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

Study PMA112509, a Phase I/II Study of Eltrombopag in Thrombocytopenic Subjects With Advanced Myelodysplastic Syndrome (MDS) or Secondary Acute Myeloid Leukemia After MDS (sAML/MDS)

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndrome
• Intervention / Treatment: Other: Placebo; Drug: eltrombopag olamine

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.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 1

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil, 20230 -130
    • GSK Investigational Site
  • Rio de Janeiro, Brazil, 20211-030
    • GSK Investigational Site
  • Bahía
    • Salvador, Bahía, Brazil, 41253-190
      • GSK Investigational Site
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30130-100
      • GSK Investigational Site
• Denmark
  • Koebenhavn Oe, Denmark, 2100
    • GSK Investigational Site
  • Odense C, Denmark, 5000
    • GSK Investigational Site
• France
  • Bayonne cedex, France, 64109
    • GSK Investigational Site
  • Besançon cedex, France, 25030
    • GSK Investigational Site
  • Bobigny Cedex, France, 93009
    • GSK Investigational Site
  • Caen cedex 9, France, 14033
    • GSK Investigational Site
  • Marseille cedex 9, France, 13273
    • GSK Investigational Site
  • Paris Cedex 12, France, 75571
    • GSK Investigational Site
  • Toulouse, France, 31059
    • GSK Investigational Site
• Germany
  • Berlin, Germany, 12200
    • GSK Investigational Site
  • Baden-Wuerttemberg
    • Stuttgart, Baden-Wuerttemberg, Germany, 70199
      • GSK Investigational Site
    • Ulm, Baden-Wuerttemberg, Germany, 89081
      • GSK Investigational Site
  • Bayern
    • Muenchen, Bayern, Germany, 81675
      • GSK Investigational Site
  • Niedersachsen
    • Goettingen, Niedersachsen, Germany, 37075
      • GSK Investigational Site
  • Nordrhein-Westfalen
    • Duesseldorf, Nordrhein-Westfalen, Germany, 40225
      • GSK Investigational Site
    • Duisburg, Nordrhein-Westfalen, Germany, 47166
      • GSK Investigational Site
    • Koeln, Nordrhein-Westfalen, Germany, 50937
      • GSK Investigational Site
  • Rheinland-Pfalz
    • Mainz, Rheinland-Pfalz, Germany, 55131
      • GSK Investigational Site
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • GSK Investigational Site
• Hong Kong
  • Hong Kong, Hong Kong
    • GSK Investigational Site
  • Shatin, New Territories, Hong Kong
    • GSK Investigational Site
• Italy
  • Calabria
    • Reggio Calabria, Calabria, Italy, 89100
      • GSK Investigational Site
  • Toscana
    • Firenze, Toscana, Italy, 50134
      • GSK Investigational Site
  • Veneto
    • Vicenza, Veneto, Italy, 36100
      • GSK Investigational Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 137-701
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 135-710
    • GSK Investigational Site
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • GSK Investigational Site
• Taiwan
  • Changhua, Taiwan, 500
    • GSK Investigational Site
  • Taichung, Taiwan, 404
    • GSK Investigational Site
  • Taipei, Taiwan, 100
    • GSK Investigational Site
  • Taipei, Taiwan, 112
    • GSK Investigational Site
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • GSK Investigational Site
  • Glasgow, United Kingdom, G12 0YN
    • GSK Investigational Site
  • Leeds, United Kingdom, LS9 7TF
    • GSK Investigational Site
  • London, United Kingdom, SE5 9RS
    • GSK Investigational Site
  • London, United Kingdom, SW17 0RE
    • GSK Investigational Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • GSK Investigational Site
  • California
    • Santa Monica, California, United States, 90404
      • GSK Investigational Site
    • Stanford, California, United States, 94305
      • GSK Investigational Site
  • Florida
    • Coral Springs, Florida, United States, 33065
      • GSK Investigational Site
    • Lake Worth, Florida, United States, 33467
      • GSK Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30341
      • GSK Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • GSK Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • GSK Investigational Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • GSK Investigational Site
  • Missouri
    • Kansas City, Missouri, United States, 64128
      • GSK Investigational Site
    • Saint Louis, Missouri, United States, 63110
      • GSK Investigational Site
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • GSK Investigational Site
  • New York
    • The Bronx, New York, United States, 10461
      • GSK Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • GSK Investigational Site
    • Philadelphia, Pennsylvania, United States, 19106
      • GSK Investigational Site
    • Pittsburgh, Pennsylvania, United States, 15224
      • GSK Investigational Site
  • South Carolina
    • Greenville, South Carolina, United States, 29601
      • GSK Investigational Site
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • GSK Investigational Site
  • Texas
    • Houston, Texas, United States, 77030
      • GSK Investigational Site
    • New Braunfels, Texas, United States, 78130
      • GSK Investigational Site
    • San Antonio, Texas, United States, 78229
      • GSK Investigational Site
  • Virginia
    • Arlington, Virginia, United States, 22205
      • GSK Investigational Site
    • Fairfax, Virginia, United States, 22031
      • GSK Investigational Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Other: Placebo; Placebo tablets with no active pharmaceutical ingredient
ACTIVE_COMPARATOR: Eltrombopag	Drug: eltrombopag olamine; thrombopoietin receptor agonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 14, 2009
• Primary Completion (ACTUAL): June 26, 2012
• Study Completion (ACTUAL): December 5, 2013

Study Registration Dates

• First Submitted: May 14, 2009
• First Submitted That Met QC Criteria: May 14, 2009
• First Posted (ESTIMATE): May 18, 2009

Study Record Updates

• Last Update Posted (ACTUAL): November 13, 2017
• Last Update Submitted That Met QC Criteria: November 8, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: MDS; Platelets; Eltrombopag; Thrombocytopenia; Thrombopoietin; Thrombopoietin receptor agonist; TPO-R agonist; Advanced Myelodysplastic Syndrome; sAML/MDS; de novo AML; secondary Acute Myeloid Leukemia after MDS
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Blood Platelet Disorders; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Thrombocytopenia
• Other Study ID Numbers: 112509