Prospective, Multicenter, Open Label and Single-arm Study of Darbepoetin Alfa for Anemia in Myelodisplastic Syndrome Patients.

NCT01039350 | Terminated Phase 2

• 2 other identifiers: GEE2004012005-002414-38
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 16

Brief Summary

This is an open-label, single-arm, multicentre, prospective study of darbepoetin alfa to treat anaemia in patients with low and intermediate-1 IPSS risk MDS. The study will consist of a 14-day screening period followed by a maximum 24-week treatment period and a final visit.

Conditions

Myelodysplastic Syndrome

Keywords

Myelodysplastic syndrome

Outcome Measures

Primary Outcomes (1)

• Proportion of patients achieving an erythroid response during the 24-week treatment period.

  weeks 8; 12; 16 and 24

Secondary Outcomes (7)

• Time to erythroid response and time it is maintained.

  week 24

• Proportion of non-responders to darbepoetin alfa who obtain an erythroid response after the addition of Filgrastim

  weeks 8, 12, 16 and 24

• Proportion of patients receiving RBC transfusions (more than 1 unit) from week 5 to 24, inclusive

  weeks 8; 12; 16 and 24

• Score changes in the FACT-Fatigue quality-of-life scale between the baseline visit, and weeks 8, 16, 24, and the end of the study.

  weeks 8; 16 and 24

• Number of morphological and cytogenetic disorders at baseline and end of treatment

  week 24

Interventions

Darbepoetin alfa DRUG

Darbepoetin alfa will be initiated at a weekly (QW) subcutaneous dose of 300 mcg over 8 weeks.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ³ 18 years
• Low or intermediate-1 risk MDS according to IPSS, and FAB classification of RA, RARS, or RAEB with blasts £ 10%
• Predictive variables of good response (serum erythropoietin levels \< 500 IU/l and transfusion requirements \< 2 packed RBC/month over the preceding 2 months)
• Anaemia (Hb £ 10 g/dL), confirmed in the 14 days before day 1 of the study
• Life expectancy of at least 6 months
• ECOG Performance status score of 0, 1, or 2
• Subject must sign and date the Informed Consent (approved by a Clinical Research Ethics Committee - CREC), before any study-specific procedure is performed

You may not qualify if:

• Known history of convulsive disorders
• Poorly controlled hypertension (diastolic blood pressure \> 100 mmHg) at screening
• Inadequate liver function (total bilirubin \> two times the upper limit of the normal range (ULN), and liver enzymes (ALT, AST) \> two times ULN)
• Inadequate renal function (serum creatinine concentration \> 2 mg/dL)
• Ferritin \< 100 ng/ml or transferrin saturation index (TSI) \< 16%; Vitamin B12 deficiency (\< 200 pg/ml) or folate deficiency (\< 2 ng/ml)
• Clinically-relevant haemorrhages
• Haemolytic anaemia
• Cardiac condition: uncontrolled angina, congestive heart failure, or uncontrolled cardiac arrhythmia
• Clinically significant systemic infection or chronic inflammatory disease present at time of screening
• Any concomitant therapy used to treat MDS (including other growth factors than those described as part of this protocol, chemotherapy, antibody-based cancer treatment, hormonal therapy, interferon, and interleukins)
• Treatment with rHuEPO or darbepoetin alfa over the 4 weeks prior to Day 1 of the study
• More than 2 RBC transfusions over the 28 days prior to Day 1 of the study
• Pregnant or breast feeding women
• Subjects of childbearing-potential who do not take adequate contraceptive measures, in the opinion of the investigator
• Known hypersensitivity to any mammal-derived recombinant product

Sponsors & Collaborators

• Fundacion para el Estudio de la Hematologia y Hemoterapia en Aragon: lead

Study Sites (16)

Hospital General Universitario de Alicante

Alicante, Alicante, 03010, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, Barcelona, 08025, Spain

Location

Hospital Vall D´Hebron

Barcelona, Barcelona, 08035, Spain

Location

Hospital Clinic i Provincial de Barcelona

Barcelona, Barcelona, 08036, Spain

Location

Hospital Duran i Reynals

Barcelona, Barcelona, 08907, Spain

Location

Hospital de Cruces

Barakaldo, Bilbao, 48903, Spain

Location

Hospital General Yagüe

Burgos, Burgos, 09005, Spain

Location

Hospital Virgen del Puerto

Plasencia, Caceres, 10600, Spain

Location

Hospital Universitario Puerta del Mar

Cadiz, Cádiz, 11009, Spain

Location

Complejo Hospitalario Universitario Juan Canalejo

A Coruña, La Coruña, 15006, Spain

Location

Hospital Ramón y Cajal

Madrid, Madrid, 28034, Spain

Location

Hospital Universitario Doce de Octubre

Madrid, Madrid, 28041, Spain

Location

Hospital Central de Asturias

Oviedo, Principality of Asturias, 33006, Spain

Location

Hospital Universitario de Salamanca

Salamanca, Salamanca, 37007, Spain

Location

Hospital Universitario La Fé

Valencia, Valencia, 46009, Spain

Location

Hospital Arnau de Vilanova

Valencia, Valencia, 46015, Spain

Location

Related Publications (38)

• 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.

  PMID: 6952920 BACKGROUND

• Nosslinger T, Reisner R, Koller E, Gruner H, Tuchler H, Nowotny H, Pittermann E, Pfeilstocker M. Myelodysplastic syndromes, from French-American-British to World Health Organization: comparison of classifications on 431 unselected patients from a single institution. Blood. 2001 Nov 15;98(10):2935-41. doi: 10.1182/blood.v98.10.2935.

  PMID: 11698274 BACKGROUND

• 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.

  PMID: 9058730 BACKGROUND

• Littlewood TJ. Erythropoietin for the treatment of anemia associated with hematological malignancy. Hematol Oncol. 2001 Mar;19(1):19-30. doi: 10.1002/hon.663.

  PMID: 11276043 BACKGROUND

• Molldrem JJ, Leifer E, Bahceci E, Saunthararajah Y, Rivera M, Dunbar C, Liu J, Nakamura R, Young NS, Barrett AJ. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med. 2002 Aug 6;137(3):156-63. doi: 10.7326/0003-4819-137-3-200208060-00007.

  PMID: 12160363 BACKGROUND

• Raza A, Meyer P, Dutt D, Zorat F, Lisak L, Nascimben F, du Randt M, Kaspar C, Goldberg C, Loew J, Dar S, Gezer S, Venugopal P, Zeldis J. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood. 2001 Aug 15;98(4):958-65. doi: 10.1182/blood.v98.4.958.

  PMID: 11493439 BACKGROUND

• Stasi R, Pagano A, Terzoli E, Amadori S. Recombinant human granulocyte-macrophage colony-stimulating factor plus erythropoietin for the treatment of cytopenias in patients with myelodysplastic syndromes. Br J Haematol. 1999 Apr;105(1):141-8.

  PMID: 10233377 BACKGROUND

• Negrin RS, Stein R, Doherty K, Cornwell J, Vardiman J, Krantz S, Greenberg PL. Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: evidence for in vivo synergy. Blood. 1996 May 15;87(10):4076-81.

  PMID: 8639764 BACKGROUND

• Koury MJ, Bondurant MC. The molecular mechanism of erythropoietin action. Eur J Biochem. 1992 Dec 15;210(3):649-63. doi: 10.1111/j.1432-1033.1992.tb17466.x. No abstract available.

  PMID: 1483451 BACKGROUND

• Rigolin GM, Porta MD, Bigoni R, Cavazzini F, Ciccone M, Bardi A, Cuneo A, Castoldi G. rHuEpo administration in patients with low-risk myelodysplastic syndromes: evaluation of erythroid precursors' response by fluorescence in situ hybridization on May-Grunwald-Giemsa-stained bone marrow samples. Br J Haematol. 2002 Dec;119(3):652-9. doi: 10.1046/j.1365-2141.2002.03867.x.

  PMID: 12437640 BACKGROUND

• Hellstrom-Lindberg E, Ahlgren T, Beguin Y, Carlsson M, Carneskog J, Dahl IM, Dybedal I, Grimfors G, Kanter-Lewensohn L, Linder O, Luthman M, Lofvenberg E, Nilsson-Ehle H, Samuelsson J, Tangen JM, Winqvist I, Oberg G, Osterborg A, Ost A. Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. Blood. 1998 Jul 1;92(1):68-75.

  PMID: 9639501 BACKGROUND

• Remacha AF, Arrizabalaga B, Villegas A, Manteiga R, Calvo T, Julia A, Fernandez Fuertes I, Gonzalez FA, Font L, Junca 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.

  PMID: 10586205 BACKGROUND

• Thompson JA, Gilliland DG, Prchal JT, Bennett JM, Larholt K, Nelson RA, Rose EH, Dugan MH. Effect of recombinant human erythropoietin combined with granulocyte/ macrophage colony-stimulating factor in the treatment of patients with myelodysplastic syndrome. GM/EPO MDS Study Group. Blood. 2000 Feb 15;95(4):1175-9.

  PMID: 10666187 BACKGROUND

• Hast R, Wallvik J, Folin A, Bernell P, Stenke L. Long-term follow-up of 18 patients with myelodysplastic syndromes responding to recombinant erythropoietin treatment. Leuk Res. 2001 Jan;25(1):13-18. doi: 10.1016/s0145-2126(00)00073-4.

  PMID: 11137555 BACKGROUND

• Italian Cooperative Study Group for rHuEpo in Myelodysplastic Syndromes; Ferrini PR, Grossi A, Vannucchi AM, Barosi G, Guarnone R, Piva N, Musto P, Balleari E. A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Br J Haematol. 1998 Dec;103(4):1070-4. doi: 10.1046/j.1365-2141.1998.01085.x.

  PMID: 9886322 BACKGROUND

• Terpos E, Mougiou A, Kouraklis A, Chatzivassili A, Michalis E, Giannakoulas N, Manioudaki E, Lazaridou A, Bakaloudi V, Protopappa M, Liapi D, Grouzi E, Parharidou A, Symeonidis A, Kokkini G, Laoutaris NP, Vaipoulos G, Anagnostopoulos NI, Christakis JI, Meletis J, Bourantas KL, Zoumbos NC, Yataganas X, Viniou NA; Greek MDS Study Group. Prolonged administration of erythropoietin increases erythroid response rate in myelodysplastic syndromes: a phase II trial in 281 patients. Br J Haematol. 2002 Jul;118(1):174-80. doi: 10.1046/j.1365-2141.2002.03583.x.

  PMID: 12100145 BACKGROUND

• Hellstrom-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. doi: 10.1111/j.1365-2141.1995.tb08909.x.

  PMID: 7833279 BACKGROUND

• Mantovani L, Lentini G, Hentschel B, Wickramanayake PD, Loeffler M, Diehl V, Tesch H. Treatment of anaemia in myelodysplastic syndromes with prolonged administration of recombinant human granulocyte colony-stimulating factor and erythropoietin. Br J Haematol. 2000 May;109(2):367-75. doi: 10.1046/j.1365-2141.2000.02016.x.

  PMID: 10848827 BACKGROUND

• Casadevall N, Durieux P, Dubois S, Hemery F, Lepage E, Quarre 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. doi: 10.1182/blood-2003-07-2252. Epub 2004 Mar 30.

  PMID: 15054036 BACKGROUND

• Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Lowenberg 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.

  PMID: 11090046 BACKGROUND

• Hellstrom-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, Lofvenberg E, Oberg G, Porwit-MacDonald A, Radlund 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. doi: 10.1046/j.1365-2141.2003.04153.x.

  PMID: 12648074 BACKGROUND

• Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer. 2001 Apr;84 Suppl 1(Suppl 1):3-10. doi: 10.1054/bjoc.2001.1746.

  PMID: 11308268 BACKGROUND

• Smith R. Applications of darbepoietin-alpha, a novel erythropoiesis-stimulating protein, in oncology. Curr Opin Hematol. 2002 May;9(3):228-33. doi: 10.1097/00062752-200205000-00009.

  PMID: 11953669 BACKGROUND

• Macdougall IC, Gray SJ, Elston O, Breen C, Jenkins B, Browne J, Egrie J. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999 Nov;10(11):2392-5. doi: 10.1681/ASN.V10112392.

  PMID: 10541299 BACKGROUND

• Kotasek D, Steger G, Faught W, Underhill C, Poulsen E, Colowick AB, Rossi G, Mackey J; Aranesp 980291 Study Group. Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind, placebo-controlled, randomised study. Eur J Cancer. 2003 Sep;39(14):2026-34. doi: 10.1016/s0959-8049(03)00456-8.

  PMID: 12957457 BACKGROUND

• Hellstrom-Lindberg E, Negrin R, Stein R, Krantz S, Lindberg G, Vardiman J, Ost A, Greenberg P. Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model. Br J Haematol. 1997 Nov;99(2):344-51. doi: 10.1046/j.1365-2141.1997.4013211.x.

  PMID: 9375752 BACKGROUND

• Glaspy JA, Jadeja JS, Justice G, Kessler J, Richards D, Schwartzberg L, Tchekmedyian NS, Armstrong S, O'Byrne J, Rossi G, Colowick AB. Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy. Br J Cancer. 2002 Jul 29;87(3):268-76. doi: 10.1038/sj.bjc.6600465.

  PMID: 12177793 BACKGROUND

• Musto P, Lanza F, Balleari E, Grossi A, Falcone A, Sanpaolo G, Bodenizza C, Scalzulli PR, La Sala A, Campioni D, Ghio R, Cascavilla N, Carella AM. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol. 2005 Jan;128(2):204-9. doi: 10.1111/j.1365-2141.2004.05288.x.

  PMID: 15638854 BACKGROUND

• Mannone L, Gardin C, Quarre MC, Bernard JF, Vassilieff D, Ades L, Park S, Vaultier S, Hamza F, Beyne-rauzy MO, Cheze S, Giraudier S, Agape P, Legros L, Voillat L, Dreyfus F, Fenaux P; Groupe Francais des Myelodysplasies. High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol. 2006 Jun;133(5):513-9. doi: 10.1111/j.1365-2141.2006.06070.x.

  PMID: 16681638 BACKGROUND

• Vansteenkiste J, Pirker R, Massuti B, Barata F, Font A, Fiegl M, Siena S, Gateley J, Tomita D, Colowick AB, Musil J; Aranesp 980297 Study Group. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst. 2002 Aug 21;94(16):1211-20. doi: 10.1093/jnci/94.16.1211.

  PMID: 12189224 BACKGROUND

• Hedenus M, Adriansson M, San Miguel J, Kramer MH, Schipperus MR, Juvonen E, Taylor K, Belch A, Altes A, Martinelli G, Watson D, Matcham J, Rossi G, Littlewood TJ; Darbepoetin Alfa 20000161 Study Group. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol. 2003 Aug;122(3):394-403. doi: 10.1046/j.1365-2141.2003.04448.x.

  PMID: 12877666 BACKGROUND

• Smith RE Jr, Tchekmedyian NS, Chan D, Meza LA, Northfelt DW, Patel R, Austin M, Colowick AB, Rossi G, Glaspy J. A dose- and schedule-finding study of darbepoetin alpha for the treatment of chronic anaemia of cancer. Br J Cancer. 2003 Jun 16;88(12):1851-8. doi: 10.1038/sj.bjc.6600994.

  PMID: 12799626 BACKGROUND

• Hellstrom-Lindberg E. Growth factor treatment for the anemia of MDS: mechanisms and efficacy. Educational Programme at the 8th Congress of the European Haematology Association (EHA), June 2003

  BACKGROUND

• Verhoef GEG, Boogaerts MA. RHuEPO in the treatment of the myelodysplastic syndromes. In: Smyth JF, Boogaerts MA, Ehmer BR-M (eds): rHuEPO in cancer supportive treatment. Marcel Dekker, New York 1996;pp.13-34.

  BACKGROUND

• Heatherington AC, Schuller J, Kotasek D, et al. The pharmacokinetics of darbepoetin alfa and changes in endogenous erythropoietin in patients with nonmyeloid malignancies receiving or not receiving chemotherapy. European Breast Cancer Conference (EBCC) 2002. Abstract.

  BACKGROUND

• Glaspy J, Appelbaum S, Henry D et al. Effects of darbepoetin alfa (Aranesp®) timing with chemotherapy administration: a randomized study. SIOG 2003. Poster.

  BACKGROUND

• WHO Classification Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon 2001

  BACKGROUND

• Villegas A, Arrizabalaga B, Fernandez-Lago C, Castro M, Mayans JR, Gonzalez-Porras JR, Duarte RF, Remacha AF, Luno E, Gasquet JA. Darbepoetin alfa for anemia in patients with low or intermediate-1 risk myelodysplastic syndromes and positive predictive factors of response. Curr Med Res Opin. 2011 May;27(5):951-60. doi: 10.1185/03007995.2011.561834. Epub 2011 Mar 7.

  PMID: 21381892 DERIVED

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

Darbepoetin alfa

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Erythropoietin; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Proteins; Amino Acids, Peptides, and Proteins

Study Officials

• Ana M Villegas, MD

  Fundacion para el Estudio de la Hematologia y Hemoterapia en Aragon

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: December 23, 2009
• First Posted: December 24, 2009
• Study Start: February 1, 2006
• Primary Completion: July 1, 2008
• Study Completion: July 1, 2009
• Last Updated: January 13, 2010

Record last verified: 2010-01

Locations

ES (16)