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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00903422
First received: May 14, 2009
Last updated: December 19, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention Phase
Myelodysplastic Syndrome
Drug: eltrombopag olamine
Other: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • 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. [ Time Frame: Approximately 46 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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. [ Time Frame: Approx. 46 months ] [ Designated as safety issue: No ]
  • Frequency and number of units of platelet transfusions during the treatment and follow-up periods for eltrombopag- and placebo-treated subjects. [ Time Frame: approx 46 months ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: approx. 46 months ] [ Designated as safety issue: No ]
  • Overall survival (OS) of eltrombopag- and placebo-treated subjects. [ Time Frame: approx. 46 months ] [ Designated as safety issue: No ]
  • Change in health-related quality of life as measured using the EQ-5D questionnaire. [ Time Frame: approx. 46 months ] [ Designated as safety issue: No ]

Enrollment: 98
Study Start Date: May 2009
Estimated Study Completion Date: December 2013
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Eltrombopag
Eltrombopag
Drug: eltrombopag olamine
thrombopoietin receptor agonist
Placebo Comparator: Placebo
Placebo
Other: Placebo
Placebo tablets with no active pharmaceutical ingredient

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00903422

  Hide Study Locations
Locations
United States, Alabama
GSK Investigational Site
Birmingham, Alabama, United States, 35294
United States, California
GSK Investigational Site
Santa Monica, California, United States, 90404
GSK Investigational Site
Stanford, California, United States, 94305
United States, Florida
GSK Investigational Site
Coral Springs, Florida, United States, 33065
GSK Investigational Site
Lake Worth, Florida, United States, 33467
United States, Georgia
GSK Investigational Site
Atlanta, Georgia, United States, 30341
United States, Maryland
GSK Investigational Site
Baltimore, Maryland, United States, 21231
United States, Massachusetts
GSK Investigational Site
Boston, Massachusetts, United States, 02111
United States, Michigan
GSK Investigational Site
Detroit, Michigan, United States, 48202
United States, Missouri
GSK Investigational Site
Kansas City, Missouri, United States, 64128
GSK Investigational Site
St. Louis, Missouri, United States, 63110
United States, New Jersey
GSK Investigational Site
Camden, New Jersey, United States, 08103
United States, New York
GSK Investigational Site
Bronx, New York, United States, 10461
United States, Pennsylvania
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19104
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19106
GSK Investigational Site
Pittsburgh, Pennsylvania, United States, 15224
United States, South Carolina
GSK Investigational Site
Greenville, South Carolina, United States, 29601
United States, Tennessee
GSK Investigational Site
Memphis, Tennessee, United States, 38120
United States, Texas
GSK Investigational Site
Houston, Texas, United States, 77030
GSK Investigational Site
New Braunfels, Texas, United States, 78130
GSK Investigational Site
San Antonio, Texas, United States, 78229
United States, Virginia
GSK Investigational Site
Arlington, Virginia, United States, 22205
GSK Investigational Site
Fairfax, Virginia, United States, 22031
United States, Wisconsin
GSK Investigational Site
Madison, Wisconsin, United States, 53705
Brazil
GSK Investigational Site
Salvador, Bahía, Brazil, 41253-190
GSK Investigational Site
Belo Horizonte, Minas Gerais, Brazil, 30130-100
GSK Investigational Site
Rio de Janeiro, Brazil, 20230 -130
GSK Investigational Site
Rio de Janeiro, Brazil, 20211-030
Denmark
GSK Investigational Site
Koebenhavn Oe, Denmark, 2100
GSK Investigational Site
Odense C, Denmark, 5000
France
GSK Investigational Site
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
Germany
GSK Investigational Site
Stuttgart, Baden-Wuerttemberg, Germany, 70199
GSK Investigational Site
Ulm, Baden-Wuerttemberg, Germany, 89081
GSK Investigational Site
Muenchen, Bayern, Germany, 81675
GSK Investigational Site
Goettingen, Niedersachsen, Germany, 37075
GSK Investigational Site
Duesseldorf, Nordrhein-Westfalen, Germany, 40225
GSK Investigational Site
Duisburg, Nordrhein-Westfalen, Germany, 47166
GSK Investigational Site
Koeln, Nordrhein-Westfalen, Germany, 50937
GSK Investigational Site
Mainz, Rheinland-Pfalz, Germany, 55131
GSK Investigational Site
Dresden, Sachsen, Germany, 01307
GSK Investigational Site
Berlin, Germany, 12200
Hong Kong
GSK Investigational Site
Hong Kong, Hong Kong
GSK Investigational Site
Shatin, New Territories, Hong Kong
Italy
GSK Investigational Site
Reggio Calabria, Calabria, Italy, 89100
GSK Investigational Site
Firenze, Toscana, Italy, 50134
GSK Investigational Site
Vicenza, Veneto, Italy, 36100
Korea, Republic of
GSK Investigational Site
Seoul, Korea, Republic of, 135-710
GSK Investigational Site
Seoul, Korea, Republic of, 138-736
GSK Investigational Site
Seoul, Korea, Republic of, 137-701
Puerto Rico
GSK Investigational Site
San Juan, Puerto Rico, 00927
Taiwan
GSK Investigational Site
Changhua, Taiwan, 500
GSK Investigational Site
Taichung, Taiwan, 404
GSK Investigational Site
Taipei, Taiwan, 100
GSK Investigational Site
Taipei, Taiwan, 112
United Kingdom
GSK Investigational Site
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, SW17 0RE
GSK Investigational Site
London, United Kingdom, SE5 9RS
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00903422     History of Changes
Other Study ID Numbers: 112509
Study First Received: May 14, 2009
Last Updated: December 19, 2013
Health Authority: Hong Kong: Department of Health
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
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

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Thrombocytopenia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Blood Platelet Disorders

ClinicalTrials.gov processed this record on July 29, 2014