Investigational new drugs · 2011
Phase I open-label study of cediranib, an oral inhibitor of VEGF signalling, in combination with the oral Src inhibitor saracatinib in patients with advanced solid tumours.
Клиническое исследование I фазыСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Trarbach Tanja, Schultheis Beate, Gauler Thomas C, Schneider Vesile, Strumberg Dirk, Eberhardt Wilfried E E, Le Scouiller Stephanie, Marotti Marcelo, Brown Kathryn H, Drevs Joachim
Аннотация
UNLABELLED: Combining different targeted anticancer agents may improve clinical outcomes. This Phase I study investigated cediranib, an oral inhibitor of vascular endothelial growth factor signalling in combination with saracatinib, an oral Src inhibitor. The primary endpoint was safety/tolerability. Secondary assessments included pharmacokinetics and preliminary efficacy.
PATIENTS AND METHODS: Patients with advanced solid tumours received cediranib 20, 30 or 45 mg/day for 7 days followed by daily treatment with cediranib at the same dose plus saracatinib 175 mg/day.
RESULTS: Thirty-nine patients received cediranib (20 mg, n = 6; 30 mg, n = 6; 45 mg, n = 27 [n = 20 in cohort expansion]) plus saracatinib. In the cediranib 45 mg cohort, 59% of patients required dose reduction/pause compared with 33% in each of the other two cohorts. There was one dose-limiting toxicity (hypertension; 45 mg cohort). The most common adverse events were hypertension (67%), diarrhoea (62%), dysphonia (46%) and fatigue (39%). There was no evidence of a clinically significant effect of saracatinib on cediranib pharmacokinetics and vice versa. 22/35 evaluable patients had a best response of stable disease.
CONCLUSIONS: All cediranib doses were tolerated; however, in patients with advanced solid tumours, for combination with saracatinib 175 mg/day, cediranib 20 or 30 mg/day was more sustainable than 45 mg/day.
PATIENTS AND METHODS: Patients with advanced solid tumours received cediranib 20, 30 or 45 mg/day for 7 days followed by daily treatment with cediranib at the same dose plus saracatinib 175 mg/day.
RESULTS: Thirty-nine patients received cediranib (20 mg, n = 6; 30 mg, n = 6; 45 mg, n = 27 [n = 20 in cohort expansion]) plus saracatinib. In the cediranib 45 mg cohort, 59% of patients required dose reduction/pause compared with 33% in each of the other two cohorts. There was one dose-limiting toxicity (hypertension; 45 mg cohort). The most common adverse events were hypertension (67%), diarrhoea (62%), dysphonia (46%) and fatigue (39%). There was no evidence of a clinically significant effect of saracatinib on cediranib pharmacokinetics and vice versa. 22/35 evaluable patients had a best response of stable disease.
CONCLUSIONS: All cediranib doses were tolerated; however, in patients with advanced solid tumours, for combination with saracatinib 175 mg/day, cediranib 20 or 30 mg/day was more sustainable than 45 mg/day.