The Food and Drug Administration (FDA) approved an oral combination of decitabine and cedazuridine (ASTX727) for adult patients with myelodysplastic syndromes (MDS) including the following:

• previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and
• intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

ASTX727 was investigated in two open-label, randomised, crossover trials.

Trial ASTX727-01-B (NCT02103478) included 80 adult patients with MDS (International Prognostic Scoring System [IPSS] Intermediate-1, Intermediate-2, or high-risk) or CMML and trial ASTX727-02 (NCT03306264) included 133 adult patients with MDS or CMML, including all French-American-British classification criteria and IPSS Intermediate-1, Intermediate-2, or high-risk prognostic scores.

In both trials, patients were randomised 1:1 to receive 35 mg decitabine and 100 mg cedazuridine orally in cycle 1 and decitabine 20 mg/m2 intravenously in cycle 2 or the reverse sequence.

Both ASTX727 and intravenous decitabine were administered once daily on days 1 through 5 of a 28-day cycle.

Starting with cycle 3, all patients received ASTX727 orally once daily on days 1 through 5 of each 28-day cycle until disease progression or unacceptable toxicity.

Both trials provided comparison of exposure and safety in the first two cycles between oral ASTX727 and IV decitabine and description of disease response with ASTX727.

Comparison of disease response between the ASTX727 and IV decitabine was not possible because all patients received ASTX727 starting from Cycle 3.

The 01-B trial demonstrated a complete response (CR) rate of 18% (95% CI: 10, 28) and median duration of CR was 8.7 months (range: 1.1, 18.2).

Among the 41 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 20 (49%) became independent of RBC and platelet transfusions during any consecutive 56-day post-baseline period.

Of the 39 patients who were independent of both RBC and platelet transfusions at baseline, 25 (64%) remained transfusion-independent during any consecutive 56-day post-baseline period.

The 02 trial demonstrated a geometric mean ratio of the 5-day cumulative decitabine AUC following 5 consecutive once daily doses of Inqovi compared to that of intravenous decitabine was 99% (90% CI: 93, 106).

Efficacy results demonstrated that 21% of patients achieved CR (95% CI: 15, 29) and median duration of CR was 7.5 months (range: 1.6, 17.5).

Among the 57 patients who were dependent on RBC and/or platelet transfusions at baseline, 30 (53%) became independent of RBC and platelet transfusions during any 56-day post-baseline period.

Of the 76 patients who were independent of both RBC and platelet transfusions at baseline, 63% remained transfusion-independent during any 56-day post-baseline period.

Most common adverse reactions (incidence ≥ 20%) to ASTX727 are fatigue, constipation, haemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhoea, rash, dizziness, febrile neutropenia, oedema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased.

The most common grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and haemoglobin decreased.

The overall safety profile of oral ASTX727 was similar to IV decitabine.

The recommended ASTX727 dose is 1 tablet (35 mg decitabine and 100 mg cedazuridine) taken orally on an empty stomach once daily on days 1 through 5 of each 28‑day cycle.

Source: The Food and Drug Administration (FDA)