Discussion
nausea, DLTs, AML, vomiting, decreased appetite, heterogenous R/R
AML, DYSFUNCTION
This is the first report to evaluate the safety and tolerability of milademetan monotherapy administered in multiple doses for R/R AML patients. Of the 14 enrolled patients, 14, 12, and 11 were included in the safety, efficacy, and MTD analysis sets, respectively. The most common TEAEs were decreased appetite (64.3%) and nausea (42.9%). No dose-dependent increase was observed in the frequency of TEAEs that were grade ≥ 3, serious, or led to dose reduction/treatment interruption. No DLTs were noted during the DLT evaluation period (cycle 1), and the MTD could not be determined, thus, recommended dose was defined as 160 mg in this study (QD 14/28-day schedule).The safety results of this study demonstrated that milademetan was well tolerated up to 160 mg in the QD 14/28-day schedule without any new safety concerns. Gastrointestinal symptoms (e.g., decreased appetite, nausea, and vomiting) are common TEAEs with milademetan as well as other MDM2 inhibitors. In addition, the drug’s safety profile observed in this study is comparable with that of other MDM2 inhibitors [The None of the 12 patients in the efficacy analysis set had CR, CRh, CRi, or PR at 90, 120, or 160 mg doses of milademetan. MLFS and SD were observed in two (16.7%) and one (8.3%) patient, respectively, and their Other phase I studies of milademetan included combination therapies with azacytidine and quizartinib for R/R AML (NCT02319369) [Previous reports in AML patients revealed that p53 pathway dysfunction is common regardless of p53 mutation status. Therefore, MDM2 could be a therapeutic target [This study had some limitations. This is a small-scale (only three to six patients in each cohort), open-label phase I study with an ethnically homogeneous population, hence it is not possible to generalize the results to more large and heterogenous R/R AML groups. Insufficient follow-up period to assess long-term safety, response duration, or survival are other limitations. In addition, MDM2 status was not defined as an eligibility criterion in this study because no robust evidence was noted to indicate whether MDM2 status is a suitable predictive biomarker when this study began. Therefore, future clinical trials are needed to comprehensively investigate the efficacy and safety of milademetan.In conclusion, milademetan was generally safe and well tolerated up to 160 mg in the QD 14/28-day schedule in Japanese patients with R/R AML. MTD was not reached at up to 160 mg with the QD 14/28 schedule in this study. The PK parameters, including 