Efficacy of Eltrombopag Plus Lenalidomide Combination Therapy in Patients With IPSS Low and Intermediate-risk Myelodysplastic Syndrome With Isolated del5q

Myelodysplastic Syndromes Clinical Trial

Official title:

Efficacy of Eltrombopag Plus Lenalidomide Combination Therapy in Patients With IPSS Low and Intermediate-risk Myelodysplastic Syndrome With Isolated del5q: a Multicenter, Randomized, Double-blind, Placebo Controlled Study - QOL-ONE Rev2MDS

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02928419
• Other study ID #: QOL-ONE Rev2MDS
• Status: Terminated
• Phase: Phase 2
• Start date: May 2015
• Est. completion date: September 2018

Study information

• Verified date: September 2018
• Source: Associazione Qol-one
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: September 2018
• Est. primary completion date: September 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

• Subjects must not have received any prior treatment course with any immunomodulating agent nor TPO-R agonists

• 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.

• Absolute Neutrophil Counts (ANC) = 0.5 GiL

• Resistant or refractory to erythropoetic stimulating agents (ESAs) and/or serum erythropoetin levels > 500 miU/L

• Subjects must be ineligible or relapsed or refractory to receive treatment options of azacitidine and decitabine.

• Subjects must have PLT count and RBC and PLT transfusion data available over a period of 8 weeks prior to screening.

• During the 2 months prior to randomization, subjects must have a baseline BM examination including all of the following: cytomorphology, cytogenetics and histology

• ECOG Performance Status must be 0-3.

• 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%.

• If subject meets the criteria for childbearing potential:

1. 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.

2. 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.

• 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:

1. Age = 50 years and naturally amenorrhoeic for = 1 year (amenorrhoea following cancer therapy or during lactation does not rule out childbearing potential).

2. Premature ovarian failure confirmed by a gynaecologist

3. Previous bilateral salpingo-oophorectomy, or hysterectomy

4. XY genotype, Turner syndrome, uterine agenesis.

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

• Subject has signed and dated informed consent.

Exclusion Criteria:

• 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).

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Eltrombopag/Revolade
From day 1, patients presenting with PLT counts = 100 Gi/L at any time will receive oral eltrombopag for a maximum of 36 months. Starting dose will depend on PLT count determined on the day of first dose of eltrombopag. For patients experiencing PLT count 70 to 100 Gi/L, initial dosing is 50 mg/day. For subjects presenting with PLT counts < 70 Gi/L initial dosing is 100 mg/day. The dose of study medication must be increased sequentially by 50 mg every 7 days, up to a maximum dose of 300 mg/day until PLT = 100 Gi/L. For East Asian subjects, a maximum dose of 150 mg is permitted.

Other:
• Placebo
From day 1, patients presenting with PLT counts = 100 Gi/L at any time will receive oral placebo for a maximum of 36 months. Starting dose will depend on PLT count determined on the day of first dose of placebo. For patients experiencing PLT count 70 to 100 Gi/L, initial dosing is 50 mg/day. For subjects presenting with PLT counts < 70 Gi/L initial dosing is 100 mg/day. The dose of study medication must be increased sequentially by 50 mg every 7 days, up to a maximum dose of 300 mg/day until PLT = 100 Gi/L. For East Asian subjects, a maximum dose of 150 mg is permitted.

Drug:
• Lenalidomide
All patients will receive oral lenalidomide 10 mg/day for 21 days every 28 days. Patients will receive lenalidomide dosing according to the lenalidomide product information. Patients obtaining an erythroid response according to IWG 2006 criteria within the first 24 weeks will continue lenalidomide treatment until progression or other reasons for permanent discontinuation

Locations

Country	Name	City	State
France	CHU d'Angers	Angers
France	Centre Henri Mondor	Creteil
France	CHU de Grenoble	Grenoble
France	Centre Le Mans	Le Mans
France	CHRU de Limoges	Limoges
France	Centre Hospitalier Lyon Sud	Lyon
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 Rouen, Centre Henri Becquerel	Rouen
France	CHU Purpan	Toulouse
France	CHU de Bretonneau	Tours
Greece	"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
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	Presidio Ospedaliero Oncologico Businco	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	Ospedale Vito Fazzi	Lecce	LE
Italy	IRCCS Ospedale Maggiore Policlinico	Milano	MI
Italy	Ospedale Niguarda	Milano	MI
Italy	A.O. San Gerardo	Monza	MB
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	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	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

Sponsors (1)

Lead Sponsor	Collaborator
Associazione Qol-one

Countries where clinical trial is conducted

France,  Greece,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Response (patients number with composite endpoint experience)	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	24 weeks
Secondary	Response (patients number with composite endpoint experience on long-term)	The composite endpoint during the entire study period	36 months
Secondary	Safety (number of adverse events)	Safety and tolerability in terms of frequency of adverse events (AE)s and serious adverse events (SAE).	36 months
Secondary	Cytogenetic responses	Proportion of cytogenetic responses, according to IWG 2006 criteria	36 months
Secondary	Duration of cytogenetic response	Duration of cytogenetic response	36 months
Secondary	Hb changes	Hb changes within the first 24 weeks.	24 weeks
Secondary	Erythroid response	Erythroid response, transfusion-independence (TI) and duration of TI.	36 months
Secondary	Quality of Life (QOL)	Changes in QOL scores	36 months
Secondary	Progression free survival	Progression free survival from baseline	36 months
Secondary	Overall survival	Overall survival from baseline	36 months