Oral formulation of bendamustine hydrochloride for patients with advanced solid tumors; a phase 1 study

To determine the maximum tolerated dose (MTD) and recommended dose (RD) of orally-administered bendamustine in Japanese patients with advanced solid tumors. The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3 + 3 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21 days every 3 weeks as one cycle. The total dose per cycle was increased from 175 to 840 mg/m(2). Eighteen patients were enrolled in this study. DLT occurred in one of six patients at 75 mg/m(2)/day × 7 days, and one of three patients at 37.5 mg/m(2)/day × 14 days and 25 mg/m(2)/day × 21 days. However, the delayed recovery from a decrease in neutrophil or platelet count hampered the start of subsequent treatment cycles, and the trend was more prominent at 37.5 mg/m(2)/day × 14 days and 25 mg/m(2)/day × 21 days than in 75 mg/m(2)/day × 7 days. MTD was determined as 75 mg/m(2)/day × 7 days to allow acceptable hematologic recovery. The pharmacokinetics of orally-administered bendamustine were generally dose-dependent; however, the inter-individual variability is relatively large. The major adverse events were hematologic toxicities; gastrointestinal disorders were generally mild. Adverse drug reactions did not lead to the discontinuation of the drug. A partial response was observed in two of six patients (prostatic small cell carcinoma and thymic carcinoma) at 75 mg/m(2)/day × 7 days. The RD and optimal dosing schedule of orally-administered bendamustine was 75 mg/m(2) once daily for 7 days every 3 weeks for the treatment of advanced solid tumors. (Trial registration number ClinicalTrials.gov NCT03604679. Registration date July 27, 2018). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10637-022-01307-6.