A Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With International Prognostic Scoring System (IPSS) Intermediate-1, Intermediate-2 or High-risk Myelodysplastic Syndromes (MDS)

NCT02158936 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: 112121
• Study Type: interventional
• Target: 356
• Locations: 29 countries
• Sites: 150

Brief Summary

Eltrombopag olamine (SB-497115-GR) is an orally bioavailable, small molecule thrombopoietin receptor agonist that may be beneficial in medical disorders associated with thrombocytopenia. Eltrombopag has been shown to increase platelet counts in patients with thrombocytopenia from various etiologies (Idiopathic thrombocytopenic purpura \[ITP\], liver disease, aplastic anemia and chemotherapy induced thrombocytopenia). Approximately 350 subjects will be randomized in a 1:1 ratio (175 into the eltrombopag arm and 175 into the placebo arm). Approximately 55 subjects will be enrolled into the azacitidine. Subjects with intermediate-1, intermediate-2 or high risk MDS by IPSS, and baseline platelet count of \<75 Giga (10\^9) per liter (Gi/L) will only be enrolled. This is a randomized, double-blind, parallel group, placebo-controlled study designed to explore the platelet supportive care effects of eltrombopag versus placebo in combination with the standard of care hypomethylating agent, azacitidine. The primary objective of this study is to determine the effect of eltrombopag versus placebo on the proportion of subjects who are platelet transfusion free during the first 4 cycles of azacitidine therapy. Key secondary endpoints include overall survival, disease response, and disease progression.

Conditions

Thrombocytopaenia

Keywords

thrombocytopenia; myelodysplastic syndromes; MDS; thrombopoietin; azacitidine; Eltrombopag; myelodysplastic syndromes (MDS)

Outcome Measures

Primary Outcomes (1)

• Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy

  A subject is defined as being platelet transfusion independent if they received no platelet transfusions within the first 4 cycles of treatment with azacitidine. Subjects who died or withdrew from investigational product within the first four cycles were treated as failures (i.e. not transfusion independent) in the analysis

  4 cycles (Cycle = 28 days)

Secondary Outcomes (19)

• Overall Survival (OS)

  Randomization until death or end of study, approximately 2 years

• Summary of Progression Free Survival From Investigator Assessment (ITT)

  First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years

• Summary of Progression Free Survival From Central Review (ITT)

  First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years

• Summary of AML Progression From Investigator Assessment and Central Review (ITT)

  First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years

• Best Disease Response From Investigator Assessment (ITT)

  At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first

Study Arms (2)

Eltrombopag

EXPERIMENTAL

Eligible subject will receive a starting dose of eltrombopag of 200 milligrams (mg) (100 mg for subjects of East Asian heritage). Dose modifications of eltrombopag will be permitted by 100 mg increments (50 mg increments for East Asians) to a lowest dose of 100 mg (50 mg for East Asian heritage) or a maximum dose of 300 mg (150 mg for East Asian heritage) in order to maintain platelet counts at a safe and effective level (i.e. a level sufficient to avoid platelet transfusions and bleeding events). Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle for as long as the subject is receiving azacitidine

Drug: Eltrombopag; Drug: Azacitidine

Placebo

PLACEBO COMPARATOR

Eligible subject will receive eltrombopag matching placebo. Subjects will receive azacitidine 75 mg/meter\^2 subcutaneously once daily for 7 days (+/- 3 day treatment window permitted) every 28 days, for at least 6 cycles if tolerated and until they are no longer receiving benefit (defined as at least stable disease per the investigator's assessment) or until disease progression, death, or unacceptable toxicity/adverse event. The subject may receive eltrombopag daily for the full 28 days each cycle for as long as the subject is receiving azacitidine

Drug: Azacitidine; Drug: Placebo

Interventions

Eltrombopag DRUG

Eltrombopag will be round film-coated tablets containing eltrombopag equivalent to 50 mg (white to off-white), 200 mg and 300 mg (green) of eltrombopag free acid

Eltrombopag

Azacitidine DRUG

Subcutaneous Injection (IV if local standard)

Eltrombopag; Placebo

Placebo DRUG

Eltrombopag matching placebo tablets

Placebo

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 (For subjects in Taiwan, Age \>= 20 years)
• MDS by World Health Organization (WHO) or French-American-British (FAB) classification
• Intermediate 1, intermediate 2 or high risk MDS by IPSS
• At least one platelet count \< 75 Gi/L
• Eastern Cooperative Oncology Group (ECOG) Status 0-2
• Adequate baseline organ function defined by the criteria below: total bilirubin =\< 1.5x the upper limit of normal (ULN) except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect \[haemolytic\] bilirubin in the absence of alanine aminotransferase \[ALT\] abnormality); ALT =\< 2.5xULN; creatinine =\< 2.5xULN
• Subjects with a corrected QT interval (QTc) \<450 milliseconds (msec) or \<480msec for subjects with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF), machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purposes of data analysis, QTcF will be used. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period
• Subject is able to understand and comply with protocol requirements and instructions
• Subject has signed and dated informed consent
• 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 of first dose of study treatment and agree to use effective contraception during the study and for 3 months following the last dose of study treatment
• 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 16 weeks after the last dose of study treatment

You may not qualify if:

• Previous treatment with hypomethylating agent or induction chemotherapy for MDS
• Proliferative type chronic myelomonocytic leukemia with white blood cell count \>12 Gi/L at any time during the 28 days before Day 1
• History of treatment with eltrombopag, romiplostim or other thrombopoietin receptor (TPO-R) agonists
• Previous allogeneic stem-cell transplantation
• 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
• Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of investigational product (eltrombopag/placebo)
• Active and uncontrolled infections, including hepatitis B or C
• Human Immunodeficiency Virus (HIV) infection
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or its excipient, or azacitidine, that contraindicates the subjects' participation
• Pregnant or lactating female
• Any serious and/or unstable pre-existing medical condition (including any advanced malignancy other than the disease under study), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance with the study procedures
• French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (155)

Novartis Investigative Site

Hartford, Connecticut, 06105, United States

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Atlanta, Georgia, 30322, United States

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Chicago, Illinois, 60612, United States

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Anderson, Indiana, 46016, United States

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Kansas City, Missouri, 64128, United States

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St Louis, Missouri, 63110, United States

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The Bronx, New York, 10461, United States

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Winston-Salem, North Carolina, 27157, United States

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Seattle, Washington, 98108, United States

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Milwaukee, Wisconsin, 53226, United States

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Buenos Aires, 1114, Argentina

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Buenos Aires, 1425, Argentina

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Buenos Aires, C1181ACH, Argentina

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Santa Fe, S3000ADL, Argentina

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Kogarah, New South Wales, 2217, Australia

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Adelaide, South Australia, 5000, Australia

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Clayton, Victoria, 3168, Australia

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East Melbourne, Victoria, 3002, Australia

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Melbourne, Victoria, 3000, Australia

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Graz, 8036, Austria

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Innsbruck, A-6020, Austria

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Linz, 4020, Austria

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Rankweil, A-6830, Austria

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Salzburg, A-5020, Austria

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Steyr, 4400, Austria

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Vienna, 1140, Austria

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Brasschaat, 2930, Belgium

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Bruges, 8000, Belgium

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Leuven, 3000, Belgium

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Lodelinsart, 6042, Belgium

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Turnhout, 2300, Belgium

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Belo Horizonte, Minas Gerais, 30130-100, 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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Florianópolis, Santa Catarina, 88034-000, Brazil

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São Paulo, São Paulo, 01236030, Brazil

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São Paulo, São Paulo, 08270-070, Brazil

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Rio de Janeiro, 20211-030, Brazil

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Sao Paulo - SP, 01323-900, Brazil

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Toronto, Ontario, M5G 2M9, Canada

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Montreal, Quebec, H2L 4M1, Canada

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Québec, Quebec, G1J 1Z4, Canada

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Sherbrooke, Quebec, J1H 5N4, Canada

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Québec, G1J 1Z4, Canada

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Brno, 625 00, Czechia

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Ostrava, 708 52, 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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Aarhus, 8000 C, Denmark

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Koebenhavn Oe, 2100, Denmark

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Angers, 49933, France

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Caen, 14033, France

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Le Mans, 72000, France

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Paris, 75010, France

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Paris, 75571, France

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Pringy, 74374, France

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Stuttgart, Baden-Wurttemberg, 70199, Germany

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Munich, Bavaria, 81675, Germany

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Göttingen, Lower Saxony, 37075, Germany

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Duisburg, North Rhine-Westphalia, 47166, Germany

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Düsseldorf, North Rhine-Westphalia, 40225, Germany

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Düsseldorf, North Rhine-Westphalia, 40479, Germany

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Dresden, Saxony, 01307, Germany

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Athens, 11 527, Greece

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Larissa, 41 110, Greece

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Pátrai, 26500, Greece

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Thessaloniki, 54636, Greece

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Thessaloniki, 54642, Greece

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Chai Wan, Hong Kong

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Hong Kong, Hong Kong

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Shatin, New Territories, Hong Kong

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Tuenmen, Hong Kong

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Debrecen, 4012, Hungary

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Szeged, 6725, Hungary

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Dublin, 7, Ireland

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Galway, 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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Haifa, 31096, Israel

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Holon, 58100, Israel

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Jerusalem, 91031, Israel

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Jerusalem, 91120, Israel

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Kfar Saba, 44281, Israel

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Petah Tikva, 49100, Israel

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Tel Aviv, 64239, Israel

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Reggio Calabria, Calabria, 89100, Italy

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Modena, Emilia-Romagna, 41124, Italy

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Genoa, Liguria, 10126, Italy

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Novara, Piedmont, 28100, Italy

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Florence, Tuscany, 50134, Italy

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Monterrey, Nuevo León, 64460, Mexico

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Oaxaca City, 68000, Mexico

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Bergen, N-5021, Norway

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Oslo, 0027, Norway

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Lima, Lima 11, Peru

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Lima, Lima 31, Peru

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Krakow, 31-501, Poland

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Legnica, 59-200, Poland

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Lublin, 20-081, Poland

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Opole, 45-061, Poland

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Słupsk, 76-200, Poland

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Torun, 87-100, Poland

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San Juan, 00927, Puerto Rico

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Kaluga, 248007, Russia

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Moscow, 115478, Russia

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Moscow, 125167, Russia

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Moscow, 129301, Russia

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Penza, 440071, Russia

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Saint Petersburg, 193024, Russia

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St'Petersburg, 197341, Russia

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Seoul, 05505, South Korea

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Seoul, 06351, South Korea

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Seoul, 06591, South Korea

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Seoul, 135-710, South Korea

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Seoul, 137-701, South Korea

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Seoul, 138-736, South Korea

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Oviedo, Principality of Asturias, 33011, Spain

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Barcelona, 08035, Spain

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Barcelona, 08036, Spain

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Girona, 17007, Spain

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La Laguna (Santa Cruz de Tenerife), 38320, Spain

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León, 24071, Spain

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Madrid, 28007, Spain

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Madrid, 28034, Spain

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Madrid, 28046, Spain

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Majadahonda (Madrid), 28222, Spain

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Málaga, 29010, Spain

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Oviedo, 33006, Spain

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Palma de Mallorca, 07014, Spain

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Palma de Mallorca, 07198, Spain

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Pozuelo de Alarcon/Madrid, 28223, Spain

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Pozuelo de Alarcón/Madrid, 28223, Spain

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Salamanca, 37007, Spain

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Valencia, 46010, Spain

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Valencia, 46026, Spain

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Gothenburg, SE-413 45, Sweden

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Stockholm, SE-141 86, Sweden

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Uppsala, SE-751 85, Sweden

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Aarau, 5001, Switzerland

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Bellinzona, 6500, Switzerland

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Bern, 3010, Switzerland

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Zurich, 8091, Switzerland

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Changhua, 500, Taiwan

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Kaohsiung City, 807, Taiwan

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Kaohsiung City, 833, Taiwan

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Taipei, 112, Taiwan

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Bangkok, 10400, Thailand

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Bangkok, 10700, Thailand

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Chiang Mai, 50000, Thailand

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Ankara, 06590, Turkey (Türkiye)

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Izmir, 35100, Turkey (Türkiye)

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Izmir, 35340, Turkey (Türkiye)

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Samsun, 55139, Turkey (Türkiye)

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Related Publications (1)

• Dickinson M, Cherif H, Fenaux P, Mittelman M, Verma A, Portella MSO, Burgess P, Ramos PM, Choi J, Platzbecker U; SUPPORT study investigators. Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. Blood. 2018 Dec 20;132(25):2629-2638. doi: 10.1182/blood-2018-06-855221. Epub 2018 Oct 10.

  PMID: 30305280 DERIVED

MeSH Terms

Conditions

Thrombocytopenia; Myelodysplastic Syndromes; Jacobs syndrome

Interventions

eltrombopag; Azacitidine

Condition Hierarchy (Ancestors)

Blood Platelet Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cytopenia; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Limitations and Caveats

The IDMC recommended terminating the study for futility (primary) and safety (secondary). Due to early termination of the trial, the final analysis of OS took place at the same time as the final analysis of the primary end point.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharma AG

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 3
• 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 5, 2014
• First Posted: June 9, 2014
• Study Start: June 10, 2014
• Primary Completion: April 30, 2016
• Study Completion: April 30, 2016
• Last Updated: December 12, 2017
• Results First Posted: December 12, 2017

Record last verified: 2017-09

Locations

IT (5); GR (5); HU (2); AU (7); FR (6); IL (7); PR (1); BR (8); CA (5); PL (6); PE (2); TH (3); DK (2); KR (6); ES (19); SE (3); TW (4); DE (7); RU (7); HK (4); BE (5); TU (4); IE (5); US (10); CZ (5); NO (2); ME (2); CH (4); AR (4)