Abstract 674: A phase I trial of Triapine and Lutetium Lu 177 Dotatate in combination for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs)

Abstract

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 Lu 177 Dotatate (Lutathera) is a beta- and gamma-emitting radionuclide. Lutathera has been recently FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on NETTER-1 Phase III trial. Despite favorable PFS, and safety profile, the drug has limited cytoreductive capability. NETTER-1 reported 17% ORR. PRRT also doesn't seem to be very effective in treating peritoneal disease. We hypothesize that addition of an effective radiation sensitizer can help improve antitumor activity of Lutathera. Rationale: Triapine is a ribonucleotide reductase (RNR) inhibitor. Radiation is a potent inducer of DNA double-strand breaks (DSBs). Targeting signaling networks involved in DSB repair is a promising approach for enhancing cellular radio sensitivity. RNR is the rate-limiting enzyme in the synthesis and repair of DNA, and it is directly involved in the cellular response to radiation, making RNR-targeted therapy to enhance radiation treatment a rational therapeutic strategy. RNR is the only enzyme responsible for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate (dNDP), the key building blocks for DNA synthesis. This study will test the hypothesis that triapine is an effective radiation sensitizer which can be safely combined with peptide receptor radionuclide therapy and can improve antitumor activity of Lutetium Lu 177 Dotatate. Method: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of triapine and Lutetium Lu 177 Dotatate in combination for 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 (BOIN design) and dose expansion cohorts. The study will be open through the entire ETCTN. Patients will be treated with 177 lutetium dotatate in combination with Triapene. Triapene will be administered orally from D1-14 with each dose of PRRT. Primary endpoint is to evaluate RP2D. Secondary endpoints are looking into clinical activity (ORR, PFS and OS). We are also evaluating NETEST, a novel blood based predicting as well as prognosticating test. In addition, the study will evaluate baseline somatostatin receptor density, somatic tumor mutations and germline mutations and correlate with clinical outcome. ClinicalTrials.gov Identifier: NCT04234568 Citation Format: Aman Chauhan, Charles Kunos, Riham El Khouli, Jill Kolesar, Heidi L. Weiss, Bill Carson, Mark Kidd, Jan Beumer, Susanne Arnold, Elise Kohn, Lowell Anthony. A phase I trial of Triapine and Lutetium Lu 177 Dotatate in combination for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 674.

Radiolabeled Somatostatin Analogues for Diagnosis and Treatment of Neuroendocrine Tumors

“…Similarly, radionuclide reductase is a rate-limiting enzyme in DNA synthesis and repair, and its inhibition might sensitize NET cells to radiation damage [ 183 ]. A phase I study of [ 177 Lu]Lu-DOTA-TATE and triapine—a radionuclide reductase inhibitor—in PRRT-naïve patients with well-differentiated GEP NETs is ongoing [ 184 ].…”