SIMIDIS: Azacitidine and Beta Erythropoietin Treatment in Patients With Myelodysplastic Syndrome

Myelodysplastic Syndrome Clinical Trial

— SIMIDIS  

Official title:

A Multicenter, Non-Randomized, Open-Label Study to Evaluate Efficacy and Safety of Azacitidine and Beta Erythropoietin Treatment in Patients With Myelodysplastic Syndrome Red Cell Transfusion Dependent With Low or Intermediate -1 Risk.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00495547
• Other study ID #: 2007-000972-18
• Secondary ID: SIMIDIS
• Status: Terminated
• Phase: Phase 2
• First received: July 2, 2007
• Last updated: April 4, 2014
• Start date: February 2009
• Est. completion date: June 2011

Study information

• Verified date: April 2014
• Source: PETHEMA Foundation
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The primary objective is to evaluate the efficacy of the treatment in response rate terms. Otherwise this study wants to evaluate the safety of the treatment.

Description:

A total of up to 30 patients diagnosed of myelodysplastic syndrome red cell transfusion dependent with low or intermediate -1 risk will be included.

The patients will be evaluated at scheduled visits in up to three study periods:

Pre-treatment, Treatment and Follow up.

The Pre-treatment includes Screening and baseline visits. After providing informed consent, patients will be evaluated for study eligibility.

During Treatment Period patients will be evaluated once a month although biochemistry and haematology parameters will be evaluated every 2 weeks.

If an erythroid response after 24 weeks is determined, a extension treatment will be carry out without disease progression.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 16
• Est. completion date: June 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Must voluntary sign the informed consent.

2. Age = 18 years.

3. Must be able to comply with the protocol requirements

4. Patient recently diagnosed with Myelodysplastic syndrome red cell transfusion dependent with low or intermediate -1 risk according IPSS criteria.

5. Red cell transfusion dependent anemia.

6. El patient has to be able to complain with the protocol visits.

7. Women and man must accept to use high efficacy anticonceptive methods

Exclusion Criteria:

1. Pregnancy or breast-feed women.

2. Patients previously received treatment with azacytidine .

3. Patients previously received treatment with erythropoietin agents.

4. Proliferative Chronic myelomonocytic Leukaemia (leukocytes = 12000/mL).

5. Patient with a previous clinical history of another cancer (except for basocellular carcinoma or spinocellular carcinoma in situ of cervix or breast) except if the patient is free of symptoms during = 3 years.

6. Cytotoxic chemotherapy or experimental agents usage for myelodysplastic syndrome treatment during 28 days.

7. Previous haematopoietic transplant.

8. Mielosupresion and antitumoral treatment during the previous 28 days.

9. The following laboratory data:

Absolute neutrophil count < 1000 cel/ml (0.5x 109L) Platelet count < 50000/µL (25 x 109/L) Creatinine > 2.0 mg/dL (177 mmol/L) Aspartate transaminase (AST) or Alanine transaminase (ALT ) > 5 x the upper limit of normal. Total bilirubin: > 2 mg/dL

10. Patients with B12 vitamin, folic acid and ferrum deficiency.

11. Patient with positive VIH-1.

12. Any other organic or mental illness that could make impossible to sign the Inform consent or involve risk to the patient.

13. Patient has hypersensitivity previous to beta ,azacytidine, erythropoietin and/or mannitol.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Azacitidine
Azacitidine
• Beta Erythropoietin
Beta Erythropoietin

Locations

Country	Name	City	State
Spain	Hospital Germans Trias i Pujol	Badalona
Spain	Hospital Clínic Universitari	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Reina Sofía	Córdoba
Spain	Hospital Virgen Blanca	Leon
Spain	Hospital la Paz	Madrid
Spain	Hospital Central de Asturias	Oviedo
Spain	Hospital Son Llatzer	Palma de mallorca
Spain	Hospital Clinico Universitario	Salamanca
Spain	Hospital La Fe de Valencia	Valencia

Sponsors (3)

Lead Sponsor	Collaborator
PETHEMA Foundation	Celgene Corporation, Roche Pharma AG

Country where clinical trial is conducted

Spain, 

References & Publications (34)

2. Brunning RD, Head D, Bennett JM, Vardiman JW, Flandrin G, Harris NL et al. Myelodysplastic syndromes: introduction. En: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Tumours of haematopoietic and lymphoid tissues. Lyon, IARC Press, 2001; 63-67.

33. Mundle S, Lefebvre P, Duh MS, et al. Erythroid response (ER) rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa (EPO) or darbepoetin alfa (DARB) using International Working Group response criteria (IWGc): Comparative meta-analysis. Blood 2006; 108; 2672 (abstr

34. Lyons RM, Cosgriff T, Modi S, et al. Hematologic improvement, transfusion independence, and safety assessed using three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. Blood 2006; 108; 2662 (abstr).

Alessandrino EP, Amadori S, Barosi G, Cazzola M, Grossi A, Liberato LN, Locatelli F, Marchetti M, Morra E, Rebulla P, Visani G, Tura S; Italian Society of Hematology. Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes. A statement from the Italian Society of Hematology. Haematologica. 2002 Dec;87(12):1286-306. — View Citation

Aul C, Giagounidis A, Germing U. Epidemiological features of myelodysplastic syndromes: results from regional cancer surveys and hospital-based statistics. Int J Hematol. 2001 Jun;73(4):405-10. Review. — View Citation

Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982 Jun;51(2):189-99. — View Citation

Bowen D, Culligan D, Jowitt S, Kelsey S, Mufti G, Oscier D, Parker J; UK MDS Guidelines Group. Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol. 2003 Jan;120(2):187-200. — View Citation

Bowen D, Hyslop A, Keenan N, Groves M, Culligan D, Johnson P, Shaw A, Geddes F, Evans P, Porter J, Cavill I. Predicting erythroid response to recombinant erythropoietin plus granulocyte colony-stimulating factor therapy following a single subcutaneous bolus in patients with myelodysplasia. Haematologica. 2006 May;91(5):709-10. — View Citation

Casadevall N, Durieux P, Dubois S, Hemery F, Lepage E, Quarré MC, Damaj G, Giraudier S, Guerci A, Laurent G, Dombret H, Chomienne C, Ribrag V, Stamatoullas A, Marie JP, Vekhoff A, Maloisel F, Navarro R, Dreyfus F, Fenaux P. Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial. Blood. 2004 Jul 15;104(2):321-7. Epub 2004 Mar 30. — View Citation

Cazzola M, Malcovati L. Myelodysplastic syndromes--coping with ineffective hematopoiesis. N Engl J Med. 2005 Feb 10;352(6):536-8. — View Citation

Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Löwenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL; World Health Organization(WHO) international working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000 Dec 1;96(12):3671-4. — View Citation

Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. Epub 2006 Apr 11. — View Citation

Galm O, Herman JG, Baylin SB. The fundamental role of epigenetics in hematopoietic malignancies. Blood Rev. 2006 Jan;20(1):1-13. Epub 2005 Feb 23. Review. — 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

Hellström-Lindberg E, Gulbrandsen N, Lindberg G, Ahlgren T, Dahl IM, Dybedal I, Grimfors G, Hesse-Sundin E, Hjorth M, Kanter-Lewensohn L, Linder O, Luthman M, Löfvenberg E, Oberg G, Porwit-MacDonald A, Rådlund A, Samuelsson J, Tangen JM, Winquist I, Wisloff F; Scandinavian MDS Group. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003 Mar;120(6):1037-46. — View Citation

Hellström-Lindberg E. Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. Br J Haematol. 1995 Jan;89(1):67-71. — View Citation

Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003 Nov 20;349(21):2042-54. Review. — View Citation

Jädersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellström-Lindberg E. Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood. 2005 Aug 1;106(3):803-11. Epub 2005 Apr 19. — View Citation

Kaminskas E, Farrell A, Abraham S, Baird A, Hsieh LS, Lee SL, Leighton JK, Patel H, Rahman A, Sridhara R, Wang YC, Pazdur R; FDA. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res. 2005 May 15;11(10):3604-8. — View Citation

Kornblith AB, Herndon JE 2nd, Silverman LR, Demakos EP, Odchimar-Reissig R, Holland JF, Powell BL, DeCastro C, Ellerton J, Larson RA, Schiffer CA, Holland JC. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002 May 15;20(10):2441-52. — View Citation

Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, Passamonti F, Arcaini L, Maffioli M, Bernasconi P, Lazzarino M, Cazzola M. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005 Oct 20;23(30):7594-603. Epub 2005 Sep 26. — View Citation

Musto P, Falcone A, Sanpaolo G, Bodenizza C, La Sala A, Perla G, Carella AM. Efficacy of a single, weekly dose of recombinant erythropoietin in myelodysplastic syndromes. Br J Haematol. 2003 Jul;122(2):269-71. — View Citation

NCCN practice guidelines for the myelodysplastic syndromes. National Comprehensive Cancer Network. Oncology (Williston Park). 1998 Nov;12(11A):53-80. — View Citation

Parker JE, Mufti GJ. The myelodysplastic syndromes: a matter of life or death. Acta Haematol. 2004;111(1-2):78-99. Review. — View Citation

Remacha AF, Arrizabalaga B, Villegas A, Manteiga R, Calvo T, Julià A, Fernández Fuertes I, González FA, Font L, Juncà J, del Arco A, Malcorra JJ, Equiza EP, de Mendiguren BP, Romero M. Erythropoietin plus granulocyte colony-stimulating factor in the treatment of myelodysplastic syndromes. Identification of a subgroup of responders. The Spanish Erythropathology Group. Haematologica. 1999 Dec;84(12):1058-64. — View Citation

Rigolin GM, Castoldi G. The role of rHuEpo in low-risk myelodysplastic syndrome patients. Leuk Lymphoma. 2005 Jun;46(6):823-31. Review. — View Citation

San Miguel JF, Sanz GF, Vallespí T, del Cañizo MC, Sanz MA. Myelodysplastic syndromes. Crit Rev Oncol Hematol. 1996 May;23(1):57-93. Review. — View Citation

Sanz GF, Sanz MA, Greenberg PL. Prognostic factors and scoring systems in myelodysplastic syndromes. Haematologica. 1998 Apr;83(4):358-68. Review. — View Citation

Sanz GF, Sanz MA, Vallespí T, Cañizo MC, Torrabadella M, García S, Irriguible D, San Miguel JF. Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood. 1989 Jul;74(1):395-408. — View Citation

Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002 May 15;20(10):2429-40. — View Citation

Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, Larson RA; Cancer and Leukemia Group B. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006 Aug 20;24(24):3895-903. — View Citation

Tehranchi R, Fadeel B, Forsblom AM, Christensson B, Samuelsson J, Zhivotovsky B, Hellstrom-Lindberg E. Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors. Blood. 2003 Feb 1;101(3):1080-6. Epub 2002 Sep 5. — View Citation

Tehranchi R, Fadeel B, Schmidt-Mende J, Forsblom AM, Emanuelsson E, Jadersten M, Christensson B, Hast R, Howe RB, Samuelsson J, Zhivotovsky B, Hellström-Lindberg E. Antiapoptotic role of growth factors in the myelodysplastic syndromes: concordance between in vitro and in vivo observations. Clin Cancer Res. 2005 Sep 1;11(17):6291-9. — View Citation

Tehranchi R, Invernizzi R, Grandien A, Zhivotovsky B, Fadeel B, Forsblom AM, Travaglino E, Samuelsson J, Hast R, Nilsson L, Cazzola M, Wibom R, Hellström-Lindberg E. Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in low-risk myelodysplastic syndromes. Blood. 2005 Jul 1;106(1):247-53. Epub 2005 Mar 8. — View Citation

* Note: There are 34 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluate the efficacy of the treatment in response rate terms		6 months	No
Secondary	Evaluate the safety of the treatment		2 months	Yes

External Links

•   Pethema Foundation web
•   Spanish association of Haematology