Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium 177 DOTATATE (Lutathera) is a beta-emitting radionuclide, FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 17% ORR. Peptide receptor radionuclide therapy (PRRT) also doesn’t seem to be very effective in treating peritoneal disease. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Radiation is a potent inducer of DNA double-strand break (DSB); targeting signaling networks involved in DSB repair is a promising approach for enhancing cellular radiosensitivity. The primary repair mechanism of radiation-induced DSBs is nonhomologous end-joining (NHEJ) pathway, in which the DNA-PK (Deoxyribonucleic acid protein kinase) complex plays a pivotal role. Upregulation of DNA-PK promotes repair of DSBs leading to tumor radio-resistance preclinically and clinically. Thus, DNA-PK is an important molecular target for inhibiting DSB repair and enhancing the cytotoxicity of radiation. Peposertib is a selective inhibitor of DNA-PK that targets tumor cell DNA damage repair and survival by blocking NHEJ. We previously reported strong anti-tumor activity when Peposertib was used as radiation sensitizer in pre-clinical NET models. Methods: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of peposertib and Lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment. A total of 29 patients will be enrolled in the dose escalation with help of Bayesian optimal interval design (BOIN) and dose expansion cohorts. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Patients will be treated with 177 lutetium dotatate in combination with peposertib. Peposertib will be administered orally from D1-21 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate recommended phase II dose (RP2D). Secondary endpoints are to evaluate safety, pharmacokinetics, and clinical activity (ORR and PFS). We are also evaluating Lu-177 DOTATATE dosimetry in collaboration with NIH IROC and plasma hPG80, a novel blood based diagnostic biomarker. In addition, the study will correlate clinical outcome with somatic tumor mutations and germline mutations. Clinical trial information: 04750954.