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

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT00903422

Collaborator

(none)

Enrollment

Locations

Arms

54.7

Actual Duration (Months)

1.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome	Drug: eltrombopag olamine Other: Placebo	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

98 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, 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)

Actual Study Start Date :

May 14, 2009

Actual Primary Completion Date :

Jun 26, 2012

Actual Study Completion Date :

Dec 5, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Eltrombopag Eltrombopag	Drug: eltrombopag olamine thrombopoietin receptor agonist
Placebo Comparator: Placebo Placebo	Other: Placebo Placebo tablets with no active pharmaceutical ingredient

Arm

Intervention/Treatment

Active Comparator: Eltrombopag

Eltrombopag

Drug: eltrombopag olamine

thrombopoietin receptor agonist

Placebo Comparator: Placebo

Placebo

Other: Placebo

Placebo tablets with no active pharmaceutical ingredient

Outcome Measures

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. [Approximately 46 months]

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. [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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Birmingham	Alabama	United States	35294
2	GSK Investigational Site	Santa Monica	California	United States	90404
3	GSK Investigational Site	Stanford	California	United States	94305
4	GSK Investigational Site	Coral Springs	Florida	United States	33065
5	GSK Investigational Site	Lake Worth	Florida	United States	33467
6	GSK Investigational Site	Atlanta	Georgia	United States	30341
7	GSK Investigational Site	Baltimore	Maryland	United States	21231
8	GSK Investigational Site	Boston	Massachusetts	United States	02111
9	GSK Investigational Site	Detroit	Michigan	United States	48202
10	GSK Investigational Site	Kansas City	Missouri	United States	64128
11	GSK Investigational Site	Saint Louis	Missouri	United States	63110
12	GSK Investigational Site	Camden	New Jersey	United States	08103
13	GSK Investigational Site	The Bronx	New York	United States	10461
14	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19104
15	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19106
16	GSK Investigational Site	Pittsburgh	Pennsylvania	United States	15224
17	GSK Investigational Site	Greenville	South Carolina	United States	29601
18	GSK Investigational Site	Memphis	Tennessee	United States	38120
19	GSK Investigational Site	Houston	Texas	United States	77030
20	GSK Investigational Site	New Braunfels	Texas	United States	78130
21	GSK Investigational Site	San Antonio	Texas	United States	78229
22	GSK Investigational Site	Arlington	Virginia	United States	22205
23	GSK Investigational Site	Fairfax	Virginia	United States	22031
24	GSK Investigational Site	Madison	Wisconsin	United States	53705
25	GSK Investigational Site	Salvador	Bahía	Brazil	41253-190
26	GSK Investigational Site	Belo Horizonte	Minas Gerais	Brazil	30130-100
27	GSK Investigational Site	Rio de Janeiro		Brazil	20211-030
28	GSK Investigational Site	Rio de Janeiro		Brazil	20230 -130
29	GSK Investigational Site	Koebenhavn Oe		Denmark	2100
30	GSK Investigational Site	Odense C		Denmark	5000
31	GSK Investigational Site	Bayonne cedex		France	64109
32	GSK Investigational Site	Besançon cedex		France	25030
33	GSK Investigational Site	Bobigny Cedex		France	93009
34	GSK Investigational Site	Caen cedex 9		France	14033
35	GSK Investigational Site	Marseille cedex 9		France	13273
36	GSK Investigational Site	Paris Cedex 12		France	75571
37	GSK Investigational Site	Toulouse		France	31059
38	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg	Germany	70199
39	GSK Investigational Site	Ulm	Baden-Wuerttemberg	Germany	89081
40	GSK Investigational Site	Muenchen	Bayern	Germany	81675
41	GSK Investigational Site	Goettingen	Niedersachsen	Germany	37075
42	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen	Germany	40225
43	GSK Investigational Site	Duisburg	Nordrhein-Westfalen	Germany	47166
44	GSK Investigational Site	Koeln	Nordrhein-Westfalen	Germany	50937
45	GSK Investigational Site	Mainz	Rheinland-Pfalz	Germany	55131
46	GSK Investigational Site	Dresden	Sachsen	Germany	01307
47	GSK Investigational Site	Berlin		Germany	12200
48	GSK Investigational Site	Hong Kong		Hong Kong
49	GSK Investigational Site	Shatin, New Territories		Hong Kong
50	GSK Investigational Site	Reggio Calabria	Calabria	Italy	89100
51	GSK Investigational Site	Firenze	Toscana	Italy	50134
52	GSK Investigational Site	Vicenza	Veneto	Italy	36100
53	GSK Investigational Site	Seoul		Korea, Republic of	135-710
54	GSK Investigational Site	Seoul		Korea, Republic of	137-701
55	GSK Investigational Site	Seoul		Korea, Republic of	138-736
56	GSK Investigational Site	San Juan		Puerto Rico	00927
57	GSK Investigational Site	Changhua		Taiwan	500
58	GSK Investigational Site	Taichung		Taiwan	404
59	GSK Investigational Site	Taipei		Taiwan	100
60	GSK Investigational Site	Taipei		Taiwan	112
61	GSK Investigational Site	Aberdeen		United Kingdom	AB25 2ZN
62	GSK Investigational Site	Glasgow		United Kingdom	G12 0YN
63	GSK Investigational Site	Leeds		United Kingdom	LS9 7TF
64	GSK Investigational Site	London		United Kingdom	SE5 9RS
65	GSK Investigational Site	London		United Kingdom	SW17 0RE