Purpose Napabucasin is a cancer stemness inhibitor that targets a number of oncogenic pathways, including signal transducer and activator of transcription 3 (STAT3). Phase 1/2 studies suggest tolerability and anti-tumor activity in various types of cancer; a Phase 3 study of napabucasin plus standard therapy in colorectal cancer is ongoing. This is a Phase 1 dose-escalation study in patients with advanced solid tumors, and the first study of napabucasin in Japanese patients. Methods Patients received napabucasin 480, 960, or 1440 mg daily in 28-day cycles until disease progression or intolerable toxicity. Primary objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and the pharmacokinetic (PK) profile of napabucasin. Blood samples were taken for PK analysis on Days 1, 2, 8, and 15 of Cycle 1, and Days 29 and 30 of Cycle 2. Secondary objectives were to assess napabucasin antitumor activity, and the relationship between biomarkers and antitumor activity. JapicCTI-No: JapicCTI-132152. Results Enrolled were 14 patients (480 mg [n = 3], 960 mg [n = 4], 1440 mg [n = 7]). One patient experienced a DLT (Grade 3, anorexia). MTD was 1440 mg/day. Most common drug-related adverse events were diarrhea (n = 9), nausea (n = 4), vomiting (n = 3), and anorexia (n = 3). Napabucasin showed a similar PK profile to previous studies and no abnormal accumulation was observed. Following treatment, two patients had stable disease; the remaining 12 had progressive disease. Conclusion Napabucasin was well-tolerated at doses up to 1440 mg/day in Japanese patients with advanced solid tumors; the PK profile was comparable to that reported previously.

SummaryMany clinical research studies evaluate a time‐to‐event outcome, illustrate survival functions, and conventionally report estimated hazard ratios to express the magnitude of the treatment effect when comparing between groups. However, it may not be straightforward to interpret the hazard ratio clinically and statistically when the proportional hazards assumption is invalid. In some recent papers published in clinical journals, the use of restricted mean survival time (RMST) or τ‐year mean survival time is discussed as one of the alternative summary measures for the time‐to‐event outcome. The RMST is defined as the expected value of time to event limited to a specific time point corresponding to the area under the survival curve up to the specific time point. This article summarizes the necessary information to conduct statistical analysis using the RMST, including the definition and statistical properties of the RMST, adjusted analysis methods, sample size calculation, information fraction for the RMST difference, and clinical and statistical meaning and interpretation. Additionally, we discuss how to set the specific time point to define the RMST from two main points of view. We also provide developed SAS codes to determine the sample size required to detect an expected RMST difference with appropriate power and reconstruct individual survival data to estimate an RMST reference value from a reported survival curve.

In 169 Japanese patients with type 2 diabetes mellitus with blood glucose levels that were inadequately controlled with diet and exercise therapy alone, or with diet and exercise therapy plus a sulfonylurea (SU) drug, we evaluated the safety and efficacy of global standard dose metformin given up to a maximum daily dose of 2250 mg for 54 weeks. The changes in HbA1c from baseline to the final evaluation visit were -1.32 ± 0.76% for metformin monotherapy and -1.29 ± 0.81% for metformin plus SU, both significantly lower than baseline. The incidences of adverse events and adverse drug reactions were 91.1% (154/169 patients) and 67.5% (114/169 patients), respectively. The most common adverse events were gastrointestinal symptoms, and most of the gastrointestinal symptoms were considered by investigators to be related to metformin treatment. An increased blood lactic acid level was observed in three subjects (1.8%); however, no clinical symptoms were reported, and there was no increase in mean lactic acid concentration throughout the evaluation period. Symptoms of hypoglycemia were reported in 16 patients, all receiving metformin plus SU, but none received metformin monotherapy. There was a decrease in mean body weight. Global standard dose metformin may be useful for maintaining good blood glucose control over the long term in the treatment of type 2 diabetes mellitus in Japanese patients.

Aim: To report results from the first phase I study of napabucasin plus paclitaxel in Japanese patients with pretreated unresectable/recurrent gastric cancer. Patients and Methods: Patients received napabucasin (480 mg bid) plus paclitaxel [80 mg/m 2 on days 3, 10 and 17 (cycles 1 and 2) and on days 1, 8 and 15 (cycle 3 and subsequent cycles)] until disease progression or unacceptable toxicity. Primary objectives were tolerability, safety and pharmacokinetics of napabucasin plus paclitaxel. Trial registration ID: JapicCTI-142420. Results: Six patients were enrolled. Paclitaxel had a minimal effect on napabucasin pharmacokinetics and median plasma paclitaxel concentrations were similar in combination and monotherapy. No dose-limiting toxicities were observed. There were no grade 4/5 adverse events. Partial response, stable disease and progressive disease were reported in two patients each. Conclusion: Napabucasin plus paclitaxel was well-tolerated in Japanese patients with gastric cancer.

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