Eltrombopag Treatment of Thrombocytopenia in Subjects With Advanced Myelodysplastic Syndrome (MDS) or Secondary Acute Myeloid Leukemia After MDS (sAML/MDS)

NCT00903422 | Completed Phase 1 DMC

• 1 other identifier: 112509
• Study Type: interventional
• Target: 98
• Locations: 11 countries
• Sites: 65

Brief Summary

This study will evaluate the safety and tolerability of eltrombopag in the treatment of low platelet counts in adult subjects with advanced myelodysplastic syndrome (MDS), secondary acute myeloid leukemia after MDS (sAML/MDS), or de novo AML that are relapsed, refractory or ineligible to receive azacitidine, decitabine, intensive chemotherapy or autologous/allogeneic stem cell transplantation. This is a placebo-controlled study in which patients will receive study medication daily for 6 months, during which time the dose of study medication may be adjusted based upon individual platelet counts and bone marrow blast counts. All subjects will receive best standard of care (platelet transfusions, mild chemotherapy, cytokines, valproic acid, all-trans retinoic acid, ESAs or G-CSF) in addition to study medication. Subjects taking placebo may be allowed to crossover to eltrombopag treatment if a clinically and statistically significant improvement in bone marrow blast counts is seen in subjects treated with eltrombopag.

Conditions

Myelodysplastic Syndrome

Keywords

Advanced Myelodysplastic Syndrome; Thrombocytopenia; sAML/MDS; Eltrombopag; TPO-R agonist; de novo AML; Thrombopoietin; MDS; Thrombopoietin receptor agonist; secondary Acute Myeloid Leukemia after MDS; Platelets

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability parameters including non-hematological laboratory Grade 3/Grade 4 toxicities, change in bone marrow blast counts from baseline and adverse events reporting.

  Approximately 46 months

Secondary Outcomes (5)

• Proportion of subjects with a baseline platelet count <20 Gi/L and an increase to >20 Gi/L and by at least 2x baseline; or a baseline platelet count between >=20-<30 Gi/L and an absolute platelet count increase to >=50 Gi/L at any time during treatment.

  Approx. 46 months

• Frequency and number of units of platelet transfusions during the treatment and follow-up periods for eltrombopag- and placebo-treated subjects.

  approx 46 months

• The incidence and severity of bleeding events, measured using the World Health Organization (WHO) Bleeding Scale, during the treatment and 4 week follow-up periods for eltrombopag- and placebo-treated subjects.

  approx. 46 months

• Overall survival (OS) of eltrombopag- and placebo-treated subjects.

  approx. 46 months

• Change in health-related quality of life as measured using the EQ-5D questionnaire.

  approx. 46 months

Study Arms (2)

Eltrombopag

ACTIVE COMPARATOR

Eltrombopag

Drug: eltrombopag olamine

Placebo

PLACEBO COMPARATOR

Placebo

Other: Placebo

Interventions

eltrombopag olamine DRUG

thrombopoietin receptor agonist

Eltrombopag

Placebo OTHER

Placebo tablets with no active pharmaceutical ingredient

Placebo

Eligibility Criteria

• Age: 18 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 advanced MDS, sAML/MDS, or de novo AML with \>=10% and \<=50% blasts in bone marrow. Peripheral blood blast change over time should not be suggestive of highly proliferative disease (as judged by the investigator).
• Subjects must be dependent on regular platelet transfusions or have a platelet count taken within the 4 weeks prior to randomization that is \<30 Gi/L.
• Subjects must be relapsed, refractory or ineligible to receive standard treatment options of azacitidine and decitabine and must be relapsed, refractory or ineligible to receive intensive chemotherapy or autologous/allogeneic stem cell transplantation. A subject may be considered relapsed/refractory to a standard treatment if it is discontinued due to lack of efficacy. For subjects ineligible for standard treatments, it is permissible to start one of these standard treatments while on study medication if the Investigator considers that the subject becomes eligible during the course of the study.
• Prior therapy with demethylating agents (azacitidine or decitabine), lenalidomide or IL-11(oprelvekin) must have been completed at least 4 weeks before Day 1; antithymocyte/antilymphocyte globulin, intensive chemotherapy, or autologous/allogeneic stem cell transplantation must have been completed at least 2 months before Day 1. If a subject must discontinue a course of therapy due to lack of efficacy, the washout periods listed above do not apply (and the patient may be screened and randomized immediately if other eligibility criteria are met).
• Subjects must have platelet count and platelet transfusion data available over a period of 4 weeks prior to randomization.
• Subjects with advanced MDS, sAML/MDS, or de novo AML must have stable disease indicated by a doubling time of peripheral blast counts \>7 days during screening.
• During the 4 weeks prior to randomization, subjects must have a baseline bone marrow examination including the following:
• cytomorphology to confirm bone marrow blasts between 10-50%,
• cytogenetics (provide only most prevalent abnormal clone),
• The results of the above tests are required prior to subject randomization.
• Supportive/palliative therapies such as cytokines (except for IL-11; oprelvekin), valproic acid, all-trans retinoic acid or mild chemotherapy are allowed if part of the local SOC, provided those therapies have been at a stable dose for 4 weeks. If the subject chooses to discontinue these therapies prior to study entry, they must be completed 4 weeks prior to enrollment into this study, unless the therapy is discontinued due to lack of efficacy. Erythropoiesis-stimulating agents (ESAs) in anemic subjects or granulocyte colony-stimulating factor (G-CSF) in subjects with severe neutropenia and recurrent infections are allowed during the study as per accepted standards. Subjects who enter the study on ESAs or G-CSF should continue at the same dose schedule until the optimal dose of study medication has been established.
• ECOG Status 0-3.
• Subject is able to understand and comply with protocol requirements and instructions.
• Subject has signed and dated informed consent.
• Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) must be within 80 to 120% of the normal range at baseline.

You may not qualify if:

• Subjects with a diagnosis of acute promyelocytic leukemia.
• History of treatment for cancer (other than MDS, sAML/MDS, or de novo AML) with systemic chemotherapy and/or radiotherapy within the last 2 years.
• History of treatment with romiplostim or other TPO-R agonists.
• Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association \[NYHA\] Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a QTc \>450 msec (QTc \>480 msec for subjects with Bundle Branch Block).
• Bone marrow fibrosis that leads to an inability to aspirate marrow for assessment.
• Spleen size \>14 cm (length as per ultrasound examination).
• Leukocytosis \>=25,000/uL prior to Day 1 of study medication.
• Female subjects who are nursing or pregnant (positive serum or urine Beta-human chorionic gonadotropin \[B-hCG\] 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.
• Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV).
• Subjects with liver cirrhosis.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (65)

GSK Investigational Site

Birmingham, Alabama, 35294, United States

Location

GSK Investigational Site

Santa Monica, California, 90404, United States

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GSK Investigational Site

Stanford, California, 94305, United States

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GSK Investigational Site

Coral Springs, Florida, 33065, United States

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GSK Investigational Site

Lake Worth, Florida, 33467, United States

Location

GSK Investigational Site

Atlanta, Georgia, 30341, United States

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GSK Investigational Site

Baltimore, Maryland, 21231, United States

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GSK Investigational Site

Boston, Massachusetts, 02111, United States

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GSK Investigational Site

Detroit, Michigan, 48202, United States

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GSK Investigational Site

Kansas City, Missouri, 64128, United States

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GSK Investigational Site

St Louis, Missouri, 63110, United States

Location

GSK Investigational Site

Camden, New Jersey, 08103, United States

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GSK Investigational Site

The Bronx, New York, 10461, United States

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GSK Investigational Site

Philadelphia, Pennsylvania, 19104, United States

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GSK Investigational Site

Philadelphia, Pennsylvania, 19106, United States

Location

GSK Investigational Site

Pittsburgh, Pennsylvania, 15224, United States

Location

GSK Investigational Site

Greenville, South Carolina, 29601, United States

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GSK Investigational Site

Memphis, Tennessee, 38120, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

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GSK Investigational Site

New Braunfels, Texas, 78130, United States

Location

GSK Investigational Site

San Antonio, Texas, 78229, United States

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GSK Investigational Site

Arlington, Virginia, 22205, United States

Location

GSK Investigational Site

Fairfax, Virginia, 22031, United States

Location

GSK Investigational Site

Madison, Wisconsin, 53705, United States

Location

GSK Investigational Site

Salvador, Estado de Bahia, 41253-190, Brazil

Location

GSK Investigational Site

Belo Horizonte, Minas Gerais, 30130-100, Brazil

Location

GSK Investigational Site

Rio de Janeiro, 20211-030, Brazil

Location

GSK Investigational Site

Rio de Janeiro, 20230 -130, Brazil

Location

GSK Investigational Site

Koebenhavn Oe, 2100, Denmark

Location

GSK Investigational Site

Odense C, 5000, Denmark

Location

GSK Investigational Site

Bayonne, 64109, France

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GSK Investigational Site

Besançon, 25030, France

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GSK Investigational Site

Bobigny, 93009, France

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GSK Investigational Site

Caen, 14033, France

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GSK Investigational Site

Marseille, 13273, France

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GSK Investigational Site

Paris, 75571, France

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GSK Investigational Site

Toulouse, 31059, France

Location

GSK Investigational Site

Stuttgart, Baden-Wurttemberg, 70199, Germany

Location

GSK Investigational Site

Ulm, Baden-Wurttemberg, 89081, Germany

Location

GSK Investigational Site

Munich, Bavaria, 81675, Germany

Location

GSK Investigational Site

Göttingen, Lower Saxony, 37075, Germany

Location

GSK Investigational Site

Cologne, North Rhine-Westphalia, 50937, Germany

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GSK Investigational Site

Duisburg, North Rhine-Westphalia, 47166, Germany

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GSK Investigational Site

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

GSK Investigational Site

Mainz, Rhineland-Palatinate, 55131, Germany

Location

GSK Investigational Site

Dresden, Saxony, 01307, Germany

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GSK Investigational Site

Berlin, 12200, Germany

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GSK Investigational Site

Hong Kong, Hong Kong

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GSK Investigational Site

Shatin, New Territories, Hong Kong

Location

GSK Investigational Site

Reggio Calabria, Calabria, 89100, Italy

Location

GSK Investigational Site

Florence, Tuscany, 50134, Italy

Location

GSK Investigational Site

Vicenza, Veneto, 36100, Italy

Location

GSK Investigational Site

San Juan, 00927, Puerto Rico

Location

GSK Investigational Site

Seoul, 135-710, South Korea

Location

GSK Investigational Site

Seoul, 137-701, South Korea

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GSK Investigational Site

Seoul, 138-736, South Korea

Location

GSK Investigational Site

Changhua, 500, Taiwan

Location

GSK Investigational Site

Taichung, 404, Taiwan

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GSK Investigational Site

Taipei, 100, Taiwan

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GSK Investigational Site

Taipei, 112, Taiwan

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GSK Investigational Site

Aberdeen, AB25 2ZN, United Kingdom

Location

GSK Investigational Site

Glasgow, G12 0YN, United Kingdom

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GSK Investigational Site

Leeds, LS9 7TF, United Kingdom

Location

GSK Investigational Site

London, SE5 9RS, United Kingdom

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GSK Investigational Site

London, SW17 0RE, United Kingdom

Location

Related Publications (2)

• Mavroudi I, Pyrovolaki K, Pavlaki K, Kozana A, Psyllaki M, Kalpadakis C, Pontikoglou C, Papadaki HA. Effect of the nonpeptide thrombopoietin receptor agonist eltrombopag on megakaryopoiesis of patients with lower risk myelodysplastic syndrome. Leuk Res. 2011 Mar;35(3):323-8. doi: 10.1016/j.leukres.2010.06.029. Epub 2010 Aug 4.

  PMID: 20688394 BACKGROUND

• Platzbecker U, Wong RS, Verma A, Abboud C, Araujo S, Chiou TJ, Feigert J, Yeh SP, Gotze K, Gorin NC, Greenberg P, Kambhampati S, Kim YJ, Lee JH, Lyons R, Ruggeri M, Santini V, Cheng G, Jang JH, Chen CY, Johnson B, Bennett J, Mannino F, Kamel YM, Stone N, Dougherty S, Chan G, Giagounidis A. Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial. Lancet Haematol. 2015 Oct;2(10):e417-26. doi: 10.1016/S2352-3026(15)00149-0. Epub 2015 Oct 1.

  PMID: 26686043 DERIVED

Related Links

• Results for study 112509 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Myelodysplastic Syndromes; Thrombocytopenia; Jacobs syndrome

Condition Hierarchy (Ancestors)

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

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2009
• First Posted: May 18, 2009
• Study Start: May 14, 2009
• Primary Completion: June 26, 2012
• Study Completion: December 5, 2013
• Last Updated: November 13, 2017

Record last verified: 2017-11

Locations

IT (3); DK (2); HK (2); KR (3); FR (7); DE (10); TW (4); US (24); BR (4); PR (1); GB (5)