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

NCT ID: NCT00903422

Last Updated: 2017-11-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 98 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-05-14
• Study Completion Date: 2013-12-05

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.

Detailed Description

A double-blind, randomized, placebo-controlled phase I/II study to evaluate the safety and tolerability of eltrombopag olamine, a thrombopoietin receptor agonist, administered for 6 months as oral tablets once daily in adult subjects with advanced MDS, sAML/MDS, or de novo AML. Study medication may be increased up to 300 mg (150 mg maximum dose for East Asian subjects), based upon individual platelet counts and bone marrow blast counts.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Eltrombopag

Eltrombopag

Group Type: ACTIVE_COMPARATOR

eltrombopag olamine

Intervention Type: DRUG

thrombopoietin receptor agonist

Placebo

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo tablets with no active pharmaceutical ingredient

Interventions

eltrombopag olamine

thrombopoietin receptor agonist

Intervention Type: DRUG

Placebo

Placebo tablets with no active pharmaceutical ingredient

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• 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.
• Adequate baseline organ function defined by the criteria below:
• total bilirubin (except for Gilbert's Syndrome) <= 1.5xULN
• ALT and AST <= 3xULN
• creatinine <= 2xULN
• albumin must not be below the lower limit of normal (LLN) by more than 20%.
• Subject is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must either be of non-childbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal >1 year), or of childbearing potential and use 1 of the following highly effective methods of contraception (i.e., Pearl Index <1.0%) from 2 weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study:
• Complete abstinence from intercourse;
• Intrauterine device (IUD);
• Two forms of barrier contraception (diaphragm plus spermicide, and for males condom plus spermicide);
• Male partner is sterile prior to entry into the study and is the only partner of the female;
• Systemic contraceptives (combined or progesterone only).

Exclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Birmingham, Alabama, United States

GSK Investigational Site

Santa Monica, California, United States

GSK Investigational Site

Stanford, California, United States

GSK Investigational Site

Coral Springs, Florida, United States

GSK Investigational Site

Lake Worth, Florida, United States

GSK Investigational Site

Atlanta, Georgia, United States

GSK Investigational Site

Baltimore, Maryland, United States

GSK Investigational Site

Boston, Massachusetts, United States

GSK Investigational Site

Detroit, Michigan, United States

GSK Investigational Site

Kansas City, Missouri, United States

GSK Investigational Site

St Louis, Missouri, United States

GSK Investigational Site

Camden, New Jersey, United States

GSK Investigational Site

The Bronx, New York, United States

GSK Investigational Site

Philadelphia, Pennsylvania, United States

GSK Investigational Site

Philadelphia, Pennsylvania, United States

GSK Investigational Site

Pittsburgh, Pennsylvania, United States

GSK Investigational Site

Greenville, South Carolina, United States

GSK Investigational Site

Memphis, Tennessee, United States

GSK Investigational Site

Houston, Texas, United States

GSK Investigational Site

New Braunfels, Texas, United States

GSK Investigational Site

San Antonio, Texas, United States

GSK Investigational Site

Arlington, Virginia, United States

GSK Investigational Site

Fairfax, Virginia, United States

GSK Investigational Site

Madison, Wisconsin, United States

GSK Investigational Site

Salvador, Estado de Bahia, Brazil

GSK Investigational Site

Belo Horizonte, Minas Gerais, Brazil

GSK Investigational Site

Rio de Janeiro, , Brazil

GSK Investigational Site

Rio de Janeiro, , Brazil

GSK Investigational Site

Koebenhavn Oe, , Denmark

GSK Investigational Site

Odense C, , Denmark

GSK Investigational Site

Bayonne, , France

GSK Investigational Site

Besançon, , France

GSK Investigational Site

Bobigny, , France

GSK Investigational Site

Caen, , France

GSK Investigational Site

Marseille, , France

GSK Investigational Site

Paris, , France

GSK Investigational Site

Toulouse, , France

GSK Investigational Site

Stuttgart, Baden-Wurttemberg, Germany

GSK Investigational Site

Ulm, Baden-Wurttemberg, Germany

GSK Investigational Site

Munich, Bavaria, Germany

GSK Investigational Site

Göttingen, Lower Saxony, Germany

GSK Investigational Site

Cologne, North Rhine-Westphalia, Germany

GSK Investigational Site

Duisburg, North Rhine-Westphalia, Germany

GSK Investigational Site

Düsseldorf, North Rhine-Westphalia, Germany

GSK Investigational Site

Mainz, Rhineland-Palatinate, Germany

GSK Investigational Site

Dresden, Saxony, Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Hong Kong, , Hong Kong

GSK Investigational Site

Shatin, New Territories, , Hong Kong

GSK Investigational Site

Reggio Calabria, Calabria, Italy

GSK Investigational Site

Florence, Tuscany, Italy

GSK Investigational Site

Vicenza, Veneto, Italy

GSK Investigational Site

San Juan, , Puerto Rico

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Changhua, , Taiwan

GSK Investigational Site

Taichung, , Taiwan

GSK Investigational Site

Taipei, , Taiwan

GSK Investigational Site

Taipei, , Taiwan

GSK Investigational Site

Aberdeen, , United Kingdom

GSK Investigational Site

Glasgow, , United Kingdom

GSK Investigational Site

Leeds, , United Kingdom

GSK Investigational Site

London, , United Kingdom

GSK Investigational Site

London, , United Kingdom

Countries

United States; Brazil; Denmark; France; Germany; Hong Kong; Italy; Puerto Rico; South Korea; Taiwan; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 20688394 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26686043 (View on PubMed)

Other Identifiers

112509

Identifier Type: -

Identifier Source: org_study_id