Clinical trial NCT02912208: Eltrombopag for the Treatment of Thrombocytopenia Due to Low- and Intermediate Risk Myelodysplastic Syndromes
Official title: Eltrombopag for the Treatment of Thrombocytopenia Due to Low- and Intermediate Risk Myelodysplastic Syndromes (EQoL-MDS)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Thrombocytopenia
Lead sponsor: Associazione Qol-one
Sponsor class: OTHER
First posted: 2016-09-23
Enrollment: 174
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: 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.


Eligibility criteria: 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).

Primary outcomes:
measure: Response rate
timeFrame: Six months
measure: Safety and Tolerability (number of adverse events)
timeFrame: Six month
measure: Duration of platelet response
timeFrame: five years
measure: long-term safety and tolerability (number adverse events in the long term)
timeFrame: five years
Secondary outcomes:
measure: Quality of life (QoL) score
timeFrame: six months
measure: number of monthly platelet transfusions
timeFrame: six months
measure: duration of transfusion independence
timeFrame: six months
measure: time to response
timeFrame: six months
measure: incidence and severity of bleeding
timeFrame: six months
measure: overall survival
timeFrame: 2 and 5 years
measure: leukemia-free survival (LFS)
timeFrame: 2 and 5 years
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens
city: Avignon
country: France
facility: Centre d'Avignon
city: Bayonne
country: France
facility: Hôpital de la Côte Basque
city: Bobigny
country: France
facility: Centre d'Avicenne, Hôpital d'Avicenne
city: Bordeaux
country: France
facility: CHU de Haut-Lévèque
city: Boulogne Sur Mer
country: France
facility: Centre Hospitalier de Boulogne Sur Mer
city: Caen
country: France
facility: CHU Clémenceau
city: Creteil
country: France
facility: Centre Henri Mondor
city: Grenoble
country: France
facility: CHU de Grenoble
city: Le Mans
country: France
facility: Centre Le Mans
city: Lille
country: France
facility: Hôpital Saint Vincent de Paul
city: Limoges
country: France
facility: CHRU de Limoges
city: Marseille
country: France
facility: Centre de Marseille
city: Nancy
country: France
facility: CHU Brabois
city: Nantes
country: France
facility: Centre de Nantes
city: Nice
country: France
facility: Hopital Archet 1
city: Nimes
country: France
facility: Centre Hospitalier Universitaire de Nimes
city: Paris
country: France
facility: Centre de St Louis, Hôpital St Louis
city: Pringy
country: France
facility: Centre Hospitalier de la Région d'Annecy
city: Rouen
country: France
facility: Centre de Rouen, Centre Henri Becquerel
city: Toulouse
country: France
facility: CHU Purpan
city: Tours
country: France
facility: CHU de Bretonneau
city: Düsseldorf
country: Germany
facility: Heinrich-Heine-Universität Düsseldorf
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
city: Alessandria
country: Italy
facility: A.O. SS. Antonio e Biagio e Cesare Arrigo
state: AL
city: Ancona
country: Italy
facility: Ospedale Riuniti
state: AN
city: Asti
country: Italy
facility: Ospedale Cardinal Massaia
state: AT
city: Avellino
country: Italy
facility: A.O. S. Giovanni Moscati
state: AV
city: Bari
country: Italy
facility: Policlinico Università di Bari
state: BA
city: Brindisi
country: Italy
facility: Ospedale A. Perrino
state: BR
city: Cagliari
country: Italy
facility: Ospedale "Roberto Binaghi"
state: CA
city: Cosenza
country: Italy
facility: Ospedale L'Annunziata
state: CS
city: Catania
country: Italy
facility: Ospedale Ferrarotto
state: CT
city: Catania
country: Italy
facility: Ospedale Garibaldi
state: CT
city: San Giovanni Rotondo
country: Italy
facility: Ospedale Casa Sollievo della Sofferenza
state: FG
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
state: FI
city: Genova
country: Italy
facility: Università degli Studi di Genova
state: GE
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi
state: LE
city: Milano
country: Italy
facility: IRCCS Ospedale Maggiore Policlinico
state: MI
city: Milano
country: Italy
facility: Ospedale Niguarda
state: MI
city: Pescara
country: Italy
facility: Ospedale Civile Spirito Santo
state: PE
city: Reggio Calabria
country: Italy
facility: Azienda Ospedaliera Bianchi-Melacrino-Morelli
state: RC
city: Reggio Emilia
country: Italy
facility: Arcispedale di Santa Maria Nuova
state: RE
city: Roma
country: Italy
facility: A.O. San Camillo Forlanini
state: RM
city: Roma
country: Italy
facility: Ospedale Sant'Eugenio
state: RM
city: Roma
country: Italy
facility: Policlinico Agostino Gemelli
state: RM
city: Roma
country: Italy
facility: Università Campus Bio Medico di Roma
state: RM
city: Rome
country: Italy
facility: Azienda Ospedaliera Sant'Andrea
state: RM
city: Rome
country: Italy
facility: IRCCS Istituto Regina Elena
state: RM
city: Rome
country: Italy
facility: Ospedale Nuova Regina Margherita
state: RM
city: Rome
country: Italy
facility: Policlinico Umberto I
state: RM
city: Rome
country: Italy
facility: Policlinico Universitario Tor Vergata
state: RM
city: Salerno
country: Italy
facility: A.O.U. San Giovanni di Dio e Ruggì D'Aragona
state: SA
city: Siena
country: Italy
facility: Policlinico Santa Maria alle Scotte
state: SI
city: Terni
country: Italy
facility: A.O. Santa Maria
state: TE
city: Torino
country: Italy
facility: A.O. Citta' della Salute e della Scienza di Torino
state: TO
city: Torino
country: Italy
facility: U.O. Citta' della Salute e della Scienza di Torino
state: TO
city: Celje
country: Slovenia
facility: General Hospital Celje
city: Ljubljana
country: Slovenia
facility: Univerzitetni klinini center Ljubljana
city: Maribor
country: Slovenia
facility: University Medical Centre Maribor
city: Murska Sobota
country: Slovenia
facility: General Hospital Murska Sobota
city: Nova Gorica
country: Slovenia
facility: General Hospital Nova Gorica
city: Novo Mesto
country: Slovenia
facility: General Hospital Novo mesto
city: Slovenj Gradec
country: Slovenia
facility: General Hospital Slovenj Gradec
Study officials:
affiliation: QOL-ONE Associazione Culturale e di Ricerca
name: Esther Natalie Oliva
role: STUDY_CHAIR
References: