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

NCT01440374 | Completed Phase 2 Results DMC

• 2 other identifiers: 1149682011-000114-19
• Study Type: interventional
• Target: 162
• Locations: 22 countries
• Sites: 120

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

Keywords

acute myeloid leukemia (AML); acute myelogenous leukemia (AML); acute non lymphocytic leukemia (ANLL); myeloproliferative disease (MDS); myelodysplastic syndrome ( secondary acute myeloid leukemia); refractory acute myeloid leukemia

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Platelet Response up to Week 8 During Part 1

  A participant was considered as a responder if he/she met the following response criteria: a Baseline platelet count \<20 Giga cells per liter (Gi/L) and a post-Baseline increased to \>20 Gi/L and at least 2 times the Baseline value; or a Baseline platelet count \>=20 Gi/L and a post-Baseline absolute platelet count increased to \>=50 Gi/L and at least 2 times the Baseline value. The response criteria was evaluated at each visit. Increase in platelet count observed up to 3 days after a platelet transfusion was not considered as a platelet response. The Part 1 Population was comprised of all participants enrolled into Part 1.

  From Baseline up to Week 8 during Part 1

• Clinically Relevant Thrombocytopenic Events (CRTE) From Week 5 up to Week 12 During Part 2

  A participant was considered to have a CRTE at a given assessment if he/she had platelet counts \<10 Gi/L, or platelet transfusions, or \>=Grade 3 hemorrhagic adverse events. CRTEs during Weeks 5 to 12 were compared between treatments using a generalized linear mixed model. Average of weekly proportion of subjects with CRTE during Week 5 to 12 was estimated for each treatment. Intent to Treat (ITT) Population was comprised of all randomized participants during Part 2.

  From Week 5 up to Week 12 during Part 2

Secondary Outcomes (13)

• Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 1 Subjects)

  Day 1 to week 8

• Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 2 Subjects)

  Day 1 to week 12

• Mean Number of Platelet Transfusions

  Weeks 5 to 12

• Hematologic Improvement

  Weeks 5 to 12

• Change in Mean Platelet Count

  Baseline to Week 12

Study Arms (4)

Part 1, Open Label

EXPERIMENTAL

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.

Drug: eltrombopag

Part 2, eltrombopag arm

EXPERIMENTAL

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)

Drug: eltrombopag

Part 2, placebo arm

EXPERIMENTAL

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)

Drug: placebo

part 3 extension

EXPERIMENTAL

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)

Drug: eltrombopag

Interventions

eltrombopag 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)

Also known as: Promacta

Part 1, Open Label; Part 2, eltrombopag arm; part 3 extension

placebo 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 2, placebo arm

Eligibility Criteria

• Age: 18 Years - 110 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (120)

Novartis Investigative Site

Phoenix, Arizona, 85016, United States

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Hot Springs, Arkansas, 71913, United States

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Jonesboro, Arkansas, 72401, United States

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Los Angeles, California, 90095, United States

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Stanford, California, 94305, United States

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Jacksonville, Florida, 32256, United States

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Orlando, Florida, 32806, United States

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West Palm Beach, Florida, 33401, United States

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Augusta, Georgia, 30912, United States

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Baltimore, Maryland, 21201, United States

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Boston, Massachusetts, 02115, United States

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Kansas City, Missouri, 64128, United States

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Hackensack, New Jersey, 07601, United States

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Voorhees Township, New Jersey, 08043, United States

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The Bronx, New York, 10467, United States

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Philadelphia, Pennsylvania, 19140, United States

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Seattle, Washington, 98108, United States

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Milwaukee, Wisconsin, 53226, United States

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Ciudad Autonoma de Buenos Aires, Buenos Aires, C1431FWO, Argentina

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La Plata, Buenos Aires, B1900AXI, Argentina

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Buenos Aires, 1405, Argentina

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Buenos Aires, C1025ABH, Argentina

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Ciudad Autónoma de Buenos Aires, 1405, Argentina

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Antwerp, 2060, Belgium

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Brasschaat, 2930, Belgium

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Bruges, 8000, Belgium

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Brussels, 1000, Belgium

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Ghent, 9000, Belgium

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Leuven, 3000, Belgium

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Yvoir, 5530, Belgium

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Goiânia - GO, Goiás, 74605-020, Brazil

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Goiânia - GO, Goiás, 74605-020, Brazil

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Curitiba, Paraná, 81520-060, Brazil

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Curitiba, Paraná, 81520-060, Brazil

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Porto Alegre, Rio Grande do Sul, 90035-903, Brazil

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Barretos, São Paulo, 14784-400, Brazil

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Barretos, São Paulo, 14784-400, Brazil

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São Paulo, São Paulo, 01236030, Brazil

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Rio de Janeiro, 20211-030, Brazil

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São Paulo, 01236030, Brazil

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Halifax, Nova Scotia, B3H 2Y9, Canada

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Toronto, Ontario, M5G 2M9, Canada

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Montreal, Quebec, H3T 1E2, Canada

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Brno, 625 00, Czechia

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Prague, 100 34, Czechia

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Prague, 128 08, Czechia

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Prague, 128 20, Czechia

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Mannheim, Baden-Wurttemberg, 68167, Germany

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Stuttgart, Baden-Wurttemberg, 70199, Germany

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Göttingen, Lower Saxony, 37075, Germany

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Cologne, North Rhine-Westphalia, 50937, Germany

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Düsseldorf, North Rhine-Westphalia, 40225, Germany

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Dresden, Saxony, 01307, Germany

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Athens, 11527, Greece

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Heraklion, Crete, 71201, Greece

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Ioannina, 45 500, Greece

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Thessaloniki, 57010, Greece

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Chai Wan, Hong Kong

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Shatin, New Territories, Hong Kong

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Budapest, 1088, Hungary

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Debrecen, 4012, Hungary

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Kaposvár, 7400, Hungary

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Kaposvár, 7400, Hungary

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Szeged, 6720, Hungary

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Cork, Ireland

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Dublin, 7, Ireland

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James Street, 8, Ireland

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Limerick, Ireland

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Tallaght, Dublin, 24, Ireland

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Tullamore, Ireland

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Beersheba, 84101, Israel

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Haifa, 31048, Israel

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Haifa, 31096, Israel

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Holon, 58100, Israel

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Jerusalem, 91120, Israel

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Petah Tikva, 49100, Israel

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Ramat Gan, 52621, Israel

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Rehovot, 76100, Israel

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Tel Aviv, 64239, Israel

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Bologna, Emilia-Romagna, 40138, Italy

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Brescia, Lombardy, 25123, Italy

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Milan, Lombardy, 20122, Italy

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Milan, Lombardy, 20162, Italy

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Alessandria, Piedmont, 15100, Italy

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Florence, Tuscany, 50134, Italy

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Monterrey, Nuevo León, 64460, Mexico

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Monterrey, Nuevo León, 64460, Mexico

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Chihuahua City, 31203, Mexico

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Mexico City, CP 14080, Mexico

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Oaxaca City, 68000, Mexico

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Amsterdam, 1081 HV, Netherlands

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Chorzów, 41-500, Poland

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Torun, 87-100, Poland

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Warsaw, 02-097, Poland

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San Juan, 00927, Puerto Rico

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Nizhny Novgorod, 603126, Russia

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Petrozavodsk, 185019, Russia

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Saint Petersburg, 197 089, Russia

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St'Petersburg, 191024, Russia

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St'Petersburg, 197341, Russia

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Novartis Investigative Site

Hwasun, 519-809, South Korea

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Seoul, 110-744, South Korea

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Seoul, 120-752, South Korea

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Barcelona, 08036, Spain

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Granada, Spain

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Madrid, 28034, Spain

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Málaga, 29010, Spain

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Málaga, 29010, Spain

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Pozuelo de Alarcón/Madrid, 28223, Spain

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Pozuelo de Alarcón/Madrid, 28223, Spain

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Salamanca, 37007, Spain

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Santander, 39008, Spain

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Kaohsiung City, 83301, Taiwan

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Tainan County, 736, Taiwan

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Taoyuan, 333, Taiwan

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Bangkok, 10330, Thailand

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Bangkok, 10400, Thailand

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Bangkok, 10700, Thailand

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Khon Kaen, 40002, Thailand

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Songkhla, 90110, Thailand

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Related Publications (2)

• 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.

  PMID: 37231838 DERIVED

• 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.

  PMID: 29241762 DERIVED

MeSH Terms

Conditions

Thrombocytopenia; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Myelodysplastic Syndromes

Interventions

eltrombopag

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

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: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 15, 2011
• First Posted: September 26, 2011
• Study Start: September 1, 2011
• Primary Completion: March 1, 2015
• Study Completion: December 1, 2015
• Last Updated: June 5, 2017
• Results First Posted: June 14, 2016

Record last verified: 2017-05

Locations

DE (6); RU (5); ES (9); BR (10); TW (3); PL (3); BE (7); CZ (4); HU (5); IT (6); CA (3); IL (9); GR (4); ME (5); AR (5); NL (1); IE (6); PR (1); KR (3); US (18); HK (2); TH (5)