Study of REVLIMID (Lenalidomide) Versus Placebo in Patients With Low Risk Myelodysplastic Syndrome

Myelodysplastic Syndrome Clinical Trial

— SINTRA-REV  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01243476
• Other study ID #: SINTRA-REV
• Secondary ID: 2009-013619-36
• Status: Completed
• Phase: Phase 3
• Start date: January 2010
• Est. completion date: June 6, 2022

Study information

• Verified date: January 2023
• Source: Fundación General de la Universidad de Salamanca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Trial Design:

This clinical trial is a phase III multicenter, 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 was initially expected to take place over a period of 24 months and was expected to be finished in February 2012, but due to low rate of recruitment it was extended until the population sample is included in the trial).

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.

Four of the sites of this Clinical Trial are member of the European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet) which is partially co-funded by the European Union within the framework of the Third Health Programme. "ERN-2016 - Framework Partnership Agreement 2017-2021." FPA 739541".

Recruitment information / eligibility

• Status: Completed
• Enrollment: 61
• Est. completion date: June 6, 2022
• Est. primary completion date: June 6, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. - The patient must, in the investigator's opinion, be able to comply with all the clinical trial requirements.

2. - The patient must voluntarily sign the informed consent form before undergoing any test of the trial that is not part of the normal patient care, and patient must be aware that he/she can withdraw from the trial at any time, without it ever affecting their future healthcare.

3. - Age > 18 years.

4. - The patient must be diagnosed with low risk MDS (low and intermediate-1 IPSS) associated with 5q deletion, either as an isolated abnormality or accompanied by other additional cytogenetic abnormalities.

5. - MDS Del(5q) with transfusion-independent anaemia (Hb = 12 g/dL), and documented confirmation that no packed red blood cells transfusion due to the patient's underlying condition (MDS) has been received.

6. - The patient must have an ECOG performance status of = 2.

7. - The patient must be able to comply with the scheduled study visits.

8. - Female patient with childbearing potential must*:

• Understands the teratogenic risk of the study drug.

• Commits herself to use two forms of effective birth control continuously, and is able to use them correctly, for the 4 weeks prior to starting treatment with the study drug, as well as during treatment with the study drug (including periods of dose interruption), and for up to 4 weeks after finishing treatment with the study drug, even if amenorrhoeic. This always applies, except in women who commit to continued complete sexual abstinence, as confirmed on a monthly basis.

• The patient must understand that even if she is amenorrhoeic she must follow all the advice on effective contraception.

• The patient must understand the possible consequences of pregnancy and the need to attend a healthcare service urgently in case there is a risk of pregnancy.

• Agree to undergo a pregnancy test with a minimum sensitivity of 25 mIU/mL, under medical supervision, on the day of the study visit or during the 3 days prior to this visit, after using effective birth control for at least 4 weeks. This requirement also applies to women with childbearing potential who practice complete and continued sexual abstinence. The test must confirm that the patient is not pregnant at the time the treatment is initiated.

• Agree to undergo a pregnancy test, under medical supervision, weekly for he first 28 days of treatment, and subsequently every 4 weeks, including a pregnancy test 4 weeks after finishing the study treatment, except in case of confirmed tubal ligation. This pregnancy test will be performed on the day of the study visit or during the 3 days prior to it. This requirement also applies to women with childbearing potential who practice complete and continued sexual abstinence.

9. - All male patients must:

• Commit himself to the use of condoms throughout all the treatment with the study drug, including all periods of dose interruption, and up to one week after finishing the treatment if their partner is a woman with childbearing potential and does not use birth control methods.

• Commit himself to not donate semen during treatment with the study drug and up to one week after finishing the treatment.

10. - All patients must:

• Refrain from donating blood while receiving treatment with the study drug and during the week following the end of the treatment.

• Refrain from sharing the study drug with others, and return all unused study drug to the investigator or pharmacist.

Exclusion Criteria:

1. - Any organic disease or psychiatric disorder which makes it impossible for the patient to sign or understand the informed consent.

2. - Having received any treatment for MDS.

3. - Del(5q) MDS with transfusion-dependent anaemia, and documented confirmation that the patient has received any pRBC transfusion due to the underlying condition (MDS).

4. - Pregnant or breast-feeding women.

5. - Any of the following laboratory abnormalities:

• Absolute neutrophil count < 500/mm3

• Platelet count < 25,000/mm3

• Serum GOT or GPT > 3 times the upper limit of normal values.

• Total serum bilirubin > 2 times the upper limit of normal values.

6. - Previous history of other malignancies other than MDS (except for basal cell or squamous cell skin carcinoma, or carcinoma in situ of the cervix or breast), unless the patient has been free of disease for more than 5 years.

7. - Known hypersensitivity to or a history of uncontrollable side effects to lenalidomide.

8. - Major surgery within the 4 weeks prior to the inclusion in the trial.

9. - The patient has received any investigational agent in the 30 days prior to inclusion.

Related Conditions & MeSH terms

• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Lenalidomide
Treatment with Revlimid (lenalidomide), oral use, 5 mg daily during study treatment (104 weeks).

Other:
• Placebo
Placebo, oral use, daily during study treatment (104 weeks)

Locations

Country	Name	City	State
France	Centre Hospitalier Universitaire d'Angers	Angers	Maine Y Loira
France	Centre Hospitalier d'Avignon	Avignon	Vaucluse
France	Centre Hospitalier Universitaire Brabois	Nancy	Meurthe Y Mosel
France	Centre Hospitalier Universitaire de Nîmes	Nîmes	Gard
France	Centre Hospitalier Régional d'Orléans	Orléans	Loiret
France	Hôspital St. Louis	Paris
France	Hôpitaux Universitaires de Strasbourg	Strasbourg	Bajo Rin
Germany	Universitaetsklinikum Carl Gustav Carus der Technischen Universitaet Dresden	Dresden
Germany	Marien Hospital Duesseldorf	Duesseldorf
Germany	Klinikum rechts der Isar der Technischen Universität München	München
Spain	Hospital Universitari Germans Trias i Pujol (ICO Badalona)	Badalona	Barcelona
Spain	Hospital de Cruces	Barakaldo	Vizcaya
Spain	Hospital Clínic i Provincial	Barcelona
Spain	Hospital Universitario Reina Sofía	Córdoba
Spain	Instituto Catalán de Oncología de Gerona	Gerona
Spain	Hospital de Cabueñes	Gijón	Asturias
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Infanta Leonor	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital General Universitario José Maria Morales Meseguer	Murcia
Spain	Hospital Central de Asturias	Oviedo	Asturias
Spain	Hospital Son Llàtzer	Palma de Mallorca	Islas Baleares
Spain	Hospital Clínico Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Universitario La Fe	Valencia

Sponsors (2)

Lead Sponsor	Collaborator
Fundación General de la Universidad de Salamanca	Celgene Corporation

Countries where clinical trial is conducted

France,  Germany,  Spain, 

References & Publications (13)

Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004 Apr;4(4):314-22. doi: 10.1038/nrc1323. No abstract available. — View Citation

Bellamy WT. Expression of vascular endothelial growth factor and its receptors in multiple myeloma and other hematopoietic malignancies. Semin Oncol. 2001 Dec;28(6):551-9. doi: 10.1016/s0093-7754(01)90023-5. — View Citation

Fenaux P, Kelaidi C. Treatment of the 5q- syndrome. Hematology Am Soc Hematol Educ Program. 2006:192-8. doi: 10.1182/asheducation-2006.1.192. — View Citation

Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88. Erratum In: Blood 1998 Feb 1;91(3):1100. — View Citation

Kelaidi C, Eclache V, Fenaux P. The role of lenalidomide in the management of myelodysplasia with del 5q. Br J Haematol. 2008 Feb;140(3):267-78. doi: 10.1111/j.1365-2141.2007.06910.x. — View Citation

List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R; Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006 Oct 5;355(14):1456-65. doi: 10.1056/NEJMoa061292. — View Citation

List A, Gordon W, Dewald G, Bennett J, Giagounidis A, Raza A et al. Long-term clinical benefit of lenalidomide (Revlimid) treatment in patients with myelodysplastic syndrome and chromosome deletion 5q [Abstract]. Blood. 2006;108:251A.

List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. doi: 10.1056/NEJMoa041668. — View Citation

List AF. New approaches to the treatment of myelodysplasia. Oncologist. 2002;7 Suppl 1:39-49. doi: 10.1634/theoncologist.7-suppl_1-39. — View Citation

List, AF. Active treatment-improving outcomes in del 5q patients. Leukemia Research, (2007)31(Suppl. 1), S9.

Mallo M, Cervera J et al. Prognostic impact of additional chromosomal aberrations to 5q- in patients with primary myelodysplastic syndromes. Oral comunication, 0906, 13th Congress of the European Hematology Association. Haematologica | 2008; 93(s1), pag. 360

McHugh SM, Deighton J, Stewart AG, Lachmann PJ, Ewan PW. Bee venom immunotherapy induces a shift in cytokine responses from a TH-2 to a TH-1 dominant pattern: comparison of rush and conventional immunotherapy. Clin Exp Allergy. 1995 Sep;25(9):828-38. doi: 10.1111/j.1365-2222.1995.tb00025.x. — View Citation

Steensma DP, Tefferi A. The myelodysplastic syndrome(s): a perspective and review highlighting current controversies. Leuk Res. 2003 Feb;27(2):95-120. doi: 10.1016/s0145-2126(02)00098-x. Erratum In: Leuk Res. 2005 Jan;29(1):117. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Period until the progression of myelodysplastic syndrome	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.	6 years (study treatment and follow up)
Secondary	Erythroid response	Erythroid response according to the Criteria of the MDS International Work Team.	6 years (study treatment and follow up)
Secondary	Duration of the red blood cells transfusion independency	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.	6 years (study treatment and follow up)
Secondary	Change of the hemoglobin concentration (Hb) in relation to baseline levels	Change of the hemoglobin concentration (Hb) in relation to baseline levels of patients who show erythroid response.	6 years (study treatment and follow up)
Secondary	Variation in platelets and neutrophils absolute count in relation to baseline levels	Variation in platelets and neutrophils absolute count in relation to baseline levels	6 years (study treatment and follow up)
Secondary	Cytogenetic response	Cytogenetic response according to the Criteria of the MDS International Work Team.	6 years (study treatment and follow up)
Secondary	Bone marrow response	Bone marrow response according to the Criteria of the MDS International Work Team.	6 years (study treatment and follow up)
Secondary	Global survival, Event Free Survival and Rate of Transformation to Acute Leukemia.	Global survival, Event Free Survival and Rate of Transformation to Acute Leukemia	6 years (study treatment and follow up)
Secondary	Time from diagnose to transfusion independence.	Time from diagnose to transfusion independence	6 years (study treatment and follow up)
Secondary	Safety( type, frequency and severity of adverse events and relationship to lenalidomide	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.	6 years (study treatment and follow up)