Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer
Mené sur des patients atteints d’une tumeur solide de stade avancé, puis validé sur 82 autres patients atteints d’un cancer du rein, de l’endomètre ou de la vessie, cet essai de phase I évalue la dose maximale tolérée du sapanisertib (un inhibiteur de mTORC1/2) et analyse ses caractéristiques pharmacocinétiques et pharmacodynamiques
Background : This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods : Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD?×?3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD?×?5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5?mg QD (39 patients), 40?mg QW (26 patients) or 30?mg QW (17 patients). Results : Maximum tolerated doses of sapanisertib were 6?mg QD, 40?mg QW, 9?mg QD?×?3dQW and 7?mg QD?×?5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD?×?3dQW/QD?×?5dQW); expansion phase doses of 5?mg QD and 30?mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions : Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.