A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia

NCT ID: NCT01440374

Last Updated: 2017-06-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 162 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2015-12-31

Brief Summary

This was a worldwide, three-part (Part 1: open-label, Part 2: randomized, double-blind, Part 3: extension), multi-center study to evaluate the effect of eltrombopag in subjects with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have thrombocytopenia due to bone marrow insufficiency from their underlying disease or prior chemotherapy. This objective was assessed by a composite primary endpoint that consists of the following: the proportion of ≥Grade 3 hemorrhagic adverse events, or platelet counts <10 Gi/L, or platelet transfusions. Patients with MDS or AML and Grade 4 thrombocytopenia due to bone marrow insufficiency from their underlying disease or prior chemotherapy were enrolled in the study. No low or intermediate-1 risk MDS subjects were enrolled in the study. Subjects must have had at least one of the following during the 4 weeks prior to enrolment: platelet count <10 Gi/L, platelet transfusion, or symptomatic hemorrhagic event. Supportive standard of care (SOC), including hydroxyurea, was allowed as indicated by local practice throughout the study. The study had 3 sequential parts. Subjects who were enrolled in Part 1 (open-label) cannot be enrolled in Part 2 of the study (randomized, double-blind); however, subjects who completed the treatment period for Part 1 or Part 2 (8 and 12 weeks, respectively) continued in Part 3 (extension) if the investigator determined that the subject was receiving clinical benefit on treatment.

Conditions

Thrombocytopaenia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: QUADRUPLE

Study Groups

Part 1, Open Label

100 mg daily (50 mg for subjects of East Asian heritage), intrasubject dose escalations to a maximum dose 300 mg (150 mg for subjects of East Asian heritage) are allowed.

Group Type: EXPERIMENTAL

eltrombopag

Intervention Type: DRUG

100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)

Part 2, eltrombopag arm

100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)

Group Type: EXPERIMENTAL

eltrombopag

Intervention Type: DRUG

100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)

Part 2, placebo arm

100 mg matching placebo daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg matching placebo (150 mg for subjects of East Asian heritage)

Group Type: EXPERIMENTAL

placebo

Intervention Type: DRUG

100 mg matching placebo daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg matching placebo (150 mg for subjects of East Asian heritage)

part 3 extension

100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)

Group Type: EXPERIMENTAL

eltrombopag

Intervention Type: DRUG

100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)

Interventions

eltrombopag

100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)

Intervention Type: DRUG

placebo

100 mg matching placebo daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg matching placebo (150 mg for subjects of East Asian heritage)

Intervention Type: DRUG

Other Intervention Names

Promacta

Eligibility Criteria

Inclusion Criteria

• Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ≤50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded.
• Subjects must have Grade 4 thrombocytopenia (platelet counts <25 Gi/L) due to bone marrow insufficiency (or Grade 4 thrombocytopenia, but platelet count greater than or equal to 25 Gi/L due to platelet transfusion). In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count <10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible.
• Subjects must have platelet count, bleeding and platelet transfusion data available over a period of at least 4 weeks prior to randomization.
• Prior systemic treatment for malignancy, with the exception of hydroxyurea, must have been discontinued prior to entry into the study: at least 4 weeks before Day 1 for the following: chemotherapy, demethylating agents (azacitidine or decitabine), lenalidomide, thalidomide, clofarabine and IL-11(oprelvekin); at least 8 weeks before Day 1 for antithymocyte/antilymphocyte globulin.
• Subjects with a prior stem cell transplant (SCT) must have relapsed after the SCT.
• Subjects must be stable and, in the opinion of the investigator, be expected to complete a 12 week treatment period.
• ECOG Status 0-2.
• Subject must be able to understand and comply with protocol requirements and instructions.
• Subject has signed and dated an informed consent form.
• Adequate baseline organ function defined by the criteria below: total bilirubin ≤ 1.5xULN except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect (hemolytic) bilirubin in the absence of ALT abnormality), ALT ≤ 3xULN, creatinine ≤ 2.5xULN
• Women must be either of non-child bearing 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 Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the first dose of study treatment.
• In France, a subject eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.

Exclusion Criteria

• Subjects with MDS and an IPSS of low or intermediate-1 risk at screening.
• Subjects with a diagnosis of acute promyelocytic or megakaryocytic leukemia or AML secondary to a myeloproliferative neoplasm.
• History of treatment with romiplostim or other TPO-R agonists.
• Subjects with a QTc >480 msec (QTc >510 msec for subjects with Bundle Branch Block).
• Leukocytosis ≥25,000/uL on Day 1 of treatment with study medication.
• Subjects with known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.
• Female subjects who are nursing or pregnant (positive serum or urine β-human chorionic gonadotropin [β-hCG] pregnancy test) at screening or pre-dose on Day 1.
• Current alcohol or drug abuse.
• Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
• Active and uncontrolled infections (e.g. sepsis, hepatitis B, hepatitis C).
• Subjects infected with Human Immunodeficiency Virus (HIV).
• Subjects with liver cirrhosis (as determined by the investigator).
• Subjects receiving or planned to receive any prohibited medication.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or excipient (microcrystalline cellulose, mannitol, polyvinylpyrrolidone, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 400 and polysorbate 80) that contraindicates the subjects' participation.
• In France, subjects who have participated in any study using an investigational drug during the previous 30 days.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 110 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

Phoenix, Arizona, United States

Novartis Investigative Site

Hot Springs, Arkansas, United States

Novartis Investigative Site

Jonesboro, Arkansas, United States

Novartis Investigative Site

Los Angeles, California, United States

Novartis Investigative Site

Stanford, California, United States

Novartis Investigative Site

Jacksonville, Florida, United States

Novartis Investigative Site

Orlando, Florida, United States

Novartis Investigative Site

West Palm Beach, Florida, United States

Novartis Investigative Site

Augusta, Georgia, United States

Novartis Investigative Site

Baltimore, Maryland, United States

Novartis Investigative Site

Boston, Massachusetts, United States

Novartis Investigative Site

Kansas City, Missouri, United States

Novartis Investigative Site

Hackensack, New Jersey, United States

Novartis Investigative Site

Voorhees Township, New Jersey, United States

Novartis Investigative Site

The Bronx, New York, United States

Novartis Investigative Site

Philadelphia, Pennsylvania, United States

Novartis Investigative Site

Seattle, Washington, United States

Novartis Investigative Site

Milwaukee, Wisconsin, United States

Novartis Investigative Site

Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina

Novartis Investigative Site

La Plata, Buenos Aires, Argentina

Novartis Investigative Site

Buenos Aires, , Argentina

Novartis Investigative Site

Buenos Aires, , Argentina

Novartis Investigative Site

Ciudad Autónoma de Buenos Aires, , Argentina

Novartis Investigative Site

Antwerp, , Belgium

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Brasschaat, , Belgium

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Bruges, , Belgium

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Brussels, , Belgium

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Ghent, , Belgium

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Leuven, , Belgium

Novartis Investigative Site

Yvoir, , Belgium

Novartis Investigative Site

Goiânia - GO, Goiás, Brazil

Novartis Investigative Site

Goiânia - GO, Goiás, Brazil

Novartis Investigative Site

Curitiba, Paraná, Brazil

Novartis Investigative Site

Curitiba, Paraná, Brazil

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, Brazil

Novartis Investigative Site

Barretos, São Paulo, Brazil

Novartis Investigative Site

Barretos, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

Rio de Janeiro, , Brazil

Novartis Investigative Site

São Paulo, , Brazil

Novartis Investigative Site

Halifax, Nova Scotia, Canada

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Brno, , Czechia

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Prague, , Czechia

Novartis Investigative Site

Prague, , Czechia

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Prague, , Czechia

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Mannheim, Baden-Wurttemberg, Germany

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Stuttgart, Baden-Wurttemberg, Germany

Novartis Investigative Site

Göttingen, Lower Saxony, Germany

Novartis Investigative Site

Cologne, North Rhine-Westphalia, Germany

Novartis Investigative Site

Düsseldorf, North Rhine-Westphalia, Germany

Novartis Investigative Site

Dresden, Saxony, Germany

Novartis Investigative Site

Athens, , Greece

Novartis Investigative Site

Heraklion, Crete, , Greece

Novartis Investigative Site

Ioannina, , Greece

Novartis Investigative Site

Thessaloniki, , Greece

Novartis Investigative Site

Chai Wan, , Hong Kong

Novartis Investigative Site

Shatin, New Territories, , Hong Kong

Novartis Investigative Site

Budapest, , Hungary

Novartis Investigative Site

Debrecen, , Hungary

Novartis Investigative Site

Kaposvár, , Hungary

Novartis Investigative Site

Kaposvár, , Hungary

Novartis Investigative Site

Szeged, , Hungary

Novartis Investigative Site

Cork, , Ireland

Novartis Investigative Site

Dublin, , Ireland

Novartis Investigative Site

James Street, , Ireland

Novartis Investigative Site

Limerick, , Ireland

Novartis Investigative Site

Tallaght, Dublin, , Ireland

Novartis Investigative Site

Tullamore, , Ireland

Novartis Investigative Site

Beersheba, , Israel

Novartis Investigative Site

Haifa, , Israel

Novartis Investigative Site

Haifa, , Israel

Novartis Investigative Site

Holon, , Israel

Novartis Investigative Site

Jerusalem, , Israel

Novartis Investigative Site

Petah Tikva, , Israel

Novartis Investigative Site

Ramat Gan, , Israel

Novartis Investigative Site

Rehovot, , Israel

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Tel Aviv, , Israel

Novartis Investigative Site

Bologna, Emilia-Romagna, Italy

Novartis Investigative Site

Brescia, Lombardy, Italy

Novartis Investigative Site

Milan, Lombardy, Italy

Novartis Investigative Site

Milan, Lombardy, Italy

Novartis Investigative Site

Alessandria, Piedmont, Italy

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Florence, Tuscany, Italy

Novartis Investigative Site

Monterrey, Nuevo León, Mexico

Novartis Investigative Site

Monterrey, Nuevo León, Mexico

Novartis Investigative Site

Chihuahua City, , Mexico

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Mexico City, , Mexico

Novartis Investigative Site

Oaxaca City, , Mexico

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Amsterdam, , Netherlands

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Chorzów, , Poland

Novartis Investigative Site

Torun, , Poland

Novartis Investigative Site

Warsaw, , Poland

Novartis Investigative Site

San Juan, , Puerto Rico

Novartis Investigative Site

Nizhny Novgorod, , Russia

Novartis Investigative Site

Petrozavodsk, , Russia

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Saint Petersburg, , Russia

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St'Petersburg, , Russia

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St'Petersburg, , Russia

Novartis Investigative Site

Hwasun, , South Korea

Novartis Investigative Site

Seoul, , South Korea

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Seoul, , South Korea

Novartis Investigative Site

Barcelona, , Spain

Novartis Investigative Site

Granada, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Málaga, , Spain

Novartis Investigative Site

Málaga, , Spain

Novartis Investigative Site

Pozuelo de Alarcón/Madrid, , Spain

Novartis Investigative Site

Pozuelo de Alarcón/Madrid, , Spain

Novartis Investigative Site

Salamanca, , Spain

Novartis Investigative Site

Santander, , Spain

Novartis Investigative Site

Kaohsiung City, , Taiwan

Novartis Investigative Site

Tainan County, , Taiwan

Novartis Investigative Site

Taoyuan, , Taiwan

Novartis Investigative Site

Bangkok, , Thailand

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Bangkok, , Thailand

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Bangkok, , Thailand

Novartis Investigative Site

Khon Kaen, , Thailand

Novartis Investigative Site

Songkhla, , Thailand

Countries

United States; Argentina; Belgium; Brazil; Canada; Czechia; Germany; Greece; Hong Kong; Hungary; Ireland; Israel; Italy; Mexico; Netherlands; Poland; Puerto Rico; Russia; South Korea; Spain; Taiwan; Thailand

References

Mittelman M, Platzbecker U, Grosicki S, Lawniczek T, Zhu Z, Selleslag D. Long-Term Safety and Efficacy of Eltrombopag for Advanced Myelodysplastic Syndromes or Acute Myeloid Leukemia and Severe Thrombocytopenia: Results of the ASPIRE Extension Study. Acta Haematol. 2023;146(5):373-378. doi: 10.1159/000531146. Epub 2023 May 19.

Reference Type: DERIVED

PMID: 37231838 (View on PubMed)

Mittelman M, Platzbecker U, Afanasyev B, Grosicki S, Wong RSM, Anagnostopoulos A, Brenner B, Denzlinger C, Rossi G, Nagler A, Garcia-Delgado R, Portella MSO, Zhu Z, Selleslag D. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial. Lancet Haematol. 2018 Jan;5(1):e34-e43. doi: 10.1016/S2352-3026(17)30228-4. Epub 2017 Dec 11.

Reference Type: DERIVED

PMID: 29241762 (View on PubMed)

Other Identifiers

2011-000114-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

114968

Identifier Type: -

Identifier Source: org_study_id