FDA approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes

On July 7, 2020, the Food and Drug Administration approved an oral combination of decitabine and cedazuridine (INQOVI, Astex Pharmaceuticals, Inc.) 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 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.

Inqovi was investigated in two open-label, randomized, 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 randomized 1:1 to receive Inqovi (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 Inqovi and intravenous decitabine were administered once daily on days 1 through 5 of a 28-day cycle. Starting with cycle 3, all patients received Inqovi 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 Inqovi and IV decitabine and description of disease response with Inqovi. Comparison of disease response between the Inqovi and IV decitabine was not possible because all patients received Inqovi 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 Inqovi are fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, 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 hemoglobin decreased. The overall safety profile of oral Inqovi was similar to IV decitabine.

The recommended Inqovi 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.

View full prescribing information for INQOVI.

This review used the Oncology Center of Excellence Assessment Aid as well as the Office of Pharmaceutical Quality’s Assessment Aid for quality review. These are voluntary submissions from the applicant to facilitate the FDA’s assessment.

The FDA collaborated with international agency counterparts on the review of this application as part of Project Orbis.

This application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

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