ABSTRACT
PURPOSE: This multicenter phase II basket trial investigated the efficacy, safety and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion. PATIENTS AND METHODS: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2) or other histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events. RESULTS: Between March 22, 2019 and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, four in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted and the trial was terminated. Three of 58 evaluable patients had partial responses, representing an ORR of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events. CONCLUSIONS: Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors.
ABSTRACT
Extracellular fluid (ECF) is associated with blood pressure, but reports on the status of the ECF volume in hypertension have been inconsistent. The aim of this study was to assess the ECF volume status in hypertensives with regard to body size in a large cohort. We performed a single-center case-control observation study for patients who visited the outpatient hypertension clinic and health examination center. For all eligible participants, we examined the body composition, including fluid compartments, using a noninvasive bioimpedance analysis. Of 2934 subjects (women 1365, 57.5 ± 12.2 years), 1166 subjects were normotensive and 1768 subjects were hypertensive. The ECF volume was larger in female hypertensives than in normotensives but was not different between the male groups. However, the relative ECF, defined as the ratio of ECF to body mass index (BMI), was significantly lower in hypertensives of both genders (P<0.001). ECF revealed an almost twofold stronger correlation with the fat-free mass (FFM) (r=0.9 in both genders) than with the fat mass, BMI or waist circumference and a negative correlation with age. In contrast, the relative ECF was positively correlated only with the FFM and inversely correlated with the other factors. In the multivariate logistic regression analysis, an increase of 1 s.d. in the relative ECF decreased the relative risk of hypertension by 30% in women (odds ratio (OR), 0.70; 95% confidence interval (CI), 0.56-0.87) and by 28% in men (OR, 0.72; 95% CI, 0.60-0.86), but the ECF was not independently associated with hypertension in either gender.The ECF with regard to the body size was contracted in hypertensives and independently associated with hypertension, whereas the absolute ECF volume was not.
