Oral azacitidine and cedazuridine met the end point of total cycle azacitidine exposure vs subcutaneous azacitidine in MDS or CMML.
The oral combination of azacitidine and cedazuridine (ASTX030) met the primary end point of total cycle azacitidine area under the curve from 0 to 24 hours (AUC0-24) exposure, measured as the ratio of exposure following oral azacitidine and cedazuridine compared with subcutaneous azacitidine, in adult patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML), according to topline findings from the phase 3 portion of the AZTOUND trial (NCT04256317).1
The announcement from Taiho Oncology and Taiho Pharmaceutical did not disclose the exposure ratio or other pharmacokinetic values, and no efficacy data were reported at this time.
"The positive topline results of the phase 3 AZTOUND trial support the potential of an all-oral regimen of azacitidine and cedazuridine to meet the treatment needs of patients with MDS and CMML without the time and treatment burden associated with parenteral therapies," Harold Keer, MD, PhD, chief medical officer of Taiho Oncology, stated in a news release. "We look forward to pursuing regulatory approval of oral azacitidine and cedazuridine to potentially bring this treatment option to patients."
Azacitidine is a DNA methyltransferase inhibitor, and cedazuridine is a cytidine deaminase inhibitor added to help azacitidine stay active in the body without being degraded; the combination is investigational and has not been approved by any health authority.
AZTOUND is a multiphase study composed of phase 1 to 3 monotherapy portions in patients with myeloid neoplasms, as well as phase 1 and 2 combination therapy portions evaluating ASTX030 plus venetoclax (Venclexta) in patients with treatment-naive acute myeloid leukemia (AML); the overall study has a planned enrollment of 316 patients.1,2
The phase 3 monotherapy portion is a randomized, open-label crossover study comparing the final fixed dose of oral ASTX030 with subcutaneous azacitidine, and it enrolled 88 adult patients with MDS or CMML.1,2
Patients in the phase 3 portion were required to have confirmed MDS or CMML and be candidates to receive and benefit from single-agent azacitidine, including French-American-British subtypes of refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and CMML, or intermediate-2– or high-risk MDS per the International Prognostic Scoring System.2
Other key inclusion criteria included an ECOG performance status of 0 or 1, adequate organ function, a projected life expectancy of at least 12 weeks, and the ability to swallow the required number of tablets or capsules within 10 minutes and tolerate 4 hours of fasting.
Patients were excluded if they had received more than 1 cycle of decitabine, azacitidine, or guadecitabine; had CMML or other MDS/myeloproliferative neoplasms with clinical extramedullary disease, including palpable hepatomegaly or splenomegaly; or could not discontinue drugs that delay gastric emptying, such as GLP-1 and/or GIP agonists, during cycles 1 and 2.
The primary end point was the ratio of azacitidine total cycle AUC0-24 exposures after oral ASTX030 over subcutaneous azacitidine. Secondary end points for the monotherapy portions include incidence of treatment-emergent adverse events; change in DNA methylation, assessed as LINE-1 demethylation compared between oral ASTX030 and subcutaneous azacitidine in cycles 1 and 2; best complete response rate; AML-free survival; duration of response; overall survival; time to response; red blood cell and platelet transfusion independence; and additional pharmacokinetic parameters, including AUC, maximum plasma concentration, and time to maximum concentration of azacitidine, cedazuridine, and cedazuridine-epimer.
The safety profile of oral azacitidine and cedazuridine was consistent with that of parenteral azacitidine, according to the news release.1 Specific adverse effect rates were not reported.
Based on these results, Taiho Oncology intends to submit a new drug application to the FDA seeking approval of azacitidine and cedazuridine as an oral treatment regimen for adults with MDS or CMML. The results from AZTOUND will be submitted for presentation at an international medical conference.
"We believe the positive topline results of the AZTOUND phase 3 trial mark a key milestone in our collective efforts to develop a portfolio of novel treatments that improve clinical outcomes and quality of life for people with hematological malignancies," Fabio Benedetti, MD, global chief medical officer of Taiho Pharmaceutical, added in a news release. "We are grateful to the patients, caregivers, and investigators participating in the AZTOUND trial and remain committed to advancing azacitidine and cedazuridine for patients with MDS and CMML."
