Nivolumab and 177Lu-DOTA0-Tyr3-Octreotate for Patients With Extensive-Stage Small Cell Lung Cancer

This research study is being done to assess the safety and tolerability of study drugs, 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) and nivolumab in subjects with small cell lung cancer or advanced or inoperable neuroendocrine tumor of the lung that has overexpressed somatostatin receptors (SSRT). Lutathera is an investigational radioactive agent that targets tumor cells that express SSRT. Nivolumab is an investigational agent that targets and inhibits a pathway that prevents your immune system from effectively fighting your cancer. The combination of these 2 study drugs is investigational. The term "Investigational" in this context means that the drugs have not been approved for clinical use by the US Food and Drug Administration (FDA). Giving Lutathera and nivolumab together may increase the effectiveness of this therapy. We first need to find out the highest dose of Lutathera that can be given safely together with nivolumab. This study will be the first study to test giving Lutathera together with nivolumab. Once we have found the highest dose of Lutathera that can be given with nivolumab, we will treat more patients with this combination to determine how effective it is. The purposes of this study are: To find the highest doses of Lutathera that can be given with nivolumab without causing severe side effects. To find out the side effects seen by giving Lutathera at different dose levels with nivolumab. To determine if the amount of something in your tumor called PD-L1 makes you more likely to have a response to the combination of Lutathera and nivolumab.

The purpose of this project to see if the combination of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab is safe and tolerable, and provides PFS benefit compared to observation alone in the maintenance setting in patients with ES-SCLC and no disease progression after first-line platinum-based chemotherapy. Treatment will be administered on an outpatient basis. A standard dose-escalation phase I design will be used. Three subjects will be enrolled at each dose level in the absence of DLT. Selection of the starting dose of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab is based on the results from previous clinical studies with each compound used as single agent and the fact that the combination has not been tested in clinical trials. The first dose of 177Lu-DOTA0-Tyr3-Octreotate will be given two weeks after the first administration of nivolumab. Studies have shown that intravenous administration of amino acids has a renal protective effect \[46\]. An infusion of amino acids (lysine 2.5% and arginine 2.5% in 1 L 0.9% NaCl; 250 mL/h) will be started 30 minutes before the administration of 177Lu-DOTA0-Tyr3-Octreotate and last 4 hours. Nivolumab will be administered as a fixed dose of 240 mg as an intravenous infusion over 30 minutes every 2 weeks. Nivolumab will be given until progressive disease, patient withdrawal or toxicities. The phase II portion will consist of patients with ES-SCLC who completed platinum based standard first-line chemotherapy (e.g. 4-6 cycles of platinum plus etoposide or irinotecan) without disease progression (responders plus stable disease) at the time of initiation of the combination therapy with 177Lu-DOTA0-Tyr3-Octreotate and nivolumab. Eligible patients will then be randomly allocated in two arms: one will be treated with the combination of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab, and the other arm will continue be followed (observation) after completion the standard chemotherapy treatment. Randomization: Patients who do not receive radiotherapy after chemotherapy * The randomization must occur within 6 weeks of the last chemotherapy cycle. * The study treatment must start within 2 weeks from randomization. Patients who receive radiotherapy (including prophylactic cranial radiation and/or thoracic radiation) after chemotherapy * The randomization must occur within 9 weeks of the last chemotherapy cycle but at least 2 weeks after completion of radiotherapy. * The first dose of 177Lu-DOTA0-Tyr3-Octreotate cannot be given within 8 weeks of radiotherapy. Randomization process: * Randomization will be stratified according to NETSPOT® PET tumor uptake score (Grade 2, 3 and 4). * OnCore will be used as statistical center and the randomization algorithm will be developed by the study biostatistician. * The project management department will be the first point of contact for assessment through email. Courses are defined as 56 days of dosing. Nivolumab will be given until progressive disease, patient withdrawal, or toxicities. For patients randomized to the observation group, cross-over at the time of disease progression will be allowed, since the primary endpoint is PFS and not OS.