A Safety and Efficacy Study of Eltrombopag in Subjects With AML

NCT ID: NCT01890746

Last Updated: 2019-09-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 148 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-05
• Study Completion Date: 2017-01-25

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

Daunorubicin

Intervention Type: 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.

Cytarabine

Intervention Type: DRUG

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

Eltrombopag

Intervention Type: 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.

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.

Group Type: PLACEBO_COMPARATOR

Daunorubicin

Intervention Type: 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.

Cytarabine

Intervention Type: DRUG

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

Placebo

Intervention Type: 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.

Interventions

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.

Intervention Type: DRUG

Cytarabine

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

Intervention Type: DRUG

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.

Intervention Type: DRUG

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 Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Farmington, Connecticut, United States

Novartis Investigative Site

Miami, Florida, United States

Novartis Investigative Site

Orlando, Florida, United States

Novartis Investigative Site

Atlanta, Georgia, United States

Novartis Investigative Site

Ames, Iowa, United States

Novartis Investigative Site

Sioux City, Iowa, United States

Novartis Investigative Site

Burlington, Massachusetts, United States

Novartis Investigative Site

Kansas City, Missouri, United States

Novartis Investigative Site

Rochester, New York, United States

Novartis Investigative Site

Durham, North Carolina, United States

Novartis Investigative Site

Canton, Ohio, United States

Novartis Investigative Site

Philadelphia, Pennsylvania, United States

Novartis Investigative Site

Providence, Rhode Island, United States

Novartis Investigative Site

Nashville, Tennessee, United States

Novartis Investigative Site

Kogarah, New South Wales, Australia

Novartis Investigative Site

Melbourne, Victoria, Australia

Novartis Investigative Site

Parkville, Victoria, Australia

Novartis Investigative Site

Brussels, , Belgium

Novartis Investigative Site

Leuven, , Belgium

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Athens, , Greece

Novartis Investigative Site

Pátrai, , Greece

Novartis Investigative Site

Debrecen, , Hungary

Novartis Investigative Site

Szeged, , Hungary

Novartis Investigative Site

Haifa, , Israel

Novartis Investigative Site

Holon, , Israel

Novartis Investigative Site

Jerusalem, , Israel

Novartis Investigative Site

Jerusalem, , Israel

Novartis Investigative Site

Kfar Saba, , Israel

Novartis Investigative Site

Tel Aviv, , Israel

Novartis Investigative Site

Słupsk, , Poland

Novartis Investigative Site

Wroclaw, , Poland

Novartis Investigative Site

Kaluga, , Russia

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Nizhny Novgorod, , Russia

Novartis Investigative Site

Penza, , Russia

Novartis Investigative Site

St'Petersburg, , Russia

Novartis Investigative Site

Tula, , Russia

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seoul, Korea, , South Korea

Countries

United States; Australia; Belgium; Canada; Greece; Hungary; Israel; Poland; Russia; South Korea

References

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.

Reference Type: DERIVED

PMID: 30704923 (View on PubMed)

Other Identifiers

2013-000642-20

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

117146

Identifier Type: -

Identifier Source: org_study_id