Eltrombopag for the Treatment of Thrombocytopenia Due to Low- and Intermediate Risk Myelodysplastic Syndromes

Myelodysplastic Syndromes Clinical Trial

Official title:

Eltrombopag for the Treatment of Thrombocytopenia Due to Low- and Intermediate Risk Myelodysplastic Syndromes (EQoL-MDS)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02912208
• Other study ID #: EQoL-MDS
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 11, 2011
• Est. completion date: October 2026

Study information

• Verified date: January 2022
• Source: Associazione Qol-one
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Myelodysplastic syndromes (MDS) prevail in older age and are characterized by ineffective erythropoiesis and peripheral cytopenias. Supportive therapy is the main therapeutic option for most patients. Quality of Life (QoL) is mainly deteriorated by anemia and by the limitations associated with thrombocytopenia, neutropenia and transfusion dependence. The only available treatment for severe thrombocytopenia, in the presence of bleeding, is platelet transfusion.

Eltrombopag is an orally bioavailable agonist of the thrombopoietin receptor. In adult patients with chronic immune thrombocytopenia (ITP), Eltrombopag rapidly increases platelet counts and significantly reduces bleeding episodes during treatment. Eltrombopag is well tolerated. In 2007, Eltrombopag has received the Orphan Drug Designation for the treatment of ITP (EMEA/OD/031/07), and in 2008 the Food and Drug Association approved Eltrombopag for the treatment of ITP refractory or resistant. It has been shown that in patients affected by MDS and by acute myeloid leukemia, Eltrombopag neither increases the proliferation, nor the clonogenic growth capacity of bone marrow blasts. Furthermore, Eltrombopag induces an increase in the megakaryocytic differentiation and in the formation of normal megakaryocytic colonies. These results provide the rationale for pursuing further research on Eltrombopag for the treatment of thrombocytopenia in case of MDS.

The study is open to adult patients with myelodysplastic syndrome (MDS) with thrombocytopenia and low- or intermediate-1 IPSS risk (Index Prognostic Score System).

Severe thrombocytopenia associated with MDS may lead to death from hemorrhage, even in low prognostic risk patients. The benefit of platelet transfusion is short-termed. Patients become refractory in the long term. The availability of a treatment that induces the increase of platelet count is extremely important, either in terms of quality of life, and in overall survival.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 174
• Est. completion date: October 2026
• Est. primary completion date: February 2, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Adult subjects (18 years of age or older) with low or intermediate-1 IPSS risk MDS and stable disease.

2. Subjects must have a platelet count taken within the 4 weeks prior to randomization that is <30 Gi/L.

3. Subjects must be ineligible or relapsed or refractory to receive other treatment options (such as azacitidine or lenalidomide) and must be ineligible to receive intensive chemotherapy or autologous/allogeneic stem cell transplantation.

4. Subjects must have platelet count and platelet transfusion data available over a period of 8 weeks prior to randomization.

5. During the 2 months prior to randomization, subjects must have a baseline Bone Marrow examination which includes cytomorphology and cytogenetics. Histopathology should be performed.

6. Erythropoiesis-stimulating agents (ESAs) in anemic subjects or granulocyte colonystimulating 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.

7. ECOG (Eastern Cooperative Oncology Group) Performance Status 0-3

8. Subject is able to understand and comply with protocol requirements and instructions.

9. Subject has signed and dated informed consent.

10. Adequate baseline organ function defined by the criteria below:

total bilirubin (except for Gilbert's Syndrome) = 1.5 x Upper Limit Normal Alanine aminotransferase and Aspartate aminotransferase = 3 x Upper Limit Normal creatinine = 2 x Upper Limit Normal albumin must not be below the lower limit of normal by more than 20%.

11. Subject is practicing an acceptable method of contraception. 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 of an highly effective method of contraception from 2 weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study.

Exclusion Criteria:

1. MDS with intermediate-2 or high IPSS risk.

2. History of treatment for cancer other than MDS with systemic chemotherapy and/or radiotherapy within the last 2 years.

3. History of treatment with romiplostim or other Thrombopoietin receptor agonists.

4. Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. persistent atrial fibrillation), or subjects with a QTc >450 msec (QTc >480 msec for subjects with Bundle Branch Block).

5. BM fibrosis that leads to an inability to aspirate marrow for assessment.

6. Peripheral monocytosis > 1000/uL prior to Day 1 of study medication.

7. Leukocytosis >=25,000/uL prior to Day 1 of study medication.

8. 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.

9. Current alcohol or drug abuse.

10. Treatment with an Investigational Product within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.

11. Active and uncontrolled infections.

12. Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV).

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome
• Thrombocytopenia

Intervention

Drug:
• Eltrombopag/Revolade
Eltrombopag 50 mg once daily has been selected as the starting dose for this study. Thereafter, dependent on platelet response the dose of study medication can be increased by 50 mg every 2 weeks, up to a maximum dose of 300 mg once daily (150 mg in subjects of East Asian ethnicity).

Other:
• Placebo
The administration is the same of eltrombopag

Locations

Country	Name	City	State
France	CHU Amiens	Amiens
France	Centre d'Avignon	Avignon
France	Hôpital de la Côte Basque	Bayonne
France	Centre d'Avicenne, Hôpital d'Avicenne	Bobigny
France	CHU de Haut-Lévèque	Bordeaux
France	Centre Hospitalier de Boulogne Sur Mer	Boulogne Sur Mer
France	CHU Clémenceau	Caen
France	Centre Henri Mondor	Creteil
France	CHU de Grenoble	Grenoble
France	Centre Le Mans	Le Mans
France	Hôpital Saint Vincent de Paul	Lille
France	CHRU de Limoges	Limoges
France	Centre de Marseille	Marseille
France	CHU Brabois	Nancy
France	Centre de Nantes	Nantes
France	Hopital Archet 1	Nice
France	Centre Hospitalier Universitaire de Nimes	Nimes
France	Centre de St Louis, Hôpital St Louis	Paris
France	Centre Hospitalier de la Région d'Annecy	Pringy
France	Centre de Rouen, Centre Henri Becquerel	Rouen
France	CHU Purpan	Toulouse
France	CHU de Bretonneau	Tours
Germany	Heinrich-Heine-Universität Düsseldorf	Düsseldorf
Germany	Universitätsmedizin Mannheim	Mannheim
Italy	A.O. SS. Antonio e Biagio e Cesare Arrigo	Alessandria	AL
Italy	Ospedale Riuniti	Ancona	AN
Italy	Ospedale Cardinal Massaia	Asti	AT
Italy	A.O. S. Giovanni Moscati	Avellino	AV
Italy	Policlinico Università di Bari	Bari	BA
Italy	Ospedale A. Perrino	Brindisi	BR
Italy	Ospedale "Roberto Binaghi"	Cagliari	CA
Italy	Ospedale Ferrarotto	Catania	CT
Italy	Ospedale Garibaldi	Catania	CT
Italy	Ospedale L'Annunziata	Cosenza	CS
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze	FI
Italy	Università degli Studi di Genova	Genova	GE
Italy	Ospedale Vito Fazzi	Lecce	LE
Italy	IRCCS Ospedale Maggiore Policlinico	Milano	MI
Italy	Ospedale Niguarda	Milano	MI
Italy	Ospedale Civile Spirito Santo	Pescara	PE
Italy	Azienda Ospedaliera Bianchi-Melacrino-Morelli	Reggio Calabria	RC
Italy	Arcispedale di Santa Maria Nuova	Reggio Emilia	RE
Italy	A.O. San Camillo Forlanini	Roma	RM
Italy	Ospedale Sant'Eugenio	Roma	RM
Italy	Policlinico Agostino Gemelli	Roma	RM
Italy	Università Campus Bio Medico di Roma	Roma	RM
Italy	Azienda Ospedaliera Sant'Andrea	Rome	RM
Italy	IRCCS Istituto Regina Elena	Rome	RM
Italy	Ospedale Nuova Regina Margherita	Rome	RM
Italy	Policlinico Umberto I	Rome	RM
Italy	Policlinico Universitario Tor Vergata	Rome	RM
Italy	A.O.U. San Giovanni di Dio e Ruggì D'Aragona	Salerno	SA
Italy	Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo	FG
Italy	Policlinico Santa Maria alle Scotte	Siena	SI
Italy	A.O. Santa Maria	Terni	TE
Italy	A.O. Citta' della Salute e della Scienza di Torino	Torino	TO
Italy	U.O. Citta' della Salute e della Scienza di Torino	Torino	TO
Slovenia	General Hospital Celje	Celje
Slovenia	Univerzitetni klinini center Ljubljana	Ljubljana
Slovenia	University Medical Centre Maribor	Maribor
Slovenia	General Hospital Murska Sobota	Murska Sobota
Slovenia	General Hospital Nova Gorica	Nova Gorica
Slovenia	General Hospital Novo mesto	Novo Mesto
Slovenia	General Hospital Slovenj Gradec	Slovenj Gradec

Sponsors (1)

Lead Sponsor	Collaborator
Associazione Qol-one

Countries where clinical trial is conducted

France,  Germany,  Italy,  Slovenia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Response rate	Proportion of patients achieving a complete response (CR) or response (R) during the treatment period	Six months
Primary	Safety and Tolerability (number of adverse events)	Safety and tolerability in terms of frequency of adverse events (AE) and serious adverse events (SAE)	Six month
Primary	Duration of platelet response		five years
Primary	long-term safety and tolerability (number adverse events in the long term)	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 and number of adverse events reporting in accordance with CTCAE v4.0	five years
Secondary	Quality of life (QoL) score	to evaluate the changes of the quality of life in the two arms	six months
Secondary	number of monthly platelet transfusions		six months
Secondary	duration of transfusion independence		six months
Secondary	time to response	time to response (time from starting treatment to time of achievement of CR or PR)	six months
Secondary	incidence and severity of bleeding	incidence and severity of bleeding using the WHO (World Health Organization)Bleeding Scale	six months
Secondary	overall survival	overall survival (OS) at 2 and at 5 years	2 and 5 years
Secondary	leukemia-free survival (LFS)	leukemia-free survival (LFS) at 2 and at 5 years (events for LFS are defined as death and progression to AML);	2 and 5 years