Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors

Abstract

Purpose Sorafenib and everolimus are both active against neuroendocrine tumors (NET). Because of potential synergy between VEGF pathway and mTOR inhibitors, we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NET. Methods Patients were treated with everolimus 10 mg daily in combination with sorafenib (dose level 1: 200 mg twice daily; dose level 2: 200 mg per morning, 400 mg per evening) using standard phase I dose escalation design. Dose-limiting toxicity (DLT) was defined within the first cycle (28 days) of therapy. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Twelve additional patients were treated at the maximum tolerated dose (MTD) level to further characterize safety and a preliminary assessment of activity. Results One patient in Cohort 1 experienced DLT (grade 3 skin rash); the cohort was expanded to 6 patients with no further DLTs. All 3 patients in Cohort 2 experienced DLT, consisting of thrombocytopenia, hand–foot skin reaction, and rash/allergic reaction. Sorafenib 200 mg twice daily in combination with everolimus 10 mg daily was established as the MTD. Independently reviewed best objective responses revealed that 62 % of patients had some degree of tumor shrinkage. By RECIST, we observed partial response in 1 patient, stable disease in 13 patients, and progressive disease in 3 patients. Conclusion Sorafenib 200 mg twice daily with everolimus 10 mg daily represents the MTD of this combination in patients with advanced NET. While the combination is active, toxicity concerns may preclude more widespread use.

Dual inhibition of mTOR pathway and VEGF signalling in neuroendocrine neoplasms: From bench to bedside

“…Sorafenib 200 mg twice daily with everolimus 10 mg daily represented the maximum tolerated dose (MTD). However, toxicity concerns from such a combination may preclude a more widespread use [6 gives a clear clinical benefit 5] [66]. An interesting study evaluating the effect of mTOR-Is and anti-VEGF agents on tumour perfusion was presented at the ASCO 2010 Annual Meeting and recently published by Yao.…”

Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence

“…Theses includes the combination of everolimus with pasireotide[75–77,79], bevacizumab[75], SIRT[79], temozolomide[83], sorafenib[84], or PRRT[85](Table 4). In a phase I study of pasireotide plus everolimus in 22 patients with GEP and lung NETs[77], the PFS at 6 months was 76%.…”

Efficacy and Safety of Everolimus in Extrapancreatic Neuroendocrine Tumor: A Comprehensive Review of Literature

“…These publications covered 2008-2015 and included different study designs. In particular, 2 were phase I studies [21,22], 4 were phase II [14,15,23,24], 1 was phase III, 2 were subanalyses of that phase III study [16][17][18], 1 was a prospective cohort study [25], 2 were retrospective studies [19,26], and 10 were case reports [27-36] ( Table 1). Altogether, the selected studies included 874 patients, and 456 of whom had NETs (non-pNETs) evaluable for treatment with everolimus.…”