Investigative Site

Providence, Rhode Island, 02903, United States

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Novartis Investigative Site

Nashville, Tennessee, 37232, United States

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Novartis Investigative Site

Kogarah, New South Wales, 2217, Australia

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Novartis Investigative Site

Melbourne, Victoria, 3004, Australia

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Novartis Investigative Site

Parkville, Victoria, 3050, Australia

Location

Novartis Investigative Site

Brussels, 1070, Belgium

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Novartis Investigative Site

Leuven, 3000, Belgium

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Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

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Novartis Investigative Site

Montreal, Quebec, H2L 4M1, Canada

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Novartis Investigative Site

Athens, 11527, Greece

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Novartis Investigative Site

Pátrai, 26500, Greece

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Novartis Investigative Site

Debrecen, 4012, Hungary

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Novartis Investigative Site

Szeged, 6720, Hungary

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Novartis Investigative Site

Haifa, 31096, Israel

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Novartis Investigative Site

Holon, 58100, Israel

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Novartis Investigative Site

Jerusalem, 91031, Israel

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Novartis Investigative Site

Jerusalem, 91120, Israel

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Novartis Investigative Site

Kfar Saba, 44281, Israel

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Novartis Investigative Site

Tel Aviv, 64239, Israel

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Novartis Investigative Site

Słupsk, 76-200, Poland

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Novartis Investigative Site

Wroclaw, 50-367, Poland

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Novartis Investigative Site

Kaluga, 248007, Russia

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Novartis Investigative Site

Moscow, 115478, Russia

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Novartis Investigative Site

Nizhny Novgorod, 603126, Russia

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Novartis Investigative Site

Penza, 440071, Russia

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Novartis Investigative Site

St'Petersburg, 197341, Russia

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Novartis Investigative Site

Tula, 300053, Russia

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Novartis Investigative Site

Seoul, 135-710, South Korea

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Novartis Investigative Site

Seoul, 138-736, South Korea

Location

Novartis Investigative Site

Seoul, Korea, 137-701, South Korea

Location

Related Publications (1)

• 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.

  PMID: 30704923 DERIVED

MeSH Terms

Conditions

Leukemia; Leukemia, Myeloid, Acute; Thrombocytopenia

Interventions

Daunorubicin; Cytarabine; eltrombopag

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Blood Platelet Disorders; Cytopenia

Intervention Hierarchy (Ancestors)

Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Clinical Disclosure Office
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 27, 2013
• First Posted: July 2, 2013
• Study Start: September 5, 2013
• Primary Completion: March 13, 2015
• Study Completion: January 25, 2017
• Last Updated: September 11, 2019
• Results First Posted: June 14, 2016

Record last verified: 2019-08

Locations

AU (3); HU (2); CA (2); BE (2); RU (6); US (14); IL (6); KR (3); GR (2); PL (2)