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Purpose: Immune checkpoint inhibitor (ICI) maintenance therapy is standard of care for frontline management of extensive stage small cell lung cancer (ES SCLC). However, overall survival benefit of addition of ICI maintenance to frontline ES SCLC treatment is modest and further improvement is needed. We hypothesized that addition of poly (ADP-ribose) polymerase inhibition to ICI maintenance therapy for patients with platinum sensitive ES SCLC could improve antitumor efficacy of ICI. Methods: A single-arm, investigator-initiated phase II trial (NCT03958045) enrolled patients with platinum sensitive ES SCLC who received frontline maintenance nivolumab 480 mg IV every 4 weeks, and rucaparib, 600 mg PO twice a day after completion of 4-6 cycles of platinum doublet. The primary outcome was median progression free survival. Secondary endpoints included assessment of objective response and adverse effects (AEs) per CTCAE 5.0. Correlative studies included pretreatment and during-treatment immune assays and circulating tumor DNA TP53 mutation status. Results: A total of 42 patients were consented and 33 met eligibility criteria and were treated. All patients received 4-6 cycles of frontline platinum doublet and had at least a partial response by RECIST at the time of enrollment. In the 33 participants, the most common grade 3 and 4 AEs (at least possibly related) were hypokalemia (3%), hyponatremia (3%), elevated alanine aminotransferase (3%), neutropenia (3%) and leukocytopenia (3%). No grade 5 AE was noted. The median PFS (mPFS) was 3 months from time of enrollment on frontline maintenance (post platinum doublet). The mPFS was 11 months from cycle 1 of platinum doublet. Overall, 89.8% patients were alive at 12 months and 54.4 % patients were alive at 24 months from the start of platinum doublet. Currently 2 patients are on active treatment and other two have completed study treatment and are on observation with stable disease. Conclusions: Maintenance rucaparib combined with immune checkpoint inhibition was tolerable and showed promising activity after completion of frontline chemotherapy in platinum sensitive extensive stage small cell lung cancer patients. Citation Format: Aman Chauhan, Jill Kolesar, Donglin Yan, Zhonglin Hao, Ronald McGarry, John Villano, Ralph Zinner, Ashish Maskey, Jordan Miller, Timothy Mullett, Aman Khurana, Xitong Zhou, Garima Gupta, Daniel Flora, Colleen Darnell, Richard O'Neil, Charles Kunos, Mark B. Evers, Lowell Anthony, Susanne Arnold. Phase II of frontline maintenance rucaparib in combination with nivolumab in ES SCLC [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 CT221.

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.

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.

Background: Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. This is especially true for high-grade NENs (small and large cell neuroendocrine carcinomas). Human circulating progastrin (hPG80) is a novel biomarker for NENs and is easily measured in plasma using an ELISA test. This study is the first to explore hPG80 in NENs. Methods: Progastrin concentrations were quantified in plasma from 95 patients with stage IV NEN using DxPG80 technology (ECS Progastrin, Switzerland) and compared with hPG80 concentrations in 50-80-year-old healthy donors (n=252) as well as a subgroup comprised of only the 18-25-year-olds (n=137). Results: The median hPG80 in NENs patients was 5.54 pM as compared to 1.5 pM for patients in the 50-80-year-old control group and 0.29 pM for patients in the 18-25-year-old cohort (p Conclusions: Plasma hPG80 in NENs suggests hPG80 may be a diagnostic blood biomarker for both low- and high-grade NENs and further study is warranted. A prospective trial is ongoing in small cell lung cancer to evaluate its role in monitoring of disease (NCT03958045) and further prospective studies in low-grade neuroendocrine tumors are underway. Citation Format: Aman Chauhan, Alexandre Prieur, Jill Kolesar, Susanne Arnold, Thierry Cousin, Lea Payen, Younes Mahi, Madison Sanders, B. Mark Evers, Dominique Joubert, Lowell Anthony. hPG80 (circulating progastrin), a novel blood-based biomarker for detection of poorly differentiated neuroendocrine carcinoma and well differentiated neuroendocrine tumors [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 735.

Background: Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms arising from multiple organs. Peptide Receptor Radionuclide Therapy (PRRT) is a novel therapy approved for treating NETs with a treatment response rate of 20-30%. To improve therapeutic response of PRRT, 3-AP (Triapine), which is a ribonucleotide reductase (RR) inhibitor with antineoplastic and radiation sensitizing properties, can be used in combination with PRRT. The purpose of our study is to examine effects of Triapine treatment on cellular proliferation, apoptosis and activation of DNA repair pathway in NET cells in vitro. Methods: For these studies, we utilized two human NET cell lines: BON, a pancreatic carcinoid tumor, and QGP-1, a somatostatinoma. (i) To determine effective dose range of Triapine (500 - 2500nM), proliferation was measured at 48, 72, and 96 h with sulforhodamine B (SRB) assay. (ii) To evaluate the effects of radiosensitivity, cultures were treated with increasing doses (250 - 5,000nM), received 2 Gy radiation (XRT) 1h later, exposed to Triapine for 24 hours, rinsed, and fed Triapine-free media; colonies were counted and quantified with SRB assays 14 days later and survival curves were generated. (iii) To further characterize cellular responses, cells were treated with Triapine (250 - 5,000 nM), irradiated 1h later, and harvested 24 h later to examine expression levels of Cyclin D1, cleaved PARP, p-DNA-PK (S2056), p-ATM (S1981) and p-ATR (S428) by Western blot. Results: (i) SRB proliferation assay demonstrated the effective dose range, determined by half maximal inhibitory concentration (IC-50), was 1,3 µM in BON cells and 1.73 µM in QGP-1 cells at 96 h. (ii) Exposure to Triapine before irradiation resulted in a significant increase in the radiosensitivity of each of the tumor cell lines with dose enhancement factors at a surviving fraction of 0.10 of 1.8 and 1.6 for BON and QGP-1, respectively. (iii) Triapine treatment alone activated DNA repair pathway in a dose-dependent fashion as determined by pDNA-PK (S2056) expression. Increasing p-ATM (S1981) expression was observed in a dose-dependent fashion in QGP-1 cells, but not in BON cells. In addition, p-ATR (S428) expression was not significantly different in either cell line. (iv) Triapine treatment alone or in combination with 2 and 4 Gy XRT resulted in dose-dependent decrease in cyclin D1 expression in both cell lines, however, no significant increase in cleaved PARP expression at 24 and 48h. Conclusion: Our results demonstrated rapid and dose dependent decrease in cyclin D1 expression after Triapine treatment, dose-dependent activation of DNA-PK, the key component of the non-homologous end joining pathway and significant increase in the radiosensitivity of each of the tumor cell lines. In conclusion, our findings provide a rationale for inclusion of Triapine as a radiosensitizer in combination with PRRT in treating NETs. Citation Format: Zeta Chow, Aman Chauhan, Lowell Anthony, Courtney Townsend, B. Mark Evers, Piotr Rychahou. Effect of 3AP on neuroendocrine tumor cell proliferation, apoptosis and activation of DNA repair pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6269.

Despite significant advances in the understanding and managing gastroenteropancreatic neuroendocrine tumors (GEPNETs), the therapeutic success of treatments remains relatively poor. Recent FDA approval of Peptide Receptor Radionuclide Therapy (PRRT) has paved the way for radiation-based treatment for GEPNETs. PRRT delivers high doses of radiation to tumor cells in the body to destroy cells or slow their growth. The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in non-homologous end-joining (NHEJ) repair after radiation therapy. A novel, clinical-stage DNA-PK inhibitor, M3814, potently and selectively blocks the NHEJ repair pathway for DNA double strand breaks (DSB). Here, we investigated the feasibility of radiosensitizing neuroendocrine (NET) cells with the DNA-PK inhibitor M3814, both in vitro and in preclinical NET models. Methods: 96-well clonogenic assays were used to evaluate efficacy of M3814 in combination with radiation therapy (XRT) in vitro in QGP-1 and BON pancreatic NET cell lines. DSB-induced DNA repair was visualized with confocal laser scanning microscopy using γ-H2AX immunofluorescence after M3814 treatment. Western blot was used to confirm activation of DNA-PKcs (pDNA-PKcs S2056) after M3814 treatment. The efficacy of M3814 in combination with XRT was evaluated in QGP-1 and BON human xenograft models in athymic nude mice. Tumor cells were injected subcutaneously into athymic nude mice, and treatment started when palpable tumors (∼200 mm3) were established. M3814 was given orally (100 mg/kg) 30 min prior to XRT, which was applied using a radiation therapy device calibrated to deliver 2 Gy daily for 4 d. Results: Clonogenic assays demonstrated lack of cytotoxicity of M3814 alone at doses below 1000 nM and a strong radiosensitizing effect at 500 nM in both QGP-1 and BON cell lines. Immunofluorescence analysis revealed high numbers of γH2AX foci, marking unrepaired DSBs inside the micronuclei. Western blot showed that activation of DNA-PKcs, induced by XRT treatment, was quickly suppressed by M3814 treatment. In combination with XRT, M3814 showed efficacy in both QGP-1 and BON xenografts as demonstrated by a strong potentiation of the effect of XRT. In all models, a dose of 2 Gy administered daily for 4 d, in combination with M3814, induced a significant tumor growth inhibition compared to XRT alone. M3814, alone or in combination with XRT, did not induce significant weight loss or visual signs of toxicity in the mice in any of the studies. Conclusions: Our results demonstrate a benefit of adding M3814 to XRT in NET treatment. Selective DNA-PK inhibition by M3814 provides a potent therapeutic strategy for disruption of NHEJ DSB repair and may offers a novel therapeutic approach in advanced NET. Citation Format: Piotr Rychahou, Aman Chauhan, Zeta Chow, Tadahidi Izumi, Quan Chen, Eun Y. Lee, Dana Napier, Lowell B. Anthony, Michael J. Cavnar, Charles Kunos, B. Mark Evers. DNA-PK inhibitor, M3814, as a radiation sensitizer in the treatment of neuroendocrine tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6402.

Background: Based on the SEER database, the incidence of gastroenteropancreatic neuroendocrine tumors (GEPNETs) has risen six-fold in the last four decades. At present, more than 150,000 GEPNET patients exist in the United States. Fosbretabulin, a synthetic, water-soluble, phosphorylated prodrug of the natural product combretastatin A4 (CA4P), initially isolated from the bark of the South African bush willow, Combretum caffrum, is the lead compound in a class of agents termed vascular disrupting agents (VDAs) and has shown activity as a single agent in ovarian cancer and GEPNETs. Everolimus, an mTOR inhibitor, is FDA approved for the management of well-differentiated NETs. A Phase I trial combining fosbretabulin and everolimus to determine the recommended Phase II trial dose (RP2D) and safety data in metastatic GEPNET patients was conducted. Method: An investigator-initiated, single center, open-label, phase I study involving GEPNETs incorporated partial order continual reassessment method (PO-CRM) to define the dose escalation. The primary objective was to establish the maximum tolerated dose (MTD) of the combination of everolimus and fosbretabulin in NETs that have progressed after at least one prior regimen for metastatic disease. Secondary objective included identifying the safety profile of the combination using NCI CTCAE4 reporting criteria. Patients received daily oral everolimus (2.5 mg, 5 mg, 7.5 mg, and 10 mg). Fosbretabulin was administered IV 60 mg/m2 either q3 weekly or q weekly based on PO-CRM. Patients were treated for 12 weeks with all combinations. Results: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance with the treatment regimen. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients that include increased abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. Only one patient had radiologic progression at the first q 3 monthly CT scan of chest, abdomen, and pelvis. A detailed table with all grade toxicities will be presented at the meeting. Conclusion: Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. ClinicalTrials.gov Identifier: NCT0301429 Citation Format: Aman Chauhan, Susanne Arnold, John Wu, Stacey Slone, Emily Dressler, Heather Flynn, Val Adams, Heidi Weiss, Lowell Anthony. A Phase I study of Fosbretabulin in combination with everolimus in neuroendocrine tumors (Grades 1-3) that have progressed after at least one prior regimen for metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT067.