Combination of Decitabine and Cedazuridine received FDA approval to treat Myelodysplastic Syndromes

For adult patients having myelodysplastic syndromes (MDS), the United States Food and Drug Administration (US FDA) approved an oral combination of decitabine (nucleoside metabolic inhibitor) and cedazuridine (cytidine deaminase inhibitor).

This combination can also be utilized for:

(a) Previously untreated and treated, secondary, and de novo MDS with the following French-American-British subtypes (refractory anemia with excess blasts, refractory anemia, refractory anemia with ringed sideroblasts and CMML; chronic myelomonocytic leukemia)

(b) Intermediate-1, intermediate-2, and elevated-risk IPSS (International Prognostic Scoring System) groups

The combination was evaluated in two randomized, open-label, crossover studies:

(1) Trial ASTX727-02 enrolled 133 adults having MDS or CMML, including all IPSS and French-American-British classification criteria Intermediate-1, Intermediate-2, or high-risk prognostic scores. (2) Trial ASTX727-01-B enrolled 80 adults having MDS (IPSS Intermediate-1, high-risk, or Intermediate-2) or CMML

In 01-B and 02 trials, the enrolled subjects were randomly allocated to either combination of decitabine 35 mg and cedazuridine 100 mg orally (in cycle 1) and decitabine 20 mg/m2 intravenously (IV) (in cycle 2) or the reverse sequence. On days one through five of a 28-day cycle, both IV decitabine and combination of decitabine and cedazuridine were administered once daily.

Initiating with cycle 3, on days one through five of each 28-day cycle, all individuals were treated with a combination of decitabine and cedazuridine orally once daily until unacceptable toxicity or progression of the disease.

Both studies yielded a comparative evaluation of safety and exposure in the initial two cycles between the oral combination of decitabine and cedazuridine and IV decitabine, and also the elucidation of disease response with the oral combination. Since all individuals were treated with a combination of decitabine and cedazuridine beginning from cycle 3, the comparative assessment of disease response between IV decitabine and I combination of decitabine and cedazuridine was not feasible.

The CR (complete response) rate and the median duration of CR of 01-B and 02 studies are shown in the following table:

A geometric mean ratio of the five-day cumulative decitabine AUC (area under the curve) after five consecutive once-daily doses of combination compared to IV decitabine was found to be 99% in the 02 clinical trial.

Among the participants who were dependent on platelet transfusions and/or RBC (red blood cell) at baseline, the number of participants becoming independent of platelet transfusions and RBC during any consecutive 56-day post-baseline period in 01-B and 02 clinical trials is depicted below:

Of the participants who were independent of both platelet transfusions and RBC at the initial baseline, the number of participants remaining transfusion-independent during any consecutive 56-day post-baseline period in 01-B and 02 clinical trials is depicted below:

The effective dose of this combination is 1 tablet (cedazuridine 100 mg and decitabine 35 mg) given orally on an empty stomach on days 1-5 of each 28-day cycle.

Constipation, fatigue, hemorrhage, mucositis, myalgia, arthralgia, dyspnoea, nausea, diarrhea, dizziness, rash, febrile neutropenia, headache, oedema, cough, upper respiratory tract infection, decreased appetite, pneumonia, and increased transaminase are the most common adverse reactions (incidence ≥ 20%) to the combination of decitabine and cedazuridine. A decline in platelet count, leukocytes, neutrophil count, and hemoglobin were the most frequently noted grade 3 or 4 laboratory abnormalities (≥ 50%).

The combination of demonstrated a similar safety profile when compared to IV decitabine.
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