Regorafenib plus Vincristine and Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors: An Innovative Therapy for Children with Cancer Study.

PURPOSE: This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan. PATIENTS AND METHODS: Patients aged 6 months to <18 years with relapsed/refractory solid malignancies [≥50% with rhabdomyosarcoma (RMS)] received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8, and irinotecan 50 mg/m2 on days 1-5 (21-day cycle). Adverse events (AE) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model. RESULTS: We enrolled 21 patients [median age, 10 years; 12, RMS; 5, Ewing sarcoma (EWS)]. The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2 of 2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate [complete response (CR)/partial response/stable disease/non-CR/non-progressive disease] was 86%. Median progression-free survival was 7.0 months [95% confidence interval (CI), 2.9-14.8] and median overall survival was 8.7 months (95% CI, 5.5-16.3). When combined with VI, regorafenib PK was similar to single-agent PK in children and adults (treated with regorafenib 160 mg/day). CONCLUSIONS: Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (ClinicalTrials.gov NCT02085148).

Age and volume dependent normal frequency volume charts for healthy males.

PURPOSE: We report age and voided volume stratified normal values for voiding diary parameters, including urine production, in a uniform, nonreferred population of 935 healthy male volunteers. MATERIALS AND METHODS: A total of 935 volunteers kept a 3-day voiding diary and also recorded the time of going to bed and getting up. Additionally, prostate volume was measured using transabdominal ultrasound and the maximum free flow rate was measured with a rotating disc flowmeter. From the diaries we calculated median voided volume and the mean number of voids during the day and night. We also calculated mean urine production in ml per hour during the day and night by assuming constant production between voids. RESULTS: Volunteers voided a median volume of 220 ml 6 times daily and 0.5 times nightly. They produced 83 ml urine per hour during the day and 48 ml per hour during the night. The median maximum flow rate was 16 ml per second and median prostate volume was 31 ml. All diary parameters, free flow rate and prostate volume depended significantly on International Prostate Symptom Score. However, all parameters except urine production during the day depended significantly on age and all except prostate volume depended significantly on voided volume. CONCLUSIONS: Values in a subgroup of 788 volunteers with an International Prostate Symptom Score of 10 or less may be considered normal for male voiding diary parameters. Age and voided volume stratified normal values were also derived.