Clinical trial NCT01440374: A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia
Official title: A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia (Part 1: Open-label, Part 2: Randomized, Double-blind, Part 3: Extension)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-09-26
Enrollment: 162
Sex: ALL
Minimum age (years): 18
Maximum age (years): 110
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.


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.

Primary outcomes:
measure: Number of Participants With Platelet Response up to Week 8 During Part 1
timeFrame: From Baseline up to Week 8 during Part 1
measure: Clinically Relevant Thrombocytopenic Events (CRTE) From Week 5 up to Week 12 During Part 2
timeFrame: From Week 5 up to Week 12 during Part 2
Secondary outcomes:
measure: Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 1 Subjects)
timeFrame: Day 1 to week 8
measure: Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 2 Subjects)
timeFrame: Day 1 to week 12
measure: Mean Number of Platelet Transfusions
timeFrame: Weeks 5 to 12
measure: Hematologic Improvement
timeFrame: Weeks 5 to 12
measure: Change in Mean Platelet Count
timeFrame: Baseline to Week 12
measure: Maximum Duration of Platelet Transfusion Independence
timeFrame: Weeks 5 to 12
measure: Number of Participants With Maximum Bleeding Grade According to World Health Organization on Bleeding Scale
timeFrame: Weeks 5 to 12
measure: Independent Reviewer-Assessed Best Response
timeFrame: up to week 12
measure: Independent Reviewer Assessed Disease Progression
timeFrame: Up to week 12
measure: Median Overall Survival
timeFrame: Up to 13 months
measure: Summary of Health Outcomes
timeFrame: week 12
measure: Functional Assessment of Cancer Therapy (FACT)
timeFrame: Change from baseline, up to week 12
measure: EQ-5D Utility Score Analysis
timeFrame: Change from baseline, up to week 12
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Hot Springs
country: United States
facility: Novartis Investigative Site
state: Arkansas
city: Jonesboro
country: United States
facility: Novartis Investigative Site
state: Arkansas
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: Stanford
country: United States
facility: Novartis Investigative Site
state: California
city: Jacksonville
country: United States
facility: Novartis Investigative Site
state: Florida
city: Orlando
country: United States
facility: Novartis Investigative Site
state: Florida
city: West Palm Beach
country: United States
facility: Novartis Investigative Site
state: Florida
city: Augusta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Kansas City
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Hackensack
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Voorhees
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: The Bronx
country: United States
facility: Novartis Investigative Site
state: New York
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Milwaukee
country: United States
facility: Novartis Investigative Site
state: Wisconsin
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: La Plata
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Ciudad AutÃ³noma de Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Antwerpen
country: Belgium
facility: Novartis Investigative Site
city: Brasschaat
country: Belgium
facility: Novartis Investigative Site
city: Brugge
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Yvoir
country: Belgium
facility: Novartis Investigative Site
city: Goiânia - GO
country: Brazil
facility: Novartis Investigative Site
state: Goiás
city: GoiÃ¢nia - GO
country: Brazil
facility: Novartis Investigative Site
state: GoiÃ¡s
city: Curitiba
country: Brazil
facility: Novartis Investigative Site
state: Paraná
city: Curitiba
country: Brazil
facility: Novartis Investigative Site
state: ParanÃ¡
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Barretos
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Barretos
country: Brazil
facility: Novartis Investigative Site
state: SÃ£o Paulo
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
city: SÃ£o Paulo
country: Brazil
facility: Novartis Investigative Site
city: Halifax
country: Canada
facility: Novartis Investigative Site
state: Nova Scotia
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Brno
country: Czechia
facility: Novartis Investigative Site
city: Praha 10
country: Czechia
facility: Novartis Investigative Site
city: Praha 2
country: Czechia
facility: Novartis Investigative Site
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Goettingen
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Dresden
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Heraklion, Crete
country: Greece
facility: Novartis Investigative Site
city: Ioannina
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Chai Wan
country: Hong Kong
facility: Novartis Investigative Site
city: Shatin, New Territories
country: Hong Kong
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Kaposvár
country: Hungary
facility: Novartis Investigative Site
city: KaposvÃ¡r
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Cork
country: Ireland
facility: Novartis Investigative Site
city: Dublin
country: Ireland
facility: Novartis Investigative Site
city: James Street
country: Ireland
facility: Novartis Investigative Site
city: Limerick
country: Ireland
facility: Novartis Investigative Site
city: Tallaght, Dublin
country: Ireland
facility: Novartis Investigative Site
city: Tullamore
country: Ireland
facility: Novartis Investigative Site
city: Beer-Sheva
country: Israel
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Holon
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Petach-Tikva
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Rehovot
country: Israel
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: Emilia-Romagna
city: Brescia
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Milano
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Milano
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Alessandria
country: Italy
facility: Novartis Investigative Site
state: Piemonte
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: Toscana
city: Hwasun
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo LeÃ³n
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo León
city: Chihuahua
country: Mexico
facility: Novartis Investigative Site
city: Mexico City
country: Mexico
facility: Novartis Investigative Site
city: Oaxaca
country: Mexico
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Chorzow
country: Poland
facility: Novartis Investigative Site
city: Torun
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: San Juan
country: Puerto Rico
facility: Novartis Investigative Site
city: Nizhniy Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Petrozavodsk
country: Russian Federation
facility: Novartis Investigative Site
city: St'Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St'Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Granada
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Málaga
country: Spain
facility: Novartis Investigative Site
city: MÃ¡laga
country: Spain
facility: Novartis Investigative Site
city: Pozuelo de AlarcÃ³n/Madrid
country: Spain
facility: Novartis Investigative Site
city: Pozuelo de Alarcón/Madrid
country: Spain
facility: Novartis Investigative Site
city: Salamanca
country: Spain
facility: Novartis Investigative Site
city: Santander
country: Spain
facility: Novartis Investigative Site
city: Kaohsiung City
country: Taiwan
facility: Novartis Investigative Site
city: Tainan County
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan County
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Khon Kaen
country: Thailand
facility: Novartis Investigative Site
city: Songkla
country: Thailand
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.