title: Design and rationale of the QUAZAR Lower-Risk MDS (AZA-MDS-003) trial: a randomized phase 3 study of CC-486 (oral azacitidine) plus best supportive care vs placebo plus best supportive care in patients with IPSS lower-risk myelodysplastic syndromes and poor prognosis due to red blood cell transfusion-dependent anemia and thrombocytopenia.
abstract: BACKGROUND
  CC-486 is an oral formulation of the epigenetic modifier azacitidine. In an expanded phase 1 trial, CC-486 demonstrated clinical and biological activity in patients with International Prognostic Scoring System (IPSS) lower-risk (low- and intermediate-1-risk) myelodysplastic syndromes (MDS) with poor prognostic features including anemia and/or thrombocytopenia who may have required red blood cell or platelet transfusions. The overall response rate was 40 %, including hematologic improvement in 28 % of patients and RBC transfusion independence sustained for 56 days in 47 % of patients with baseline transfusion dependence. Based on the results of this study, the randomized, placebo-controlled phase 3 QUAZAR Lower-Risk MDS trial (AZA-MDS-003) was initiated. The design and rationale for this trial comparing CC-486 with placebo for the treatment of patients with IPSS lower-risk MDS with poor prognostic features are described.
  
  
  METHODS
  Patients must have IPSS lower-risk MDS with red blood cell (RBC) transfusion-dependent anemia and thrombocytopenia. Eligible patients are randomized 1:1 to receive 300 mg of CC-486 or placebo once daily for the first 21 days of 28-day treatment cycles. Disease status assessments occur at the end of cycle 6 and patients may continue to receive treatment unless there is evidence of progressive disease, lack of efficacy, or unacceptable toxicity. The primary endpoint is RBC transfusion independence for ≥ 84 days, assessed according to International Working Group 2006 criteria. Secondary endpoints include overall survival, hematologic response including platelet response and erythroid response, RBC transfusion independence for ≥ 56 days, duration of RBC transfusion independence, time to RBC transfusion independence, rate of acute myeloid leukemia (AML) progression, time to AML progression, clinically significant bleeding events, safety, health-related quality of life, and healthcare resource utilization.
  
  
  CONCLUSIONS
  This study will provide data on the efficacy and safety of CC-486 in the treatment of IPSS lower-risk MDS with poor prognosis due to the presence of both RBC transfusion-dependent anemia and thrombocytopenia. Positive results of the AZA-MDS-003 study may expand treatment options for patients with IPSS lower-risk MDS.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01566695, registered March 27, 2012.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Instituto Portugues de Oncologia Francisco Gentil, Lisbon, Portugal.
authors.forename: Antonio
authors.initials: A
authors.lastname: Almeida
authors.affiliation: Marien-Hospital Akademisches Lehrkrankenhaus, Dusseldorf, Germany.
authors.forename: Aristoteles
authors.initials: A
authors.lastname: Giagounidis
authors.affiliation: Medizinschen Fakultat Carl Gustav Carus der TU Dresden, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Hospital Clinico Universitario Virgen de la Victoria, Malaga, Spain.
authors.forename: Regina
authors.initials: R
authors.lastname: Garcia
authors.affiliation: Universita Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Voso
authors.affiliation: Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Larsen
authors.affiliation: Hospital Vall D'Hebron, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Valcarcel
authors.affiliation: Mount Sinai School of Medicine, New York, NY USA.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Silverman
authors.affiliation: Celgene Corporation, Overland Park, KS USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Skikne
authors.affiliation: Hematology, University of Florence, AOU Careggi, Florence, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Santini
keywords: Anemia; Azacitidine; CC-486; IPSS lower risk; MDS; Myelodysplastic syndromes; Red blood cell transfusion dependence; Thrombocytopenia