Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours

Abstract

Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m À2 on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33 -69) were entered; 11 had prior taxane therapy for breast (n ¼ 5), ovarian (n ¼ 3), and vaginal cancer (n ¼ 1) or angiosarcoma (n ¼ 2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m À2 , warranting further clinical investigation.

18F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

“…Among the downstream effectors of AKT is the mammalian target of rapamycin (mTOR) (3), which is inhibited by several molecules including rapamycin, temsirolimus (CCI-779; Wyeth) (4,5), and everolimus (RAD001; Novartis) (6). Everolimus has been shown to inhibit human ovarian cancer cell proliferation and to enhance the effect of cisplatin in vivo in an ovarian cancer xenograft model (7).…”

Selective Inhibition of Kras Signaling by Combination of Low Dose Rapamycin and Paclitaxel in Vivo

“…Использование комбинации PAC и ингибиторов сигнального каскада PI3K/AKT (RAP и BEZ235) более эффективно тормо-зило рост клеток рака толстой кишки HCT-116 и HT-29, чем каждый из препаратов в отдельности [20]. В ряде клинических испытаний также показан синергический ингибирующий эффект рапалогов и PAC на рост со-лидных опухолей, рака эндомет рия и молочной железы [21,22].…”

Active TGF-β signaling and decreased expression of PTEN separates angiosarcoma of bone from its soft tissue counterpart

“…Beuvinck et al demonstrated in human tumor xenografts that everolimus inhibits angiogenesis by preventing the proliferation of endothelial cells. 63 So far, there is only one report demonstrating the anti-proliferative effect of rapamycin in angiosarcoma cell lines. 64 In addition, new drugs such as pure PI3K inhibitors, dual PI3K-mTOR inhibitors, Akt inhibitors and mTOR kinase inhibitors are evolving and passing through the early phases of clinical development.…”