Study of REVLIMID (Lenalidomide) Versus Placebo in Patients With Low Risk Myelodysplastic Syndrome (SINTRA-REV)
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Purpose
Trial Design:
This clinical trial is a phase III multi-center, randomized, double blind and controlled with placebo trial and with two arms designed to assess the efficiency and toxicity of the scheme Lenalidomide versus observation in a series of 60 patients with low risk myelodysplastic syndrome associated to 5q deletion with anemia (Hb≤12g/dL) but without the need of transfusion. Patients are randomized in the study in a 2:1 ratio. They will receive treatment for 104 weeks until progression of the disease, which implies that the patient suffering from anemia due to myelodysplastic syndrome requires transfusion of at least 2 UCH/56 days (2 months) with a minimum follow up of 112 days (4 months), or unacceptable toxicity.
Disease:
Low risk myelodysplastic syndrome associated to the loss of 5q without transfusion requirements.
Total number of patients:
In total 60 patients will be included, 40 assigned to the treatment branch and 20 to the placebo branch.
Calendar:
First patient first visit: February 2010, and Last patient last visit expected in February 2016. (Recruitment will take place over a period of 24 months and is expected to be finished in February 2012).
| Condition | Intervention | Phase |
|---|---|---|
|
Myelodysplastic Syndrome |
Drug: Lenalidomide Other: Placebo |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | Multicenter, Randomized, Double-blind, Phase III Study of REVLIMID (Lenalidomide) Versus Placebo in Patients With Low Risk Myelodysplastic Syndrome (Low and Intermediate-1 IPSS) With Alteration in 5q- and Anemia Without the Need of Transfusion. |
- Period until the progression of myelodysplastic syndrome [ Time Frame: 6 years (study treatment and follow up) ] [ Designated as safety issue: No ]To assess if treatment with Revlimid (Lenalidomide) extends the period until the progression to MDS of(5q) considered as transfusion independent, documented verification that the patient suffering from anemia due to MDS requires transfusion of at least 2 UCH/56 days (2 months) with a minimum follow up of 112 days (4 months). Revlimid will be compared to the current standard treatment for patients with low risk MDS associated with the loss of 5q without transfusion dependent anemia, which is the therapeutic abstention and monitoring until its progression.
- Safety [ Time Frame: 6 years (study treatment and follow up) ] [ Designated as safety issue: Yes ]Safety (type, frequency and severity [Criteria of normal terminology of adverse reactions of the National Cancer Institute (NCI CTCAE) version 3.0] of adverse reactions (AR)and list of the AR with Lenalidomide.
- Erythroid response [ Time Frame: 6 years (study treatment and follow up) ] [ Designated as safety issue: No ]Erythroid response according to the Criteria of the MDS International Work Team.
- Duration of the red blood cells transfusion independency [ Time Frame: 6 years (study treatment and follow up) ] [ Designated as safety issue: No ]Red blood cells transfusion independency,defined as the number of days elapsed between the randomization and the first transfusion after this period free of transfusions.
- Change of the hemoglobin concentration (Hb) in relation to baseline levels [ Time Frame: 6 years (study treatment and follow up) ] [ Designated as safety issue: No ]Change of the hemoglobin concentration (Hb) in relation to baseline levels of patients who show erythroid response.
- Variation in platelets and neutrophils absolute count in relation to baseline levels [ Time Frame: 6 years (study treatment and follow up) ] [ Designated as safety issue: No ]
- Cytogenetic response [ Time Frame: 6 years (study treatment and follow up) ] [ Designated as safety issue: No ]Cytogenetic response according to the Criteria of the MDS International Work Team.
- Bone marrow response [ Time Frame: 6 years (study treatment and follow up) ] [ Designated as safety issue: No ]Bone marrow response according to the Criteria of the MDS International Work Team.
- Global survival, Event Free Survival and Rate of Transformation to Acute Leukemia. [ Time Frame: 6 years (study treatment and follow up) ] [ Designated as safety issue: Yes ]
- Time from diagnose to transfusion independence. [ Time Frame: 6 years (study treatment and follow up) ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 60 |
| Study Start Date: | January 2010 |
| Estimated Study Completion Date: | January 2016 |
| Estimated Primary Completion Date: | January 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: lenalidomide
Experimental treatment branch with Lenalidomide 5 mg/day (oral use)
|
Drug: Lenalidomide
Treatment with Revlimid (lenalidomide), oral use, 5 mg daily during study treatment (104 weeks).
Other Name: Revlimid 5 mg
|
|
Placebo Comparator: placebo
Placebo branch (oral use)
|
Other: Placebo
Placebo, oral use, daily during study treatment (104 weeks)
Other Name: Placebo
|
Hide Detailed DescriptionDetailed Description:
General summary of myelodysplastic syndrome with alteration in 5q. Myelodysplastic syndromes (MDS) are a very heterogenic group of diseases characterized by the presence of morphologic features of dyshemopoiesis in bone marrow (BM) and in peripheral blood (PB), which is translated into an inefficient hematopoiesis. This will lead to the concomitant development of peripheral cytopenias which will be the cause of complications in these patients and, in most cases, the cause of death. In addition, these patients have an increased risk of developing acute leukemia, and this risk increases with the progression of the disease.MDS represents an incurable disease with standard treatments with a quite variable survival mean ranging from 3 months to 15 years depending on the number of blasts, the number of cytopenias and the type of cytogenetic disorders2. The sole curative treatment of the MDS is the allogenic transplant of hematopoietic progenitors but this option is only available for a 5% of the patients with MDS.
Lenalidomide, initially known as CC-5013, is an analogue of the immunomodulator Drug Thalidomide (Thalidomid®; Pharmion Corp., Boulder, CO, USA), which was the first drug with anti-angiogenic and immunomodulator properties investigated in MDS. Lenalidomide has, as well as thalidomide, a broad array of potential activities against dysplastic cells, not fully known, among which we find immunomodulator and non-immunomodulator properties (anti-angiogenic effect, anti-proliferative and pro-apoptotic). The greater advantage of Lenalidomide in comparison with thalidomide is that the former is between 50 and 2000 times stronger tan thalidomide in what respects to its immunomodulator effects. And moreover, the toxic profile of Lenalidomide seems lower than that of its analogue; Thalidomide.
There is no treatment indication on the present times for patients with low risk MDS associated to the loss of 5q without transfusion dependent anemia. The results with Lenalidomide are highly promising for patients with low risk MDS associated to the loss of 5q when (it has so been tested) there is red blood cells transfusion dependent anemia. In this sense, the proposal consists on being able to state that treatment with Lenalidomide can be efficient from diagnose preventing CH transfusions with an acceptable toxicity.
In this sense, the present study has the intention to treat early patients with low-risk MDS associated to the loss of 5q with a view to prevent CH transfusion. Therefore, we could extend in these patients the time until CH transfusion and even assess the possibility of eradicating the disease at a cytogenetic/morphologic level. In the present trial and given the characteristics of the patients, we have chosen the option of supplying Lenalidomide at a dose of 5mg/day. The option of considering a lower dose to the one currently considered as "standard" (10mg/day) is to reduce toxicity, mainly hematologic, in patients who do not receive treatment normally. A dose with lower toxicity has been chosen which has revealed itself efficient.
Main efficiency objective:
•To assess if treatment with Revlimid (Lenalidomide) extends the period until the progression to myelodysplastic syndrome del(5q) considered as transfusion independent, documented verification that the patient suffering from anemia due to MDS requires transfusion of at least 2 UCH/56 days (2 months) with a minimum follow up of 112 days (4 months). Revlimid will be compared to the current standard treatment for patients with low risk myelodysplastic syndrome associated with the loss of 5qwithout transfusion dependent anemia, which is the therapeutic abstention and monitoring until its progression.
Secondary efficiency objectives:
- Erythroid response according to the Criteria of the myelodysplastic syndrome International Work Team 2006).
- Duration of the red blood cells transfusion independency (defined as the number of days elapsed between the randomization and the first transfusion after this period free of transfusions).
- Change of hemoglobin concentration (Hb) in relation to baseline levels of patients who show erythroid response.
- Variation in platelets absolute count in relation to baseline levels.
- Variation in neutrophils absolute count in relation to baseline levels.
- Cytogenetic response according to the Criteria of the myelodysplastic syndrome International Work Team.
- Bone marrow response according to the Criteria of the myelodysplastic syndrome International Work Team.
- To assess the safety and tolerance of the Lenalidomide scheme, measured according to the incidence of clinical and laboratory toxicity.
- Global survival, Event Free Survival and Rate of Transformation to Acute Leukemia.
- Time from diagnose to transfusion independence.
Main safety objective:
Safety (type, frequency and severity [Criteria of normal terminology of adverse reactions of the National Cancer Institute (NCI CTCAE) version 3.0] of adverse reactions (AR)and list of the AR with Lenalidomide.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patient must be capable of meeting all requirements of the clinical trial.
- Patient will have to freely sign the informed consent before undergoing any test of the trial which does not form part of the normal care of patients
- Age > 18 years.
- Patient will have to have a diagnose of low risk myelodysplastic syndrome (MDS)(low and intermediate-1 IPSS)associated to the loss of 5q, either as isolated abnormality or accompanied by other additional cytogenetic abnormalities.
- MDS 5q- with anemia (Hb ≤ 12 g/dL) transfusion independent, and documented confirmation of not having received any transfusion of packed red blood cells due to his/her baseline disease (MDS).
- Patient will have a general state measured according to the ECOG scale ≤ 2
- Patient should be capable of meeting all scheduled visits of the study.
All women patient with childbearing potential will have to:
- Understand the teratogenic risk of the study drug
- Commit herself to use an effective contraceptive method on a continuous basis during the 4 weeks prior to the beginning of the treatment with the drug under study (including dose interruption periods) and until 4 weeks after the end of the treatment with drug under study.
- Understand that, even if she suffers amenorrhea, she will have to follow all warnings in relation to an effective contraception.
- Understand the potential consequences of pregnancy and the need to attend a healthcare attention service urgently in the event of pregnancy risk.
- Access to the development of a pregnancy tests with a minimum sensibility of 25mUI/ml under medical supervision, on the day of the visit of the study or on the previous 3 days, when she has been using effective contraceptive methods for at least 4 weeks.
- Access to the performance of a pregnancy test, under medical supervision, each 4 weeks, including a pregnancy test 4 weeks after the end of the treatment of the study,unless in the case of confirmed tubal ligation.
All male patients will have to:
- Commit themselves to use condoms during all the treatment with the drug under study, including all dose interruption periods and until one week after the end of the treatment if his partner is a women with childbearing potential and does not use contraceptive methods.
- Commit themselves not to donate semen during the treatment with the drug under study and until one week after the end of the treatment.
All patients will have to:
- Refrain from donating blood while receiving treatment with the drug under study and during the week following its end.
- Refrain from share the drug under study with other people and to return all drugs under study which have not been used to the investigator or pharmacist.
Exclusion Criteria:
- Organic disease or psychiatric disorder which made possible that the patient did not sign nor understood the informed consent.
- Having received any treatment for MDS.
- MDS 5q- with transfusion dependent anemia, documented confirmation that the patient has received some CH transfusion due to the baseline disease (MDS).
- Pregnant women or on lactation period.
Any of the following lab abnormalities:
- Absolute count of neutrophils < 500/mm3
- Platelet count < 25000/mm3
- GOT or GPT in serum > 3 times the normal higher threshold
- Total serum bilirubin > 2 times the normal higher threshold
- Prior history of other malign disease different to MDS (except for carcinoma of baseline cells or skin squamous, or cervix or breast in situ carcinoma) unless the patient is free from disease for more than 5 years.
- Known hypersensibility or history of uncontrollable side effects to Lenalidomide.
- Major surgery within the 4 weeks prior to the inclusion in the trial.
- The patient has received any agent under research in the 30 days prior to the inclusion
Contacts and Locations| Spain | |
| Hospital de Cabueñes | Active, not recruiting |
| Gijón, Asturias, Spain, 33394 | |
| Hospital Central de Asturias | Active, not recruiting |
| Oviedo, Asturias, Spain, 33006 | |
| Hospital Universitari Germans Trias i Pujol (ICO Badalona) | Recruiting |
| Badalona, Barcelona, Spain, 08916 | |
| Contact: Blanca Xicoy Cirici, MD 0034 93 497 89 24 bxicoyc@comb.es | |
| Principal Investigator: Blanca Xicoy Cirici, MD | |
| Hospital Son Llàtzer | Recruiting |
| Palma de Mallorca, Islas Baleares, Spain, 07198 | |
| Contact: Joan Bargay Lleonart, MD 0034 871 20 21 38 jbargay@hsll.es | |
| Principal Investigator: Joan Bargay Lleonart, MD | |
| Hospital de Cruces | Recruiting |
| Barakaldo, Vizcaya, Spain, 48930 | |
| Contact: Beatriz Arrizabalaga Amuchastegui, MD 0034 946 00 60 89 BEATRIZ.ARRIZABALAGAAMUCHASTEG@osakidetza.net | |
| Principal Investigator: Beatriz Arrizabalaga Amuchastegui, MD | |
| Hospital Clínic i Provincial | Recruiting |
| Barcelona, Spain, 08036 | |
| Contact: Benet Nomdedeu Tobella, MD 0034 93 227 54 00 ext 2805 nomdedeu@clinic.ub.es | |
| Principal Investigator: Benet Nomdedeu Tobella, MD | |
| Hospital Universitario Reina Sofía | Active, not recruiting |
| Córdoba, Spain, 14004 | |
| Hospital Universitario La Paz | Active, not recruiting |
| Madrid, Spain, 28046 | |
| Hospital Clínico San Carlos | Active, not recruiting |
| Madrid, Spain, 28040 | |
| Hospital General Universitario José Maria Morales Meseguer | Active, not recruiting |
| Murcia, Spain, 30008 | |
| Hospital Clínico Universitario de Salamanca | Recruiting |
| Salamanca, Spain, 37007 | |
| Contact: José Ramón González Porras, MD 0034 923 29 13 16 jrgp@usal.es | |
| Principal Investigator: José Ramón González Porras, MD | |
| Hospital Universitario Virgen del Rocío | Active, not recruiting |
| Sevilla, Spain, 41013 | |
| Hospital Universitario La Fe | Active, not recruiting |
| Valencia, Spain, 46009 | |
| Study Chair: | Jose Ramón González Porras, MD | Hospital Clínico Universitario de Salamanca |
| Study Chair: | María Díez Campelo, MD | Hospital Clínico Universitario de Salamanca |
More Information
Publications:
| Responsible Party: | Miguel Angel Salinero, Fundación General de la Universidad de Salamanca |
| ClinicalTrials.gov Identifier: | NCT01243476 History of Changes |
| Other Study ID Numbers: | SINTRA-REV, 2009-013619-36 |
| Study First Received: | November 17, 2010 |
| Last Updated: | January 11, 2013 |
| Health Authority: | Spain: Agencia Española de Medicamentos y Productos Sanitarios |
Keywords provided by Fundación General de la Universidad de Salamanca:
|
myelodysplastic syndrome 5q deletion anemia lenalidomide red blood cells transfusion |
Additional relevant MeSH terms:
|
Myelodysplastic Syndromes Preleukemia Bone Marrow Diseases Hematologic Diseases Precancerous Conditions Neoplasms Lenalidomide Thalidomide Antineoplastic Agents Therapeutic Uses Pharmacologic Actions |
Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Leprostatic Agents Anti-Bacterial Agents Anti-Infective Agents Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Growth Inhibitors |
ClinicalTrials.gov processed this record on May 16, 2013