13 May 2022 - - Top-line results from the ASCERTAIN phase 3 study evaluating oral decitabine and cedazuridine fixed-dose combination (ASTX727 or DEC-C) tablets versus IV decitabine in adults with AML who are not candidates to receive standard induction chemotherapy, US-based Astex Pharmaceuticals, Inc. said.

The study met its primary endpoint of decitabine exposure equivalence of five-day dosing between orally administered ASTX727 and intravenous decitabine as per the protocol analysis plan with a high degree of confidence.

Safety observations were similar to those observed with IV decitabine.

The full data will be presented on June 10 as part of EHA2022.

Astex plans to file a Marketing Authorization Application with the European Medicines Agency and similar applications in other countries where IV decitabine is indicated for the treatment of AML.

Based on the data from the ASCERTAIN clinical program, the oral decitabine and cedazuridine fixed-dose combination is also being investigated in combination with other agents in hematological malignancies.

The first of these studies is investigating the all-oral combination of decitabine and cedazuridine with venetoclax for the treatment of AML.

Oral decitabine and cedazuridine fixed-dose combination is approved as Inqovi in the US and Canada for the treatment of intermediate and high-risk myelodysplastic syndromes, including chronic myelomonocytic leukemia and is the only approved oral hypomethylating agent that has demonstrated equivalent exposure to its IV form.

Commercialization of Inqovi in the US and Canada for the above indication is conducted by Taiho Oncology, Inc., and by Taiho Pharma Canada, Inc., respectively.

Astex, Otsuka and Taiho are all members of the Otsuka group of companies.

The ASCERTAIN AML clinical trial was designed as a randomized crossover study comparing oral decitabine and cedazuridine (100mg) fixed-dose combination tablet given once daily for five days on a 28-day cycle to IV decitabine (20mg/m2) administered as a daily 1-hour infusion for five days on a 28-day cycle, in the first 2 cycles in AML patients who were unfit to receive intensive chemotherapy.

Patients continued to receive oral decitabine and cedazuridine from cycle 3 onwards.

The primary endpoint for the study was total five-day decitabine area-under-the-curve equivalence of oral decitabine and cedazuridine and IV decitabine.

ASTX727 is an orally administered, fixed dose combination of the approved anti-cancer DNA hypomethylating agent, decitabine, together with cedazuridine,2 an inhibitor of cytidine deaminase.

By inhibiting cytidine deaminase in the gut and the liver, ASTX727 is designed to allow for oral delivery of decitabine over five days in a given cycle to achieve comparable systemic exposure to IV decitabine administered over five days.

ASTX727 has been evaluated in a phase 1/2 pharmacokinetics-guided dose escalation and dose confirmation study, and a phase 3 exposure equivalence study in patients with MDS and CMML.

The phase 1 and phase 2 clinical study results have been published in Lancet Haematology and Blood, respectively, and the phase 3 results have been presented at the American Society of Hematology annual meeting in December 20196 and the International Congress on Myelodysplastic Syndromes in September 2021.

Astex is also expanding the evaluation of decitabine - cedazuridine combinations through a program of investigator-sponsored trials.

ASTX727 is an investigational compound and is not currently approved in any country other than the US, Canada, and Australia.

In the US, Inqovi (decitabine and cedazuridine) is indicated for treatment of adult patients with myelodysplastic syndromes, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.