Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes

Abstract

PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion–dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.

Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

“…Alternative treatment may overcome adaptive responses due to repetitive use of HMA. Recent clinical trials have also explored novel HMAs along with combination therapy as potential strategies to overcome HMA resistance [ 195 ].…”

“…Its impressive activity is first elucidated in a multicenter phase I/II study among MDS and CMML patients, where non-inferiority of ASTX727 towards IV DEC is established, along with a CR rate of 18% and transfusion independence rate of 49% [ 201 , 202 ]. In the randomized phase III ASCERTAIN study among MDS patients, comparable demethylation activity and safety profiles between ASTX727 and IV DEC were demonstrated [ 195 ]. These satisfactory results have prompted FDA-approval of ASTX727 for previously treated and untreated, de novo and secondary MDS with specific FAB subtypes (RA, MDS-RARS, MDS-RAEB, and CMML) and IPSS scores (intermediate-1, intermediate-2, and high-risk) in 2020.…”

“…The most frequent grade 3-4 adverse events were neutropenia, anemia, and gastrointestinal disturbances [194]. In a placebo-controlled randomized phase III trial, CC-486 significantly enhanced red cells and platelet improvement rates at the cost of increased incidence of adverse events compared to placebo (90% vs. 73%) [195]. In spite of the higher infection-related mortality rate in the CC-486 arm in the first 56 days, the overall mortality rates remained similar between the two arms [196].…”

DNA Methylation and Intra-Clonal Heterogeneity: The Chronic Myeloid Leukemia Model

“…However, the myelosuppression induced by these drugs and the constraints related to injectable forms remain an ethical obstacle to the implementation of a clinical research protocol in patients with CP-CML because of the benefit/risk balance and the difficulty to formally identify patients with CML that will be resistant or less sensitive to TKIs. New drugs or dosage forms, especially oral ones, which have already proven their efficacy in AML and myelodysplastic syndromes [ 118 , 119 , 120 ] could be an interesting alternative.…”

Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial

“…Injectable azacitidine has been shown to prolong disease-free survival (DFS)—but not OS—as maintenance therapy in patients ≥ 60 years of age with AML in remission after IC [ 12 ]. Oral azacitidine (formerly CC-486) has been evaluated in patients with hematologic malignancies in multiple clinical trials [ 13 – 19 ]. Oral administration allows for extended dosing schedules (> 7 days per cycle) to sustain the therapeutic activity of azacitidine across the entire treatment cycle.…”