Phase I study of pasireotide (SOM 230) and everolimus (RAD001) in advanced neuroendocrine tumors

Abstract

Octreotide and everolimus have demonstrated efficacy in neuroendocrine tumors. Pasireotide is a somatostatin analog with binding affinity to a broader range of somatostatin receptor subtypes than octreotide. We performed a phase I study to evaluate the safety and feasibility of combining pasireotide with everolimus in patients with advanced neuroendocrine tumors. Cohorts of patients with advanced neuroendocrine tumors were treated with escalating doses of pasireotide (600-1200 μg s.c. b.i.d., followed by pasireotide LAR 40-60 mg i.m. monthly) and everolimus (5-10 mg daily). Twenty-one patients were treated. Dose-limiting toxicities consisting of grade 3 rash and grade 3 diarrhea were observed. Twelve patients were safely treated at the maximum protocol-defined dose level of pasireotide LAR 60 mg i.m. monthly and everolimus 10 mg daily. Hyperglycemia was common; other observed toxicities were consistent with the known toxicities of either agent alone. Partial tumor response was observed in one patient; 17 (81%) patients experienced at least some tumor regression as their best response to therapy. In conclusion, pasireotide LAR 60 mg i.m. monthly in combination with everolimus 10 mg daily is feasible and associated with preliminary evidence of antitumor activity in patients with advanced neuroendocrine tumors. Further studies evaluating this combination are warranted.

Conflict of interest statement

Declarations of Interest

Jennifer Chan has received research funding from Novartis, Bayer-Onyx, Merck.

Andrew Zhu has served as a consultant for Sanofi-aventis, Bristol-Myers Squibb and has received research funding from Bayer-Onyx, Imclone-Lilly.

Charles Fuchs has served as a consultant for Genentech, Roche, Sanofi-aventis, Pfizer, Infinity Pharmaceuticals.

Matthew Kulke has served as a consultant for Novartis.

Figures

Figure 1

Study schema. • DLT was defined within the first 56 days of treatment. • Dose levels are listed in Table 2.

Figure 2

Maximum reduction in sum of tumor diameters by patient and dose level. * = progressive disease due to new lesions.