Paul Scigalla

Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With Cancer

PURPOSEnTo establish the safety, pharmacokinetics, and recommended dose of sunitinib, a novel oral multitargeting tyrosine kinase inhibitor with antiangiogenic and antitumor properties, in patients with advanced malignancies.nnnPATIENTS AND METHODSnSunitinib was given orally for 4 weeks every 6 weeks.nnnRESULTSnTwenty-eight patients received doses ranging from 15 to 59 mg/m2 (ranging from 50 mg every other day to 150 mg/d). Dose-limiting toxicities reported at the maximum-tolerated doses > or = 75 mg/d were reversible grade 3 fatigue, grade 3 hypertension, and grade 2 bullous skin toxicity. Therefore, the recommended dose was 50 mg/d. At this dose, the main adverse effects were sore mouth, edema, and thrombocytopenia. Hair discoloration and yellow coloration of the skin were observed at doses > or = 50 mg/d. Pharmacokinetic data indicate that potentially active target plasma concentrations > or = 50 ng/mL can be achieved with moderate interpatient variability and a long half-life compatible with a single daily dosing. Six objective responses were observed in three renal cell carcinomas, one neuroendocrine tumor, one stromal tumor, and one unknown primary adenocarcinoma patient. At higher doses (> or = 75 mg/d), tumor responses were often associated with reduced intratumoral vascularization and central tumor necrosis, eventually resulting in organ perforation or fistula.nnnCONCLUSIONnAt the dose of 50 mg/d (4 weeks on, 2 weeks off), sunitinib displays manageable toxicity. Antitumor activity supports further studies in patients with renal cell carcinoma, gastrointestinal, neuroendocrine, and stromal tumors. Future studies may consider including prospective imaging techniques such as high frequency ultrasound to monitor tumor density.

Treatment of von Hippel-Lindau retinal hemangioblastoma by the vascular endothelial growth factor receptor inhibitor SU5416 is more effective for associated macular edema than for hemangioblastomas.

PURPOSEnTo test the efficacy of the novel vascular endothelial growth factor (VEGF) receptor inhibitor SU5416, in a case of refractory von Hippel-Lindau (VHL) retinal hemangioblastoma (RHB).nnnDESIGNnInterventional case report.nnnMETHODSnPatient included in a multicenter phase II trial. A 30-year-old woman presenting with VHL disease and multiple RHB on her only eye, refractory to conventional treatments, had decreased visual acuity due to cystoid macular edema (CME). SU5416 was administered intravenously for 7 months. Best-corrected visual acuity (BCVA) and macular thickness were measured by optical coherence tomography.nnnRESULTSnUnder treatment, the size of the RHB did not change, but CME improved significantly. Best-corrected visual acuity rose from 20/40 to 20/25. However, CME recurred after the end of the treatment.nnnCONCLUSIONnThe VEGF receptor inhibitor SU5416 failed to reduce the size of RHB but was very effective for the associated CME.

Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naive advanced or metastatic esophagogastric cancer

BackgroundThis phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS).MethodsPatients aged ≥18xa0years with advanced or metastatic solid tumors were enrolled in a 3xa0+xa03 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50xa0mg/m2 followed by oxaliplatin 130xa0mg/m2 (maximum 8 cycles) and then S-1 [20xa0mg/m2 (cohort 1) or 25xa0mg/m2 (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2–14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer.ResultsDLT was reported for two of the five patients in cohort 2, defining 20xa0mg/m2 twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25xa0mg/m2 twice daily; no DLTs were reported; median overall survival was 13.1xa0months. Of the 11 evaluable patients, three (27xa0%) had partial responses and seven (64xa0%) had stable disease. The safety profile was in line with expectations.ConclusionsThe promising activity of EOS (S-1 dose level, 25xa0mg/m2 twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.