Clinical trial NCT00903422: Eltrombopag Treatment of Thrombocytopenia in Subjects With Advanced Myelodysplastic Syndrome (MDS) or Secondary Acute Myeloid Leukemia After MDS (sAML/MDS)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-05-18
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: 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.
timeFrame: Approximately 46 months
Secondary outcomes:
measure: 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.
timeFrame: Approx. 46 months
measure: Frequency and number of units of platelet transfusions during the treatment and follow-up periods for eltrombopag- and placebo-treated subjects.
timeFrame: approx 46 months
measure: 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.
timeFrame: approx. 46 months
measure: Overall survival (OS) of eltrombopag- and placebo-treated subjects.
timeFrame: approx. 46 months
measure: Change in health-related quality of life as measured using the EQ-5D questionnaire.
timeFrame: approx. 46 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Santa Monica
country: United States
facility: GSK Investigational Site
state: California
city: Stanford
country: United States
facility: GSK Investigational Site
state: California
city: Coral Springs
country: United States
facility: GSK Investigational Site
state: Florida
city: Lake Worth
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Missouri
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Camden
country: United States
facility: GSK Investigational Site
state: New Jersey
city: The Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Greenville
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: New Braunfels
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Arlington
country: United States
facility: GSK Investigational Site
state: Virginia
city: Fairfax
country: United States
facility: GSK Investigational Site
state: Virginia
city: Madison
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Salvador
country: Brazil
facility: GSK Investigational Site
state: Bahía
city: Belo Horizonte
country: Brazil
facility: GSK Investigational Site
state: Minas Gerais
city: Rio de Janeiro
country: Brazil
facility: GSK Investigational Site
city: Rio de Janeiro
country: Brazil
facility: GSK Investigational Site
city: Koebenhavn Oe
country: Denmark
facility: GSK Investigational Site
city: Odense C
country: Denmark
facility: GSK Investigational Site
city: Bayonne cedex
country: France
facility: GSK Investigational Site
city: Besançon cedex
country: France
facility: GSK Investigational Site
city: Bobigny Cedex
country: France
facility: GSK Investigational Site
city: Caen cedex 9
country: France
facility: GSK Investigational Site
city: Marseille cedex 9
country: France
facility: GSK Investigational Site
city: Paris Cedex 12
country: France
facility: GSK Investigational Site
city: Toulouse
country: France
facility: GSK Investigational Site
city: Stuttgart
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Ulm
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Goettingen
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Duesseldorf
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Duisburg
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hong Kong
country: Hong Kong
facility: GSK Investigational Site
city: Shatin, New Territories
country: Hong Kong
facility: GSK Investigational Site
city: Reggio Calabria
country: Italy
facility: GSK Investigational Site
state: Calabria
city: Firenze
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Vicenza
country: Italy
facility: GSK Investigational Site
state: Veneto
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
city: Changhua
country: Taiwan
facility: GSK Investigational Site
city: Taichung
country: Taiwan
facility: GSK Investigational Site
city: Taipei
country: Taiwan
facility: GSK Investigational Site
city: Taipei
country: Taiwan
facility: GSK Investigational Site
city: Aberdeen
country: United Kingdom
facility: GSK Investigational Site
city: Glasgow
country: United Kingdom
facility: GSK Investigational Site
city: Leeds
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.