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

Myelodysplastic Syndrome Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00903422
• Other study ID #: 112509
• Status: Completed
• Phase: Phase 1
• First received: May 14, 2009
• Last updated: November 8, 2017
• Start date: May 14, 2009
• Est. completion date: December 5, 2013

Study information

• Verified date: November 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 98
• Est. completion date: December 5, 2013
• Est. primary completion date: June 26, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome
• Thrombocytopenia

Intervention

Drug:
• eltrombopag olamine
thrombopoietin receptor agonist

Other:
• Placebo
Placebo tablets with no active pharmaceutical ingredient

Locations

Country	Name	City	State
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	Salvador	Bahía
Denmark	GSK Investigational Site	Koebenhavn Oe
Denmark	GSK Investigational Site	Odense C
France	GSK Investigational Site	Bayonne cedex
France	GSK Investigational Site	Besançon cedex
France	GSK Investigational Site	Bobigny Cedex
France	GSK Investigational Site	Caen cedex 9
France	GSK Investigational Site	Marseille cedex 9
France	GSK Investigational Site	Paris Cedex 12
France	GSK Investigational Site	Toulouse
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen
Germany	GSK Investigational Site	Duisburg	Nordrhein-Westfalen
Germany	GSK Investigational Site	Goettingen	Niedersachsen
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Germany	GSK Investigational Site	Mainz	Rheinland-Pfalz
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg
Germany	GSK Investigational Site	Ulm	Baden-Wuerttemberg
Hong Kong	GSK Investigational Site	Hong Kong
Hong Kong	GSK Investigational Site	Shatin, New Territories
Italy	GSK Investigational Site	Firenze	Toscana
Italy	GSK Investigational Site	Reggio Calabria	Calabria
Italy	GSK Investigational Site	Vicenza	Veneto
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Puerto Rico	GSK Investigational Site	San Juan
Taiwan	GSK Investigational Site	Changhua
Taiwan	GSK Investigational Site	Taichung
Taiwan	GSK Investigational Site	Taipei
Taiwan	GSK Investigational Site	Taipei
United Kingdom	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 States	GSK Investigational Site	Arlington	Virginia
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Boston	Massachusetts
United States	GSK Investigational Site	Camden	New Jersey
United States	GSK Investigational Site	Coral Springs	Florida
United States	GSK Investigational Site	Detroit	Michigan
United States	GSK Investigational Site	Fairfax	Virginia
United States	GSK Investigational Site	Greenville	South Carolina
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Kansas City	Missouri
United States	GSK Investigational Site	Lake Worth	Florida
United States	GSK Investigational Site	Madison	Wisconsin
United States	GSK Investigational Site	Memphis	Tennessee
United States	GSK Investigational Site	New Braunfels	Texas
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	Saint Louis	Missouri
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	Santa Monica	California
United States	GSK Investigational Site	Stanford	California
United States	GSK Investigational Site	The Bronx	New York

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Brazil,  Denmark,  France,  Germany,  Hong Kong,  Italy,  Korea, Republic of,  Puerto Rico,  Taiwan,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Frequency and number of units of platelet transfusions during the treatment and follow-up periods for eltrombopag- and placebo-treated subjects.		approx 46 months
Secondary	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
Secondary	Overall survival (OS) of eltrombopag- and placebo-treated subjects.		approx. 46 months
Secondary	Change in health-related quality of life as measured using the EQ-5D questionnaire.		approx. 46 months

External Links

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