Efficacy of Eltrombopag Plus Lenalidomide Combination Therapy in Patients With IPSS Low and Intermediate-risk Myelodysplastic Syndrome With Isolated del5q
- Conditions
- Myelodysplastic Syndromes
- Interventions
- Registration Number
- NCT02928419
- Lead Sponsor
- Associazione Qol-one
- Brief Summary
Myelodysplastic syndromes (MDS) prevail in elderly patients and are characterized by inefficient erythropoiesis and peripheral cytopenias. Supportive care still represents the main therapeutic option in most patients. Quality of life is deteriorated mostly by anemia and by limitations due to dependence on transfusions, thrombocytopenia, and neutropenia. The only treatment available for severe thrombocytopenia consists of PLT transfusions, mainly in the presence of bleeding.
In patients with low and intermediate-1 risk MDS with an isolated deletion 5q cytogenetic abnormality, red blood cell (RBC) transfusion-dependence is a prevalent condition. For these latter patients reaching transfusion-dependence, lenalidomide, an immunomodulatory drug, has been approved by FDA and EMA. It has been shown that the drug induces significant erythroid (about 65%) and cytogenetic responses which have been associated with a survival benefit. In patients with MDS with del5q and serum erythropoietin levels \> 500 miU/L, lenalidomide dosing of 10 mg/day for 21 days every 28, rather than 5 mg dosing, induces higher rates of transfusion-independence and cytogenetic responses with a trend to survival advantage. As a consequence, the recommended starting dose of lenalidomide is 10 mg orally once daily on days 1-21 of repeated 28-day cycles. Lenalidomide treatment must not be started if the Absolute Neutrophil Counts (ANC) \< 0.5 Gi/L and/or PLT counts \< 25 Gi/L.
For patients who are dosed initially at 10 mg and who experience thrombocytopenia \< 25 Gi/L (45-75%), it is recommended to interrupt lenalidomide treatment until PLT count returns to ≥ 25 Gi/L on at least 2 occasions for ≥ 7 days or when the PLT count recovers to ≥ 50 Gi/L at any time, to resume lenalidomide at 50% dose reduction.
Eltrombopag is an orally bioavailable agonist of the thrombopoietin receptor. 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.
Preliminary results of an ongoing randomized trial, EQoL-MDS, for the evaluation of efficacy, safety of eltrombopag for thrombocytopenia of low and intermediate-1 IPSS risk MDS has shown that eltrombopag is able to significantly raise PLT counts in about 65% of patients without additional toxicity Furthermore, the combination of lenalidomide and eltrombopag resulted in significant inhibitory effects on the growth of leukemic colonies in the majority of primary MDS and AML samples. Most importantly, eltrombopag was able to reverse the anti-megakaryopoietic effects of lenalidomide in primary MDS patient samples. These results provide a preclinical rationale for the use of this combination in MDS and AML
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 2
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Adult subjects (18 years of age or older) with MDS and low or intermediate-1 IPSS risk and del5q as a single abnormality, at the time of their screening and enrollment into the study
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Subjects must not have received any prior treatment course with any immunomodulating agent nor TPO-R agonists
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Subjects must be dependent on regular packed RBC transfusions, as defined by international working group 2006 criteria, and must have a PLT count taken within the 4 weeks prior to screening that is >25 Gi/L.
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Absolute Neutrophil Counts (ANC) ≥ 0.5 GiL
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Resistant or refractory to erythropoetic stimulating agents (ESAs) and/or serum erythropoetin levels > 500 miU/L
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Subjects must be ineligible or relapsed or refractory to receive treatment options of azacitidine and decitabine.
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Subjects must have PLT count and RBC and PLT transfusion data available over a period of 8 weeks prior to screening.
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During the 2 months prior to randomization, subjects must have a baseline BM examination including all of the following: cytomorphology, cytogenetics and histology
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ECOG Performance Status must be 0-3.
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The following clinical chemistries MUST NOT exceed the upper limit of normal (ULN) reference range: creatinine, ALT, AST, total bilirubin (except for Gilbert's Syndrome), gamma-gt and alkaline phosphatase. In addition, albumin must not be below the lower limit of normal (LLN) by more than 10%.
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If subject meets the criteria for childbearing potential:
- Negative pregnancy test in female subjects within the 3 days prior to Day 1 of 1st cycle and effective contraception for at least 4 weeks.
- 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 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.
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Criteria for women of non-childbearing potential: A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria:
- Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea following cancer therapy or during lactation does not rule out childbearing potential).
- Premature ovarian failure confirmed by a gynaecologist
- Previous bilateral salpingo-oophorectomy, or hysterectomy
- XY genotype, Turner syndrome, uterine agenesis.
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Subject is able to understand and comply with protocol requirements and instructions.
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Subject has signed and dated informed consent.
- MDS with intermediate-2 or high IPSS risk
- Additional cytogenetic abnormalities
- Transfusion independence (TI) by IWG 2006 criteria
- Absolute Neutrophil Count < 0.5 Gi/L and/or Platelet counts < 25 Gi/L
- History of treatment for cancer with systemic chemotherapy and/or radiotherapy within the last 2 years
- History of treatment with immunomodulatory drugs or other TPO-R agonists.
- Thrombophilia, pre-existing history of thrombosis, 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.
- Leukocytosis >=25,000/uL prior to Day 1 of study medication.
- Monocytosis > 1000/ 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).
- Women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme illustrated in sections 6.4 are met (see sections 6.4).
- Known hypersensitivity to lenalidomide.
- Current alcohol or drug abuse.
- Treatment with an Investigational Product 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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 2 (Placebo) Placebo Arm 2 is the control arm Arm 1 (Eltrombopag) Eltrombopag/Revolade Arm 1 is the active treatment arm Arm 1 (Eltrombopag) Lenalidomide Arm 1 is the active treatment arm Arm 2 (Placebo) Lenalidomide Arm 2 is the control arm
- Primary Outcome Measures
Name Time Method Response (patients number with composite endpoint experience) 24 weeks To evaluate the effect of eltrombopag treatment relative to placebo on the incidence of the "composite endpoint" (PLT\<25 Gi/L or bleeding event with WHO bleeding score \>1 or study discontinuation), in the first 24 weeks, after experiencing PLT\<100 Gi/L
- Secondary Outcome Measures
Name Time Method Safety (number of adverse events) 36 months Safety and tolerability in terms of frequency of adverse events (AE)s and serious adverse events (SAE).
Hb changes 24 weeks Hb changes within the first 24 weeks.
Response (patients number with composite endpoint experience on long-term) 36 months The composite endpoint during the entire study period
Erythroid response 36 months Erythroid response, transfusion-independence (TI) and duration of TI.
Quality of Life (QOL) 36 months Changes in QOL scores
Overall survival 36 months Overall survival from baseline
Cytogenetic responses 36 months Proportion of cytogenetic responses, according to IWG 2006 criteria
Duration of cytogenetic response 36 months Duration of cytogenetic response
Progression free survival 36 months Progression free survival from baseline
Trial Locations
- Locations (50)
CHU d'Angers
🇫🇷Angers, France
Centre Henri Mondor
🇫🇷Creteil, France
Centre de Marseille
🇫🇷Marseille, France
Centre Le Mans
🇫🇷Le Mans, France
CHU de Grenoble
🇫🇷Grenoble, France
Centre Hospitalier Lyon Sud
🇫🇷Lyon, France
CHU Brabois
🇫🇷Nancy, France
Hopital Archet 1
🇫🇷Nice, France
Centre Hospitalier Universitaire de Nimes
🇫🇷Nimes, France
Centre de Nantes
🇫🇷Nantes, France
Centre de Rouen, Centre Henri Becquerel
🇫🇷Rouen, France
CHU Purpan
🇫🇷Toulouse, France
CHU de Bretonneau
🇫🇷Tours, France
A.O. SS. Antonio e Biagio e Cesare Arrigo
🇮🇹Alessandria, AL, Italy
Ospedale Casa Sollievo della Sofferenza
🇮🇹San Giovanni Rotondo, FG, Italy
Ospedale Vito Fazzi
🇮🇹Lecce, LE, Italy
Ospedale Civile Spirito Santo
🇮🇹Pescara, PE, Italy
Arcispedale di Santa Maria Nuova
🇮🇹Reggio Emilia, RE, Italy
Policlinico Agostino Gemelli
🇮🇹Roma, RM, 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, Italy
Policlinico Universitario Tor Vergata
🇮🇹Rome, RM, Italy
A.O. Santa Maria
🇮🇹Terni, TE, Italy
Policlinico Umberto I
🇮🇹Rome, RM, Italy
Policlinico Santa Maria alle Scotte
🇮🇹Siena, SI, Italy
"G.Gennimatas" General Hospital of Athens
🇬🇷Athens, Greece
University Hospital "Atticon",
🇬🇷Athens, Greece
University Hospital "Laikon"
🇬🇷Athens, Greece
University Hospital of Crete
🇬🇷Crete, Greece
University Hospital of Larissa
🇬🇷Larissa, Greece
University Hospital of Patras
🇬🇷Patras, Greece
"George Papanicolaou General Hospital of Thessaloniki
🇬🇷Thessaloniki, Greece
CHRU de Limoges
🇫🇷Limoges, France
Ospedale Riuniti
🇮🇹Ancona, AN, Italy
A.O. S. Giovanni Moscati
🇮🇹Avellino, AV, Italy
Ospedale L'Annunziata
🇮🇹Cosenza, CS, Italy
Ospedale Ferrarotto
🇮🇹Catania, CT, Italy
A.O. San Camillo Forlanini
🇮🇹Roma, RM, Italy
Ospedale Cardinal Massaia
🇮🇹Asti, AT, Italy
Ospedale Niguarda
🇮🇹Milano, MI, Italy
Azienda Ospedaliera Sant'Andrea
🇮🇹Rome, RM, Italy
Ospedale Nuova Regina Margherita
🇮🇹Rome, RM, Italy
Presidio Ospedaliero Oncologico Businco
🇮🇹Cagliari, CA, Italy
Ospedale Garibaldi
🇮🇹Catania, CT, Italy
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, FI, Italy
A.O. San Gerardo
🇮🇹Monza, MB, Italy
IRCCS Istituto Regina Elena
🇮🇹Rome, RM, Italy
IRCCS Ospedale Maggiore Policlinico
🇮🇹Milano, MI, Italy
Azienda Ospedaliera Bianchi-Melacrino-Morelli
🇮🇹Reggio Calabria, RC, Italy
Ospedale Sant'Eugenio
🇮🇹Roma, RM, Italy