Study design and treatment
toxicity, lymphomas, AML, hematologic malignancies
MYELODYSPLASTIC SYNDROME, SOLID TUMORS, AML, HEMATOLOGIC MALIGNANCIES, LYMPHOMAS
This phase I, open-label, and dose-escalation study conducted at eight centers in Japan recruited patients with R/R AML. Four fixed-dose milademetan schedules were planned (Supplementary Fig. 1A). Increases in the milademetan dose were guided by the modified continual reassessment method (mCRM), with a planned maximum dose of 160 mg/day (Supplementary Fig. 1B). Each cohort (90, 120, and 160 mg) consisted of three to six patients. The first cycle was defined as the dose-limiting toxicity (DLT) evaluation period where patients required hospitalization. The number of treatment cycles was not specified, and the study treatment for each patient was continued unless the discontinuation criteria were met.A phase I study conducted in the USA (NCT02319369) administered oral milademetan once daily for 14 days, followed by 14 days of rest in a 28-day cycle (QD 14/28-day schedule, data not published), with other treatment schedules for hematologic malignancies like R/R AML and high-risk myelodysplastic syndrome. The maximum tolerated dose (MTD) was 160 mg, while it was 90 mg on a QD 21/28-day schedule for the Japanese phase I study (Japic CTI-142693) in patients with solid tumors or lymphomas [In this study, we only assessed the patients with schedule A‒milademetan was administered once daily on days 1–14 followed by a 14-day rest in a 28-day cycle.