Evers, Mark B.

Abstract Background: Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis and repair of DNA, making RNR-targeted therapy a rationale therapeutic strategy for radiosensitization. ETCTN 10388 (NCT04234568) evaluated safety and efficacy of the combination of lutetium 177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. Method: This study was a multicenter phase 1 dose escalation trial [using the Bayesian optimal interval design (BOIN)] of triapine in combination with fixed dose lutetium Lu 177 DOTATATE for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment with an expansion cohort at the recommended phase 2 dose (RP2D). Oral triapine (100mg, 150mg, 200mg) was administered once daily on days 1-14 and Lu-177 DOTATATE [200 mCi] intravenously on day 1 of every 56-day cycle. A total of 4 cycles were administered. Response and adverse effects were assessed per RECIST and CTCAE 5.0, respectively. Exploratory correlative studies included tumor somatic and germline mutation testing, RNA sequencing, pharmacokinetics, deoxynucleosides and circulating cell free DNA analysis. Primary endpoints were safety and RP2D. Results: Overall, 31 patients were enrolled between 6 sites, 15 in the dose escalation phase and 16 in the dose expansion phase. Adverse events (AE) were assessed in all 31 patients per CTCAE 5.0. One DLT in dose level 1, seven DLTs in dose level 2, and one grade 5 DLT in dose level 3 were observed. The RP2D of the combination is triapine 150 mg QD (dose level 2) on days 1-14 in combination with Lu-177 DOTATATE on day 1 of every 56-day cycle. Detailed safety and adverse event data will be presented at the meeting. There were 28 patients evaluable for efficacy, of which 6 (21%) achieved a partial response. At 12 months, 6 patients had progressed, while 22 (86%) remained progression free. Median PFS has not been reached. PK data were available for 12 patients enrolled in the dose escalation cohort. The geometric mean (SD) AUC0-inf was 1159 (1.22) µg/L•h for the 100mg dose level and 1862 (1.76) µg/L•h for the 150 mg dose level, suggesting that exposure increased with dose, and inter-patient variability was as expected for an oral agent. Conclusion: The combination of triapine and Lu-177 DOTATATE was safe with preliminary efficacy signals, which will be further evaluated in ETCTN 10558, a randomized phase 2 study that is comparing the effectiveness of triapine and Lu-177 DOTATATE to Lu-177 DOTATATE alone. Citation Format: Aman Chauhan, Susanne Arnold, Jill Kolesar, William Carson, Heidi Weiss, Rani Jayswal, Donglin Yan, Riham El Khouli, Aman Khurana, Jan Beumer, Heloisa Soares, Mary Mulcahy, Thorvardur Halfdanarson, Daneng Li, Heather Jacene, Percy Ivy, Elise Kohn, John Wright, Larry Rubinstein, Zeta Chow, Piotr Rychahou, Mark B. Evers, Charles Kunos, Lowell Anthony, Bhavana Konda. ETCTN 10388: a first in human phase I trial of triapine and lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT194.

648 Background: Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate, and thus repair of DNA in this setting. ETCTN 10388 evaluated safety of combination Lu-177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. Methods: This investigator initiated, NCI sponsored, multicenter phase 1 trial, enrolled a total of 31 patients in the dose escalation [using the Bayesian optimal interval design (BOIN)] and dose expansion cohorts. Oral triapine was administered on days 1-14 and Lu-177 DOTATATE [200 mCi] intravenously on day 1 of every 56-day cycle. A total of 4 cycles were administered. All enrolled patients had blood samples collected for triapine pharmacokinetic (PK) analysis in EDTA tubes prior to and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after oral administration during cycle 1. Results: Five patients were enrolled in triapine Dose Level 1 (100 mg/day), twenty-five to dose level two (150 mg/day), and one patient to dose level three (200 mg/day). PK data were available for 12 patients enrolled in the dose escalation cohort. The geometric mean (SD) AUC0-inf was 1159 (1.22) µg/L•h for the 100mg dose level and 1862 (1.76) µg/L•h for the 150 mg dose level, suggesting that exposure increased with dose, and inter-patient variability was as expected for an oral agent. Triapine PK parameter values observed in this trial, were comparable to previous reports that used a previous formulation [ 1 ]. While exposure was similar, variability appeared smaller with the current oral formulation. Adverse events (AE) were assessed in all 31 patients per CTCAE 5.0. A total of one DLT in dose level 1, seven DLTs (Transient cytopenia; primarily neutropenia and rarely thrombocytopenia) in dose level 2, and one grade 5 DLT (Death probably from progressive cancer and carcinoid heart disease but possibly from trial drugs) in dose level 3 were observed. Detailed AE profile will be presented at the meeting. Conclusions: The RP2D of triapine is 150 mg QD on days 1-14 in combination with Lu-177 DOTATATE on day 1 of every 56-day cycle. Clinical trial information: 04234568 .