A phase 2/3 trial of oral azacitidine (Oral-AZA) in patients (pts) with low- or intermediate-risk myelodysplastic syndromes (MDS).

person Guillermo Garcia-Manero MD Anderson Cancer Center, Houston, TX info_outline Guillermo Garcia-Manero, Valeria Santini, Pierre Fenaux, Takahiro Suzuki, Mikkael A. Sekeres, Jun He, Ronit Barkalifa, Carlos Enrique Vigil, Thomas Prebet, Rami S. Komrokji, Aristoteles Giagounidis

Authors person Guillermo Garcia-Manero MD Anderson Cancer Center, Houston, TX info_outline Guillermo Garcia-Manero, Valeria Santini, Pierre Fenaux, Takahiro Suzuki, Mikkael A. Sekeres, Jun He, Ronit Barkalifa, Carlos Enrique Vigil, Thomas Prebet, Rami S. Komrokji, Aristoteles Giagounidis Organizations MD Anderson Cancer Center, Houston, TX, MDS Unit, Azienda Ospedaliero Universitaria (AOU) Careggi, University of Florence, Florence, Italy, Service d’Hématologie Séniors, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris and Université Paris 7, Paris, France, Kitasato University Hospital School of Medicine, Sagamihara-Shi Minami-Ku, Japan, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, Bristol Myers Squibb, Summit, NJ, Bristol Myers Squibb, Madison, NJ, Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, Marien Hospital Düsseldorf, Düsseldorf, Germany Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Bristol-Myers Squibb Background: MDS, a heterogeneous group of clonal myeloid malignancies, are characterized by ineffective hematopoiesis and peripheral blood cytopenias, which can often lead to red blood cell (RBC) transfusion dependence and a risk of progression to acute myeloid leukemia (AML). In early clinical trials, 14- and 21-day (d) dosing regimens of the hypomethylating agent Oral-AZA were well tolerated and induced hematologic improvement (HI) in pts with lower-risk (LR) MDS. In a phase 3 trial, Oral-AZA 300 mg QD for 21d per 28d cycle significantly improved the rate of RBC transfusion independence (TI) and induced durable HI versus placebo (PBO) in patients (pts) with LR-MDS with RBC-transfusion-dependent anemia and thrombocytopenia (Garcia-Manero, et al. J Clin Oncol 2021). Grade 3/4 cytopenias were common in the Oral-AZA arm. Given the substantial clinical benefit of Oral-AZA observed in this setting, a new phase 2/3 trial is ongoing to further evaluate the 14d Oral-AZA regimen in pts with International Prognostic Scoring System Revised (IPSS-R)-defined low or intermediate (int)-risk MDS. Methods: This ongoing, multicenter, randomized, phase 2/3 trial (CA055-026; NCT05469737) will evaluate the safety and efficacy of Oral-AZA in pts with IPSS-R low- or int-risk MDS. Key eligibility criteria include ≥ 18 years, ECOG performance status score ≤ 2, and ≥ 1 cytopenia (anemia, thrombocytopenia, or neutropenia). Pts with an absolute neutrophil count < 0.5 × 10 9 /L within a week of randomization will be excluded. Informed consent will be obtained from all participants. The phase 2 portion will enroll and randomize ~42 pts 1:1 to receive open-label Oral-AZA 200 or 300 mg QD for 14d per 28d cycle, plus best supportive care (BSC), to determine the recommended phase 3 dose (RP3D). The primary endpoints are safety and rate of complete remission (CR) within 6 Tx cycles. The secondary endpoints are overall response rate (ORR), and packed (p) RBC-TI and platelet-TI sustained for 84d in ≤ 6 Tx cycles. ORR includes CR, partial remission (PR), marrow CR, and any HI, per IWG 2006 response criteria. In the phase 3 portion, ~188 additional pts will be enrolled and randomized 1:1 to Oral-AZA at the RP3D or PBO for 14d per 28d cycle, plus BSC. Pts in the PBO arm with stable disease at Tx cycle 6 disease assessment or with documented disease progression after ≥ 3 Tx cycles will have the option to cross over into the Oral-AZA arm. The primary endpoint is CR in ≤ 6 Tx cycles. The key secondary endpoint is 84d pRBC-TI. Other secondary endpoints include those described in the phase 2 portion plus overall survival, event-free survival, time to AML progression, iron parameters, health-related quality of life, healthcare resource utilization, and safety parameters. Pts who benefit from Oral-AZA in phase 2 or 3 may continue to receive Tx in an extension phase. Trial recruitment began in December 2022 and is ongoing. Clinical trial information: NCT05469737.

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