Study design
toxicity, diarrhea, anemia, nausea, vomiting
ADVERSE EVENTS, MAY, ANEMIA
This study (NCT03604679) was conducted from May 16, 2018 to May 12, 2020 in Japan as a two-center, open-label, standard 3 + 3 dose escalation study, according to Good Clinical Practice, the Declaration of Helsinki, and other applicable regulations. A 3-week treatment period was considered as one cycle, and the maximum tolerated dose (MTD) and RD were assessed in Cohort 1 (once daily for 7 days), 2 (once daily for 14 days), and 3 (once daily for 21 days). Patient enrollment began with Cohort 1-Level 1 and was increased using a 3 + 3 design based on the dose-limiting toxicity (DLT). The starting dose was determined to be 25 mg/mDose escalation schedule of orally-administered bendamustine per cohort and level. Thick frame indicates the evaluated dosage, and gray highlight indicates the unexamined dosage at each level in each cohort; MTD, maximum tolerated dose. *Total dose of bendamustine per cycle (3-week schedule)Three to six patients were enrolled at each level in each cohort, starting with Cohort 1-Level 1 (25 mg/mThe daily doses at each level in each cohort are shown in Fig. DLT was defined as the following adverse events (AEs) for which a causal relationship to the study drug could not be ruled out: 1) Grade 4 neutrophil count decrease, lasting for more than 8 days; 2) FN; 3) grade ≥ 3 platelet count decrease, requiring platelet transfusion; 4) grade ≥ 3 anemia requiring red blood cell transfusion; 5) Grade 4 platelet count decrease; 6) Grade ≥ 3 non-hematologic toxicity except in grade ≥ 3 nausea, vomiting, and diarrhea controlled with appropriate supportive care or grade ≥ 3 abnormalities in laboratory test results controlled with appropriate supportive care or without clinically significant symptoms; and 7) unresolved hematologic toxicity (platelet count < 75,000/μL, ANC < 1000/μL) or bendamustine-related non-hematologic toxicity that prevented starting of the next cycle within 8 days. DLT evaluation was performed only during cycle 1. If AEs equivalent to DLT were observed even outside the evaluation period, the decision of DLT was left to the Data and Safety Monitoring Board (DSMB).