NeuroEndocrine Tumor Therapy with Lutetium-177-octreotate and Everolimus (NETTLE): A Phase I Study

Objective: To establish the optimal safe dose of everolimus in combination with Lu-177-octreotate peptide receptor radionuclide therapy (PRRT) of advanced progressive gastro-entero pancreatic neuroendocrine tumors (GEP-NETs) and to define dose-limiting toxicity. Patients and Methods: Patients with advanced unresectable progressive well-differentiated GEP-NETS avid for Ga-68-octreotate on positron emission tomography-computed tomography imaging underwent PRRT with four cycles of 7.8GBq Lu-177-octreotate at 8 week intervals. Successive cohorts of 3 patients received escalating doses of everolimus comprising 5, 7.5, and 10mg daily for 24 weeks. Results: Sixteen patients comprised 4 at 5mg, 9 at 7.5mg, and 3 at 10mg everolimus. Patient cohorts at 5 and 7.5mg received 83% and 80% of the total planned dose of everolimus over 24 weeks. All patients required dose reduction or complete cessation of everolimus at the 10mg level, which induced neutropenia and thrombocytopenia, and reduced creatinine clearance. The overall response rate was 44% (7 of 16 patients), and no patient progressed over the 6 month period of treatment. Four of 5 pancreatic NET patients achieved PR 80%. No patient progressed on study. Conclusion: In combination, PRRT with Lu-177-octreotate, the maximum tolerated dose of everolimus is 7.5mg daily.