A Survival Study in Patients With High Risk Myelodysplastic Syndromes Comparing Azacitidine Versus Conventional Care

Myelodysplastic Syndromes Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00071799
• Other study ID #: AZA PH GL 2003 CL001
• Status: Completed
• Phase: Phase 3
• Start date: November 1, 2003
• Est. completion date: July 1, 2007

Study information

• Verified date: October 2019
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 358
• Est. completion date: July 1, 2007
• Est. primary completion date: July 1, 2007
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Azacitidine
Azacitidine was injected subcutaneously (SC) at an initial dose of 75mg/m^2/day for 7 days. The 7-day dosing was repeated every 28 days with dose adjustment based on predefined hematology and renal laboratory results. Number of cycles: Azacitidine treatment was to be continued until the end of the study unless treatment was discontinued due to unacceptable toxicity, relapse after complete or partial response, transformation to AML or disease progression.

Other:
• Physician Choice
Physician Choice was one of 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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Peter MacCallum Cancer Institute	East Melbourne	Victoria
Australia	Royal Brisbane Hospital	Hersten	Queensland
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	The Royal Perth Hospital	Perth	Western Australia
Australia	Royal North Shore Hospital	St. Leonards	New South Wales
Australia	The Newcastle Mater Miseriecordiae Hospital	Warratah	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Bulgaria	First Clinical Base - Clinic of Hematology, MHAT - Pleven	Pleven
Bulgaria	III-rd Internal Department, District Dispensary for Oncology diseases with stationary(DDOncDIU)	Plovdiv
Bulgaria	MHAT "St George" Clinic of Hematology, Plovdiv	Plovdiv
Bulgaria	National Centre of Hematology and Transfusiology, Sofia	Sofia
Bulgaria	Multiprofile Hospital for Active Treatment (MHAT), "St. Marina" Clinic of Hematology	Varna
Bulgaria	University Multiprofile Hospital for Active Treatment "Sveta Marina"	Varna
Czechia	Fakultni nemocnice Brno	Jihlavska	Brno
Czechia	Fakultni Nemocnice Olomouc	Olomouc
Czechia	Uslav Hematologie a Krevni Transfuze	Praha
Czechia	Vseobecna Fakultni Nemocnice	Praha
Czechia	Fakultni nemocnice Hradec Kralove	Sokolska	Hradec Kralove
France	Chu D'Angers	Angers
France	Hopital Beaujon	Clichy
France	Che De Lille	Lille
France	Hospital Edouard Herriot	Lyon
France	Institute Paoli Calmettes	Marseille
France	Chu De Nantes	Nantes
France	Hopital Cochin	Paris
France	Hospital Saint Louis	Paris
France	Centre Henri Becquerel	Rouen
France	Chu Purpan	Toulouse
Germany	Universitatsklinikum Bonn	Bonn
Germany	Klinikum Chemnitz gGmbH	Chemnitz
Germany	Universitatsklinikum Carl Gustav Carus	Dresden
Germany	St Johannes Hospital	Duisburg
Germany	Heinrich-Heine University Dusseldorf	Dusseldorf
Germany	University Essen	Essen
Germany	Gerorg-August-Universitat Gottingen	Gottingen
Germany	Allgemeines Krankenhaus St. Georg	Hamburg
Germany	Universitatsklinikum Hambur-Eppendorf	Hamburg
Germany	Universitatsklinikum Benjamin Franklin	Hindenburgdamm	Berlin
Germany	Universitatsklinikum Kiel II	Kiel
Germany	Universitatsklinikum Ulm	Ulm
Greece	District General Hospital of Athens	Athens
Greece	General Hospital of Chest Disease	Athens
Greece	University Hospital-Attikon	Haidari	Athens
Greece	University General Hospital of Heraklio Voutes	Heraklio	Crete
Greece	University General Hospital of Ioannina	Ioannina
Greece	University General Hospital of Patra Rio	Patra
Hungary	Orszagos Gyogyintezeti Kozpont	Budapest
Hungary	University of Pecs, 1st Dept of Internal Medicine	Pecs
Hungary	University of Szeged, 2nd Department of Internal Medicine	Szeged
Italy	Policlinico S. Orsola-Malpighi	Bologna
Italy	Universita di Firenze	Firenze
Italy	Ospedale San Martino	Genova
Italy	Instituto Nazionale Dei Tumori	Milano
Italy	Centro Oncologico Modenese	Modena
Italy	Instituto Nazionale Tumori "Regina Elena"	Roma
Italy	Ospedale San Eugenio	Roma
Italy	Policlinico Gemelli	Roma
Italy	Ospedale Casa Sollievo Della Sofferenza - Irrc	San Giovanni Rotondo
Italy	Universita Degli Studi Di Sassari	Sassari
Netherlands	VU University Medical Center Amsterdam	Amsterdam
Netherlands	Univ Hospital St. Radboud	Nijmejen
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 1	Gdansk
Poland	Wojewodzki Szpital Specjalistyczny	Lodz
Poland	Samodzielny Publiczny Szpital Kliniczny	Lublin
Poland	Samodzelny Publiczny Centralny Szpital Kliniczny	Warszawa
Poland	Wojskowy Instytut Medyczny	Warszawa
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 1	Wroclaw
Russian Federation	Blokhin Cancer Research Center	Moscow
Russian Federation	Burdenko Central Military Clinical Hospital	Moscow
Russian Federation	Scientific Haematology Center, Moscow	Moscow
Russian Federation	City Hospital #31	St. Petersburg
Russian Federation	Institute of Haematology & Blood Transfusion	St. Petersburg
Russian Federation	Pavlov State Medical University	St. Petersburg
Russian Federation	Pavlov State Medical University	St. Petersburg
Spain	Hospital Clinic	Barcelona
Spain	Hospital Santa Creu I Sant Pau	Barcelona
Spain	Hospital Universitario Germans Trias I Pujol	Barcelona
Spain	Hospital de Leon	Leon
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital La Paz, Madrid	Madrid
Spain	Hospital Ramon Y Cajal	Madrid
Spain	Hospital Universitario De La Princesa	Madrid
Spain	Hospital Son Llatzer	Palma de Mallorca
Spain	Hospital Universitario Del Salamanca	Salamanca
Spain	Hospital Universitario La Fe	Valencia
Sweden	Sahlgrenska University Hospital	Goteborg
Sweden	Lund Universtiy Hospital	Lund
Sweden	University Hospital MAS	Malmo
Sweden	Huddinge University Hospital	Stockholm
Sweden	Uppsala University Hospital	Uppsala
United Kingdom	Royal Bournemouth General Hospital	Bournemouth
United Kingdom	Kings College Hospital NHS Trust	London
United Kingdom	St. Bartholomew's Hospital	London
United Kingdom	Christie Hospital	Manchester
United Kingdom	Norfolk and Norwich University Hospital	Norwich
United Kingdom	John Radcliffe Hospital	Oxford
United Kingdom	Royal Cornwall Hospital	Truro
United States	University of Alabama School of Medicine	Birmingham	Alabama
United States	Case Western Reserve University	Cleveland	Ohio
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	Froedtert Memorial Lutheran Hospital	Milwaukee	Wisconsin
United States	Mount Sinai Medical Center	New York	New York
United States	Western Pennsylvania Cancer Institute	Pittsburgh	Pennsylvania
United States	Oregon Cancer Center	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Australia,  Bulgaria,  Czechia,  France,  Germany,  Greece,  Hungary,  Italy,  Netherlands,  Poland,  Russian Federation,  Spain,  Sweden,  United Kingdom, 

References & Publications (5)

Fenaux P, Gattermann N, Seymour JF, Hellström-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 — View 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 — View Citation

Fenaux P, Mufti GJ, Hellström-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 ca — View Citation

Santini V, Fenaux P, Mufti GJ, Hellström-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 H — View Citation

Seymour JF, Fenaux P, Silverman LR, Mufti GJ, Hellström-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 myelodysp — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Kaplan-Meier Estimates for Median Time to Death From Any Cause	Kaplan-Meier estimates for the median months until death from any cause within the intent-to-treat population. Patients surviving at the end of the follow-up period were censored at the date of last contact. If a patient withdrew consent to follow-up or was lost to follow-up, the patient was censored as of the last date of contact.	Day 1 (randomization) to 42 months
Primary	Summary of Subgroup Analyses for Kaplan-Meier Estimates for Time to Death From Any Cause	Kaplan-Meier estimates for the median months until death from any cause within the intent-to-treat population. Patients surviving at the end of the follow-up period were censored at the date of last contact. If a patient withdrew consent to follow-up or was lost to follow-up, the patient was censored as of the last date of contact.; Subgroups that were analyzed are age, gender, French-American-British (FAB) classification, World Health Organization (WHO) classification and International Prognostic Scoring System (IPSS) classification.	Day 1 (randomization) to 42 months
Primary	Number of Participants Who Died	Count of participants who died during the study	42 months
Secondary	Kaplan-Meier Estimate for Median Time to Transformation to Acute Myeloid Leukemia (AML) or Death From Any Cause, Whichever Occurred First	The time to transformation to AML or death from any cause (whichever occurred first) was defined as the number of days from the date of randomization until the date of documented AML transformation or death from any cause. Patients who did not transform to AML or die were censored at the date of last follow-up.	Day 1 (randomization) to 42 months
Secondary	Kaplan-Meier Estimates for Median Time to Transformation to Acute Myeloid Leukemia (AML)	The time to transformation to AML was defined as the number of days from the date of randomization until the date of documented AML transformation, defined as a bone marrow blast count = 30% independent of baseline bone marrow count. Patients who did not transform to AML were censored at the date of last follow-up or date of death.	Day 1 (randomization) to 42 months
Secondary	Summary of Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Dependent at Baseline	Summary of dependence and independence from red blood cell (RBC) transfusion at baseline and during treatment, for patients who were dependent at baseline. A patient was considered transfusion independent at baseline if the patient had no transfusions during the 56 days prior to randomization. During study, a patient was considered transfusion independent during the on-treatment period if the patient had no transfusions during any 56 consecutive days or more. Otherwise, the patient was considered transfusion dependent.	Day 1 (randomization) to 42 months
Secondary	Summary of Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Independent at Baseline	Summary of dependence and independence from red blood cell (RBC) transfusion at baseline and during treatment, for patients who were independent at baseline. A patient was considered transfusion independent at baseline if the patient had no transfusions during the 56 days prior to randomization. During study, a patient was considered transfusion independent during the on-treatment period if the patient had no transfusions during any 56 consecutive days or more. Otherwise, the patient was considered transfusion dependent.	Day 1 (randomization) to 42 months
Secondary	Summary of Participants' Platelet Transfusion Status for Participants Who Were Transfusion Dependent at Baseline	Summary of dependence and independence from platelet transfusion at baseline and during treatment for patients who were dependent at baseline. A patient was considered transfusion independent at baseline if the patient had no transfusions during the 56 days prior to randomization. During study, a patient was considered transfusion independent during the on-treatment period if the patient had no transfusions during any 56 consecutive days or more. Otherwise, the patient was considered transfusion dependent.	Day 1 (randomization) to 42 months
Secondary	Summary of Participants' Platelet Transfusion Status for Participants Who Were Transfusion Independent at Baseline	Summary of dependence and independence from platelet transfusion at baseline and during treatment for patients who were independent at baseline. A patient was considered transfusion independent at baseline if the patient had no transfusions during the 56 days prior to randomization. During study, a patient was considered transfusion independent during the on-treatment period if the patient had no transfusions during any 56 consecutive days or more. Otherwise, the patient was considered transfusion dependent.	Day 1 (randomization) to 42 months
Secondary	Number of Participants Considered Hematologic Responders by Investigator Determinations Using International Working Group (IWG 2000) Criteria for Myelodysplastic Syndrome (MDS)	Investigator determined responses followed IWG criteria for; complete remission(CR): repeat bone marrow show <5% myeloblasts, and peripheral blood evaluations lasting >=2 months of hemoglobin(>110 g/L), neutrophils(>=1.5x10^9/L), platelets(>=100x10^9/L), blasts (0%) and no dysplasia; partial remission(PR) is the same as CR for peripheral blood: bone marrow shows blasts decrease by >=50% or a less advanced FAB classification from pretreatment; stable disease(SD) is a failure to achieve at least a partial remission, but with no evidence of progression for at least 2 months.	Day 1 to 42 months
Secondary	Number of Participants Showing Hematologic Improvement Using International Working Group (IWG 2000) Criteria for Myelodysplastic Syndrome (MDS) Assessed by Independent Review Committee	IWG 2000 Criteria: Pretreatment=hemoglobin <100g/L or RBC transfusion-dependent, platelet count <100x10^9/L or platelet transfusion dependent, absolute neutrophil count <1.5x10^9/L.; Erythroid response: Major->20g/L increase or transfusion independent. Minor- 10-20g/L increase or >=50% decrease in transfusion requirements.; Platelet response: Major-absolute increase of >=30x10^9/L or platelet transfusion independence. Minor->=50% increase.; Neutrophil response: Major->=100% increase or an absolute increase of >0.5x10^9/L. Minor->=100% increase and absolute increase of <0.5x10^9/L.	Day 1 to 42 months
Secondary	Time to Disease Progression, Relapse After Complete or Partial Remission, or Death From Any Cause	The time to disease progression, relapse after complete or partial remission (CR, PR), or death from any cause was defined as the time from the date of randomization until the first date of documented disease progression, relapse after CR or PR, or death from any cause.	Day 1 (randomization) to 42 months
Secondary	Duration of Any Hematologic Improvement	The duration of improvement was defined as the time from the date of hematologic improvement until the date of first documented progression or relapse after hematologic improvement or death from any cause.	Day 1 (randomization) to 42 months
Secondary	Number of Infections Per Treatment Year Requiring Intravenous Antibiotics, Antifungals or Antivirals	The on-treatment adverse event rate of infection requiring IV antibiotics, antifungals, or antivirals per patient-years. The on-treatment period was considered the period from the date of randomization to the last treatment study visit.	Day 1 (randomization) to 42 months
Secondary	Number of Participants in Different Categories of Adverse Experiences During Core Study Period	Patient counts for a variety of subsets of adverse experiences for the core study period (day 1 to 42 months). The individual options for Conventional Care Regimens (Best Supportive Care Only, Low-Dose Cytarabine, and Standard Chemotherapy) are presented as separate treatments.	Day 1 (randomization) to 42 months

External Links

•   Study record for the extension study of AZA PH GL 2003 CL 001