Octreotide and everolimus have demonstrated efficacy in neuroendocrine tumors. patient; 17 (81%) patients experienced at least some tumor regression as their best response to therapy. In conclusion, pasireotide LAR 60 mg IM 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. in human corticotroph or somatotroph tumor cell lines, where it was found to suppress cell proliferation (Batista, et al. 2006; Danila, et al. 2001). Pasireotide has also been associated with inhibition of PF-3644022 cell proliferation in cell lines derived from small intestine or pancreatic neuroendocrine tumors (Kidd, PF-3644022 et al. 2008). In clinical trials, pasireotide has shown preliminary evidence of efficacy in treating symptoms of hormone hypersecretion in patients with acromegaly or with octreotide-refractory carcinoid syndrome (Kvols, et al. 2006; Petersenn, et al. 2010). In these studies, doses of pasireotide ranged from 200C1200 micrograms (mcg) subcutaneously twice daily. Adverse events were generally mild, and included hyperglycemia, nausea, diarrhea, and abdominal pain. A long PF-3644022 acting formulation, pasireotide LAR, administered monthly at doses of 40 or 60 mg resulted in drug exposure that was similar to that previously observed with the subcutaneous formulation at doses of 600 or 900 mcg administered twice daily (Wolin, et al. 2009). The side effect profile of pasireotide LAR was also similar to that observed with subcutaneous pasireotide. The mTOR inhibitor everolimus is also associated with antitumor activity in patients with advanced neuroendocrine tumors. In initial phase II studies, treatment with everolimus was associated with partial responses and encouraging progression-free survival durations in both pancreatic neuroendocrine tumors and carcinoid tumors (Yao, et al. 2010; Yao, et al. 2008). In a subsequent randomized study in pancreatic neuroendocrine tumors, treatment with everolimus was Rabbit polyclonal to ADORA1. associated with a significant improvement in progression free survival compared to placebo, leading to the approval of everolimus for this indication (Yao, et al. 2011). In a parallel placebo-controlled study performed in advanced carcinoid tumors, treatment with everolimus and octreotide was associated with a longer progression-free survival duration compared to octreotide alone, when measured according to local investigator assessment (Pavel, et al. 2011). These results suggest that everolimus is also associated with antitumor activity in carcinoid tumors; however, the study did not meet its primary statistical endpoint, which mandated improvement in progression-free survival based on central radiology review. PF-3644022 We performed a phase 1 study evaluating the safety and feasibility of combining pasireotide and everolimus in patients with pancreatic neuroendocrine or carcinoid tumors. Cohorts of patients were treated with escalating doses of pasireotide, beginning with the subcutaneous twice daily formulation and if tolerated, transitioned to the intramuscular LAR formulation. In parallel, everolimus was dose escalated from 5 mg to 10 mg in sequential cohorts. Patients were followed for evidence of toxicity and preliminary evidence of efficacy. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. PATIENTS AND METHODS Patient Population All patients were required to be 18 years of age or older and have histologically documented, locally unresectable or metastatic carcinoid or pancreatic neuroendocrine tumors of low grade or intermediate histologic grade. Patients with poorly differentiated or high grade neuroendocrine carcinomas were not eligible. Treatment with prior chemotherapy was allowed, as was prior chemoembolization, cryotherapy, or radiofrequency ablation if measurable disease was not affected. Mandated laboratory requirements included: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 3 times the upper limit of normal (ULN) (<5 times ULN if liver metastasis was present), total bilirubin 2 times ULN, serum creatinine 1.5 times ULN, absolute neutrophil count (ANC) 1500/mm3, platelet count 100,000/mm3. All patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status <2. Patients with uncontrolled diabetes mellitus or a fasting plasma glucose >1.5 times ULN were excluded. Patients with a history of congestive heart failure, myocardial infarction, or unstable angina pectoris within 6 months preceding enrollment were excluded. Patients with prolonged QTc (>450 msec at screening), a history of clinically significant cardiac arrhythmias, or on medications known to prolong QTc were excluded, as were.