Clinical trial NCT00071799: A Survival Study in Patients With High Risk Myelodysplastic Syndromes Comparing Azacitidine Versus Conventional Care
Official title: A Multicenter, Randomized, Open-label, Parallel-group, Phase 3 Trial of Subcutaneous Azacitidine Plus Best Supportive Care Versus Conventional Care Regimens Plus Best Supportive Care for the Treatment of Myelodysplastic Syndromes (MDS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myelodysplastic Syndromes
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2003-11-05
Enrollment: 358
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The purpose of this study is to determine whether patients with high-risk myelodysplastic syndromes (MDS) treated with azacitidine have improved survival compared to conventional care treatments. The study will also assess the effect of treatments on response, duration of response, and transformation to acute myeloid leukemia (AML). The study will continue for 12 months following last patient enrolled.

See study AZA PH GL 2003 CL 001 E for information about the extension to this study.

Detailed description: Comparison/Control Interventions offered the physician three options:

* Best supportive care (BSC) alone,
* Low-dose cytarabine subcutaneously for 14 days every 28 to 42 days, or
* Standard chemotherapy administered for induction as a continuous intravenous infusion of cytarabine over 7 days plus an anthracycline (daunorubicin, idarubicin, or mitoxantrone) on Days 1, 2, and 3; and, for those eligible, 1 or 2 consolidation cycles administered as continuous intravenous infusions of cytarabine for 3 to 7 days with the same anthracycline that was used at induction on Days 1 and 2 (each cycle between 28 to 70 days from the start of the previous cycle).

All three options included best supportive care. Neither the experimental group (azacitidine) nor any of the comparison/control options allowed use of erythropoietin.

Duration of Intervention: Patients will be treated until death, withdrawal, unacceptable toxicity or conclusion of the study.

Eligibility criteria: Inclusion Criteria:

* Have a diagnosis of refractory anemia with excess blasts or refractory anemia with excess blasts in transformation according to the French-American-British classification system for myelodysplastic syndromes (MDS) and a relatively high risk of acute myeloid leukemia (AML) transformation, with an International Prognostic Scoring System score of INT-2 or High.
* Be 18 years of age or older
* Have a life expectancy of at least 3 months
* Be unlikely to proceed to bone marrow or stem cell transplantation therapy following remission
* Have serum bilirubin levels less than or equal to 1.5 times the upper limit of normal range for the laboratory
* Have serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) or serum glutamic-pyruvic transaminase (alanine aminotransferase) levels less than or equal to 2 times the upper limit of normal (unless these are considered to be related to transfusion-induced secondary hemosiderosis)
* Have serum creatinine levels less than or equal to 1.5 times the upper limit of normal

Exclusion Criteria:

* Secondary myelodysplastic syndromes (MDS)
* Prior treatment with azacitidine;
* Prior history of acute myeloid leukemia (AML);
* Malignant disease diagnosed within prior 12 months;
* Metastatic disease;
* Hepatic tumors;
* Radiation, chemotherapy, cytotoxic therapy for non-MDS conditions within prior 12 months;
* Prior transplantation or cytotoxic therapy to treat MDS;
* Serious medical illness likely to limit survival to 12 months or less;
* Treatment with erythropoietin or myeloid growth factors during prior 21 days or androgenic hormones during prior 13 days;
* Active HIV, viral hepatitis type B or C;
* Treatment with investigational drugs during prior 30 days;
* Within the 28-day screening period, documented red cell folate deficiency, as evidenced by red blood cell folate (not serum folate) or vitamin B12 deficiency

Primary outcomes:
measure: Kaplan-Meier Estimates for Median Time to Death From Any Cause
timeFrame: Day 1 (randomization) to 42 months
measure: Summary of Subgroup Analyses for Kaplan-Meier Estimates for Time to Death From Any Cause
timeFrame: Day 1 (randomization) to 42 months
measure: Number of Participants Who Died
timeFrame: 42 months
Secondary outcomes:
measure: Kaplan-Meier Estimate for Median Time to Transformation to Acute Myeloid Leukemia (AML) or Death From Any Cause, Whichever Occurred First
timeFrame: Day 1 (randomization) to 42 months
measure: Kaplan-Meier Estimates for Median Time to Transformation to Acute Myeloid Leukemia (AML)
timeFrame: Day 1 (randomization) to 42 months
measure: Summary of Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Dependent at Baseline
timeFrame: Day 1 (randomization) to 42 months
measure: Summary of Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Independent at Baseline
timeFrame: Day 1 (randomization) to 42 months
measure: Summary of Participants' Platelet Transfusion Status for Participants Who Were Transfusion Dependent at Baseline
timeFrame: Day 1 (randomization) to 42 months
measure: Summary of Participants' Platelet Transfusion Status for Participants Who Were Transfusion Independent at Baseline
timeFrame: Day 1 (randomization) to 42 months
measure: Number of Participants Considered Hematologic Responders by Investigator Determinations Using International Working Group (IWG 2000) Criteria for Myelodysplastic Syndrome (MDS)
timeFrame: Day 1 to 42 months
measure: Number of Participants Showing Hematologic Improvement Using International Working Group (IWG 2000) Criteria for Myelodysplastic Syndrome (MDS) Assessed by Independent Review Committee
timeFrame: Day 1 to 42 months
measure: Time to Disease Progression, Relapse After Complete or Partial Remission, or Death From Any Cause
timeFrame: Day 1 (randomization) to 42 months
measure: Duration of Any Hematologic Improvement
timeFrame: Day 1 (randomization) to 42 months
measure: Number of Infections Per Treatment Year Requiring Intravenous Antibiotics, Antifungals or Antivirals
timeFrame: Day 1 (randomization) to 42 months
measure: Number of Participants in Different Categories of Adverse Experiences During Core Study Period
timeFrame: Day 1 (randomization) to 42 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama School of Medicine
state: Alabama
city: Indianapolis
country: United States
facility: Indiana University Cancer Center
state: Indiana
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Portland
country: United States
facility: Oregon Cancer Center
state: Oregon
city: Pittsburgh
country: United States
facility: Western Pennsylvania Cancer Institute
state: Pennsylvania
city: Milwaukee
country: United States
facility: Froedtert Memorial Lutheran Hospital
state: Wisconsin
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Warratah
country: Australia
facility: The Newcastle Mater Miseriecordiae Hospital
state: New South Wales
city: Hersten
country: Australia
facility: Royal Brisbane Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Institute
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Perth
country: Australia
facility: The Royal Perth Hospital
state: Western Australia
city: Pleven
country: Bulgaria
facility: First Clinical Base - Clinic of Hematology, MHAT - Pleven
city: Plovdiv
country: Bulgaria
facility: MHAT "St George" Clinic of Hematology, Plovdiv
city: Plovdiv
country: Bulgaria
facility: III-rd Internal Department, District Dispensary for Oncology diseases with stationary(DDOncDIU)
city: Sofia
country: Bulgaria
facility: National Centre of Hematology and Transfusiology, Sofia
city: Varna
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment (MHAT), "St. Marina" Clinic of Hematology
city: Varna
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment "Sveta Marina"
city: Jihlavska
country: Czechia
facility: Fakultni nemocnice Brno
state: Brno
city: Sokolska
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
state: Hradec Kralove
city: Olomouc
country: Czechia
facility: Fakultni Nemocnice Olomouc
city: Praha
country: Czechia
facility: Vseobecna Fakultni Nemocnice
city: Praha
country: Czechia
facility: Uslav Hematologie a Krevni Transfuze
city: Angers
country: France
facility: Chu D'Angers
city: Clichy
country: France
facility: Hopital Beaujon
city: Lille
country: France
facility: Che De Lille
city: Lyon
country: France
facility: Hospital Edouard Herriot
city: Marseille
country: France
facility: Institute Paoli Calmettes
city: Nantes
country: France
facility: Chu De Nantes
city: Paris
country: France
facility: Hospital Saint Louis
city: Paris
country: France
facility: Hopital Cochin
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Toulouse
country: France
facility: Chu Purpan
city: Hindenburgdamm
country: Germany
facility: Universitatsklinikum Benjamin Franklin
state: Berlin
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus
city: Duisburg
country: Germany
facility: St Johannes Hospital
city: Dusseldorf
country: Germany
facility: Heinrich-Heine University Dusseldorf
city: Essen
country: Germany
facility: University Essen
city: Gottingen
country: Germany
facility: Gerorg-August-Universitat Gottingen
city: Hamburg
country: Germany
facility: Allgemeines Krankenhaus St. Georg
city: Hamburg
country: Germany
facility: Universitatsklinikum Hambur-Eppendorf
city: Kiel
country: Germany
facility: Universitatsklinikum Kiel II
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Haidari
country: Greece
facility: University Hospital-Attikon
state: Athens
city: Heraklio
country: Greece
facility: University General Hospital of Heraklio Voutes
state: Crete
city: Athens
country: Greece
facility: District General Hospital of Athens
city: Athens
country: Greece
facility: General Hospital of Chest Disease
city: Ioannina
country: Greece
facility: University General Hospital of Ioannina
city: Patra
country: Greece
facility: University General Hospital of Patra Rio
city: Budapest
country: Hungary
facility: Orszagos Gyogyintezeti Kozpont
city: Pecs
country: Hungary
facility: University of Pecs, 1st Dept of Internal Medicine
city: Szeged
country: Hungary
facility: University of Szeged, 2nd Department of Internal Medicine
city: Bologna
country: Italy
facility: Policlinico S. Orsola-Malpighi
city: Firenze
country: Italy
facility: Universita di Firenze
city: Genova
country: Italy
facility: Ospedale San Martino
city: Milano
country: Italy
facility: Instituto Nazionale Dei Tumori
city: Modena
country: Italy
facility: Centro Oncologico Modenese
city: Roma
country: Italy
facility: Ospedale San Eugenio
city: Roma
country: Italy
facility: Policlinico Gemelli
city: Roma
country: Italy
facility: Instituto Nazionale Tumori "Regina Elena"
city: San Giovanni Rotondo
country: Italy
facility: Ospedale Casa Sollievo Della Sofferenza - Irrc
city: Sassari
country: Italy
facility: Universita Degli Studi Di Sassari
city: Amsterdam
country: Netherlands
facility: VU University Medical Center Amsterdam
city: Nijmejen
country: Netherlands
facility: Univ Hospital St. Radboud
city: Gdansk
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1
city: Lodz
country: Poland
facility: Wojewodzki Szpital Specjalistyczny
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny
city: Warszawa
country: Poland
facility: Wojskowy Instytut Medyczny
city: Warszawa
country: Poland
facility: Samodzelny Publiczny Centralny Szpital Kliniczny
city: Wroclaw
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1
city: Moscow
country: Russian Federation
facility: Burdenko Central Military Clinical Hospital
city: Moscow
country: Russian Federation
facility: Blokhin Cancer Research Center
city: Moscow
country: Russian Federation
facility: Scientific Haematology Center, Moscow
city: St. Petersburg
country: Russian Federation
facility: Institute of Haematology & Blood Transfusion
city: St. Petersburg
country: Russian Federation
facility: Pavlov State Medical University
city: St. Petersburg
country: Russian Federation
facility: Pavlov State Medical University
city: St. Petersburg
country: Russian Federation
facility: City Hospital #31
city: Barcelona
country: Spain
facility: Hospital Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic
city: Barcelona
country: Spain
facility: Hospital Universitario Germans Trias I Pujol
city: Leon
country: Spain
facility: Hospital de Leon
city: Madrid
country: Spain
facility: Hospital Universitario De La Princesa
city: Madrid
country: Spain
facility: Hospital Ramon Y Cajal
city: Madrid
country: Spain
facility: Hospital La Paz, Madrid
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Palma de Mallorca
country: Spain
facility: Hospital Son Llatzer
city: Salamanca
country: Spain
facility: Hospital Universitario Del Salamanca
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Goteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Lund
country: Sweden
facility: Lund Universtiy Hospital
city: Malmo
country: Sweden
facility: University Hospital MAS
city: Stockholm
country: Sweden
facility: Huddinge University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth General Hospital
city: London
country: United Kingdom
facility: St. Bartholomew's Hospital
city: London
country: United Kingdom
facility: Kings College Hospital NHS Trust
city: Manchester
country: United Kingdom
facility: Christie Hospital
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
Study officials:
affiliation: Celgene Corporation
name: CL Beach
role: STUDY_DIRECTOR
References:
citation: Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. doi: 10.1200/JCO.2009.23.8329. Epub 2009 Dec 21.
citation: Fenaux P, Gattermann N, Seymour JF, Hellstrom-Lindberg E, Mufti GJ, Duehrsen U, Gore SD, Ramos F, Beyne-Rauzy O, List A, McKenzie D, Backstrom J, Beach CL. Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C. Br J Haematol. 2010 Apr;149(2):244-9. doi: 10.1111/j.1365-2141.2010.08082.x. Epub 2010 Feb 5.
citation: Santini V, Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Silverman LR, List A, Gore SD, Seymour JF, Backstrom J, Beach CL. Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*. Eur J Haematol. 2010 Aug;85(2):130-8. doi: 10.1111/j.1600-0609.2010.01456.x. Epub 2010 Apr 12.
citation: Seymour JF, Fenaux P, Silverman LR, Mufti GJ, Hellstrom-Lindberg E, Santini V, List AF, Gore SD, Backstrom J, McKenzie D, Beach CL. Effects of azacitidine compared with conventional care regimens in elderly (>/= 75 years) patients with higher-risk myelodysplastic syndromes. Crit Rev Oncol Hematol. 2010 Dec;76(3):218-27. doi: 10.1016/j.critrevonc.2010.04.005. Epub 2010 May 6.
citation: Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009 Mar;10(3):223-32. doi: 10.1016/S1470-2045(09)70003-8. Epub 2009 Feb 21.
citation: Gore SD, Fenaux P, Santini V, Bennett JM, Silverman LR, Seymour JF, Hellstrom-Lindberg E, Swern AS, Beach CL, List AF. A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. Haematologica. 2013 Jul;98(7):1067-72. doi: 10.3324/haematol.2012.074831. Epub 2013 Apr 12.