KEY TAKEAWAYS
- The Phase 1/2 study assessed the efficacy of lower dose oral DEC/CED in LR-MDS pts.
- The study’s primary endpoints were RP2D based on safety and DLT. Secondary endpoints were TI, LFS, and OS.
- The study indicated that the LD-5Day regimen is well-tolerated and may be a preferable treatment option for LR-MDS.
Cedazuridine (CED), which inhibits cytidine deaminase (CDA), makes it possible for decitabine (DEC) to be administered orally. Research by Garcia-Manero et al. in 2020 showed that taking five daily doses of a fixed combination of 35 mg DEC and 100 mg CED achieved the same drug exposure levels as intravenous (IV) DEC at a dosage of 20 mg/m2 for five days. Additionally, Jabbour et al. 2017 found that shorter courses of IV DEC are effective for treating lower-risk myelodysplastic syndromes (LR-MDS).
In this Phase 1/2 clinical trial, the researchers aimed to investigate the efficacy of reduced dosages of oral DEC/CED in LR-MDS patients (pts). During the first phase, various 28-day regimens ranging from 5-20 mg DEC combined with 100 mg CED were studied. The main focus was identifying the recommended Phase 2 dose (RP2D) based on safety concerns and dose-limiting toxicity (DLT).
In the second phase, 81 pts were evenly divided to receive either the RP2D from Phase 1 or a standard dose for three days. Both phases considered similar efficacy and safety endpoints, including transfusion independence, leukemia-free survival (LFS), and overall survival (OS).
In Phase 1, 47 pts underwent treatment using five different combinations of DEC and CED. Dose-limiting toxicity (DLT), primarily in the form of myelosuppression, increased as treatment doses and duration went up. Hematologic improvement was observed in 30% (14 out of 47) of the pts. The 8-week red blood cell (RBC) transfusion independence rate stood at 33% (7 out of 21).
The median overall survival (mOS) was 31 months, and the median leukemia-free survival (mLFS) was 23 months. The recommended Phase 2 dose (RP2D) was established as 10 mg DEC combined with 100 mg CED for five days every 28 days (LD-5Day), based on both safety and efficacy metrics.
Phase 2 included mostly Intermediate-1 risk pts, with 48% having prior MDS treatment and 46% being RBC transfusion-dependent. About 80 subjects had completed a median of 4.5 treatment cycles, and roughly 10 proceeded to receive a transplant. Pharmacokinetic (PK) data revealed that LD-5Day had about half the exposure as the three-day standard dose regimen (SD-3Day). Adverse events were similar in terms of LD-5Day and SD-5Day, with myelosuppression being the most common grade 3 or higher adverse event. Neutrophil counts by cycle 8 were generally higher in the LD-5Day group compared to the SD-3Day group. Out of 8 reported deaths, only one occurred within 30 days and was in the SD-3Day group.
The study concluded that the LD-5Day regimen appears more tolerable and could be a better treatment option for LR-MDS, although longer-term efficacy comparisons with SD-3Day are still pending.
Source: https://clml-soho2023.elsevierdigitaledition.com/376/index.html
Clinical Trial: https://clinicaltrials.gov/study/NCT03502668
Garcia-Manero, G., Bachiashvili, K., Griffiths, E.A., Zeidan, A.M., Traer, E., Saini, L., Amin, H., Mohan, S., Lubbert, M., Maness-Harris, L., Foran, J., Selleslag, D., Xicoy, B., Pollyea, D.A., Sallman, D.A., Al-Kali, A., Berdeja, J.G., Al-Ali, H., Zhu, N.Y., Lopez, P.F., Santillana, G.S., Santini, V., Yimer, H., Cripe, L.D., Priego, V., Odenike, O., Heyrman, B., Ferreiras, D.V., Vachhni, P.J., Chan, W., Sano, Y., Mirakhur, B., Oganesian, A., Keer, H., Yacoub, A. Randomized Phase 1‑2 Study to Assess Safety and Efficacy of Low‑Dose (LD) Oral Decitabine/ Cedazuridine (ASTX727) in Lower‑Risk Myelodysplastic Syndromes (LR‑MDS) Patients: Interim Safety Analysis.
