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Introduction: Many patients do not benefit from immunotherapies targeting immune checkpoints such as PD(L)-1 due to a variety of resistance mechanisms. The AhR pathway is downstream of the Trp-IDO/TDO-Kyn axis. High levels of immune-suppressive AhR-activating ligands, such as kynurenine derived from IDO1/TDO2-expressing tumors, have been implicated as a potential resistance mechanism and are associated with poor responses to PD-1 therapies. Compared with inhibition of IDO1/TDO2 alone, direct AhR inhibition can block the activation of this transcription factor and may better counteract immune suppression. BAY2416964 is a novel, oral AhR inhibitor currently in a Phase I clinical trial in patients with solid tumors. Preclinically, BAY2416964 can block the activation of AhR by kynurenine and relieve its immune-suppressive effects, thereby restoring anti-tumor T-cell activity, reducing the level of inhibitory myeloid-derived suppressor cells and regulatory T cells, and improving the effectiveness of PD-1 blockade. We have analyzed PK and biomarker data from the ongoing monotherapy dose-escalation study to explore a potential optimal dose and schedule for effective AhR inhibition. Methods: PK data were intensely sampled from patients in 10 different groups with different dosing regimens (once and twice daily) and various food-intake scenarios. AhR downstream target gene expression after ex vivo kynurenic acid stimulation of patients’ peripheral blood mononuclear cells (PBMCs) was assessed. A population PK (popPK) model was developed and calibrated to characterize the PK of BAY2416964 across treatment groups. This model accounts for the non-linear relationship between dose and bioavailability as well as the effect of food intake. Results: The preliminary popPK model identified a non-linear relationship between the BAY2416964 dose and its (relative) bioavailability which was dependent on the respective food condition. The popPK model was able to describe the clinical BAY2416964 plasma exposures from all dose groups, including the effect of food intake. Ex vivo analysis of PBMCs showed inhibition of kynurenic acid-induced AhR downstream gene expression (such as CYP1A1, CYP1B1), suggesting effective in vivo target engagement in the doses tested. Conclusion: This modeling-based PK analysis along with target engagement in peripheral blood informed the posology to be tested in the dose-expansion part of the ongoing clinical trial. Citation Format: Kyriakos Papadopoulos, Michael Cecchini, Juanita S. Lopez, Dirk Jäger, Ki Young Chung, Michael Platten, Florian Prinz, Yuko Ishii, David Schaer, Ilona Gutcher, Gabriele Leder, Radost Pencheva, Thomas Wagener, Christian Scheerans, Carsten Zieschang, Andrea Wagner, Spyros Stamatelos, Ecaterina Dumbrava. Preliminary analysis of pharmacokinetic (PK) and target engagement biomarkers from a first in human phase 1 study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 [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 CT276.

Introduction: ATRi and PARPi combinations kill tumor cells via synergistic modulation of complementary DDR pathways but clinical utility is limited by overlapping toxicities. A genome-wide CRISPR-Cas9 screen identified DDR alterations that sensitize tumors to the ATRi camonsertib (cam) plus PARPi. Based on preclinical models, tolerability and efficacy of cam plus PARPi given intermittently at low doses in pts with solid tumors with DDR alterations, including BRCA-mutated PARPi-resistant cancers, was evaluated. Methods: Pts (≥ 18 yrs) with relapsed/refractory (r/r) solid tumors with DDR alterations were treated with cam plus talazoparib (tala), niraparib (nira), or olaparib (ola) in 2 phase I trials (NCT04497116, NCT04972110). An adaptive BOIN design was used to optimize dose/schedule. Endpoints were safety, recommended phase II dose (RP2D), pharmacokinetics (PK), response (RECIST v1.1 [confirmed/unconfirmed], CA 125, or PSA), clinical benefit rate (CBR; RECIST/tumor marker response or treatment duration ≥ 16 wk), and ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency [mVAF] ≥ 50%). Results: As of Nov 2022, 99 pts were enrolled (61 with ≥ 3 prior lines of therapy, 36 PARPi-pretreated); 43, 27, 29 pts in tala, nira, and ola combinations, respectively. Tumors included ovarian (n=20), prostate (n=13), breast (n=17), bile duct (n=3); most common genotypes were ATM (n=26), BRCA1 (n=19), and BRCA2 (n=33). Grade 3+ toxicities included reversible myelosuppression (neutropenia, anemia, and thrombocytopenia in 35%, 28%, and 14% of pts overall; 33%, 16%, and 11% at preliminary RP2Ds), fatigue (3%), and alkaline phosphatase increase (2%). Two pts discontinued treatment due to drug-related toxicity. Forty pts remain on therapy, up to 63 wks. Preliminary RP2Ds: cam 80 mg QD (d 5-7) + tala 0.25 mg QD, 1 wk on/1 wk off; cam 80 mg QD + nira 100 mg QD, 2 d on/5 d off; cam 50 mg QD + ola 100 mg BID, 3 d on/4 d off. As of abstract submission, response rate was 13% in 85 evaluable pts; CBR was 49%. Responders included pts with ovarian (n=6), bile duct (n=2), and breast, pancreatic, and carcinoma of unknown primary (n=1 each) cancers harboring alterations in BRCA1/2 (n=9), IDH1 (n=1), and ATM (n=1). Of 30 evaluable PARPi-pretreated pts, response rate was 23% and CBR was 52%. MRR was 64% (14/22 evaluable); change in mVAF correlated with a change in target lesion size (r=0.63, P=0.001). PK of each drug in the combination was consistent with respective monotherapy PK. Conclusion: Combination of cam plus PARPi at low doses on intermittent schedules was generally well-tolerated with clinical activity in DDR-aberrant tumors, including those pretreated with PARPi. RP2D optimization and translational correlative studies are ongoing. Citation Format: Timothy A. Yap, Siddhartha Yadav, Benjamin Herzberg, Benedito A. Carneiro, Elisa Fontana, Martin Højgaard, Michael J. Pishvaian, Ruth Plummer, Theresa L. Werner, Vaibhav Sahai, Stephanie Lheureux, Elizabeth K. Lee, Niharika B. Mettu, Gregory M. Cote, Joseph D. Schonhoft, Victoria Rimkunas, Ian M. Silverman, Marisa Wainszelbaum, Gerson Peltz, Adrian J. Fretland, Kezhen Fei, Danielle Ulanet, Insil Kim, Maria Koehler, Ezra Rosen, Michael Cecchini. Safety and efficacy of three PARP inhibitors (PARPi) combined with the ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in patients (pts) with solid tumors harboring DNA damage response (DDR) alterations [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 CT018.

Background: Ramucirumab is a monoclonal antibody that binds to the vascular endothelial growth factor receptor 2, increasing hypoxia in the tumor microenvironment. In advanced gastric cancer, single agent ramucirumab is well tolerated and improves overall survival (OS) compared to placebo although it is largely cytostatic with a response rate ≤3%. Preclinical in vitro and in vivo experiments reveal that hypoxia induces homologous recombination deficiency (HRD) in tumors, which may be exploited by the addition of inhibitors of poly (ADP-ribose) polymerase (PARPi). We thus designed NCI10066 for metastatic gastric cancer with the hypothesis that ramucirumab would sensitize tumors to the PARPi olaparib. Methods: NCI 10066 (NCT03008278) was a phase 1/2, multicenter, open-label clinical trial sponsored by the Cancer Therapy Evaluation Program. Eligible patients had histologically confirmed metastatic gastric or GEJ adenocarcinoma with measurable disease refractory to ≥ 1 prior therapy that did not contain ramucirumab. Patients were treated with escalating doses of olaparib with ramucirumab 8 mg/kg every 2 weeks in a 3+3 design. Dose escalation evaluated two dose levels: olaparib 200 mg twice daily with ramucirumab 8 mg/kg every 2 weeks (dose level 1) and olaparib 300 mg twice daily with ramucirumab 8 mg/kg every 2 weeks (dose level 2). The primary objective of dose escalation was to assess safety and measure dose limiting toxicities (DLT) to determine the recommended phase 2 dose (RP2D). The primary objective in phase 2 was to evaluate clinical activity at the RP2D in a 40-patient expansion cohort. Results: From 2/8/18 - 9/17/21, 51 patients were enrolled at 10 centers throughout the Experimental Therapeutics Clinical Trials Network and 28/51 (55%) patients had ≥2 prior lines of therapy. In dose escalation 3 patients were treated at dose level 1 and 8 at dose level 2. No DLTs were observed at dose level 1 and at dose level 2 there was 1 DLT (fatigue) in 6 evaluable patients. The RP2D was determined to be olaparib 300 mg twice daily and ramucirumab 8 mg/kg every 2 weeks. Forty patients were treated in dose expansion at the RP2D. Of 46 patients evaluable for a response there were 5/46 (11%) partial responses (PR) and the disease control rate (PR/SD) was 29/46 (63%) at 6 weeks. The median progression free survival (PFS) was 2.8 months (95% CI 2.3 - 4.2) and the median OS was 7.3 months (95% CI 5.6 - 13.0). Grade ≥ 3 treatment related adverse events were seen in 13 (25%) of patients and there were no treatment related deaths. Conclusions: The combination of olaparib and ramucirumab is well tolerated with a RP2D of olaparib 300 mg twice daily and ramucirumab 8 mg/kg every 2 weeks. The ORR, PFS, and OS exceed the historical control with ramucirumab monotherapy, suggesting that the combination is clinically active. Biomarkers are critical to defining patient subsets more likely to benefit from the combination and HRD biomarker analysis is ongoing. Citation Format: Michael Cecchini, Joseph Chao, Yu Shyr, James Cleary, Nataliya Uboha, May Cho, Anthony Shields, Shubham Pant, Laura Goff, Kristin Spencer, Edward Kim, Chih-Yuan Hsu, Stacey Stein, Jaykumar Thumar, Jeremy Kortmansky, John Kunstman, Patricia LoRusso, Percy Ivy, Jill Lacy. A phase 1/2 study of olaparib in combination with ramucirumab in metastatic gastric and gastroesophageal junction adenocarcinoma (GEJ) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT170.

Background: The release of ATP from dying cancer cells in response to platinum-based chemotherapy increases immunosuppressive extracellular adenosine, which can bind and activate the A2a and A2b receptors on immune cells, diminishing the effectiveness of the anti-tumor immune response. Concomitant dual adenosine receptor blockade may therefore enhance the therapeutic efficacy of some chemotherapeutic agents. Etrumadenant (etruma, AB928) is the first clinical-stage small-molecule, selective dual antagonist of A2aR and A2bR for which combination data with mFOLFOX-6 in mCRC were previously presented1,2. Here we present updated results for safety in all patients (pts) and efficacy in 3L+ pts. Methods: ARC-3 (NCT03720678) was a phase 1/1b, multicenter, open-label study to evaluate etruma + mFOLFOX-6 in pts with mCRC. Eligible pts had histologically confirmed mCRC with ≥1 measurable lesion. Pts received 75 mg (phase 1 only) or 150 mg etruma orally once daily (QD) + mFOLFOX-6. The primary objective was to assess the safety of the combination; secondary objectives included evaluation of clinical activity. Results: As of 20Nov2020, 44 pts were enrolled and received etruma (75mg: n=4; 150mg: n=40) + mFOLFOX-6. Etruma-related AEs were reported in 34 pts and were mostly Grade 1 or 2; those reported in >30% of pts were fatigue and nausea. One pt had an etruma-related Grade 3 acute kidney injury and there were no Grade 4-5 etruma-related SAEs. There were 22 efficacy-evaluable 3L+ subjects, all of which had received prior FOLFOX and/or FOLFIRI. In this subgroup, the ORR was 9.1% and the median PFS and OS were 3.9 and 15.7 mos respectively. Conclusions: Updated results confirm etruma + mFOLFOX-6 was well tolerated in pts with mCRC without significant additive toxicity and was associated with disease control in heavily pretreated pts. Based on these encouraging data, a platform study (ARC-9) has been initiated to further explore this and other combinations in mCRC pts. References 1. Cecchini M, et.al. AACR Annual Meeting 2020, Abstract# 99532. Udyavar A, et.al. SITC Annual Meeting 2020, Abstract# 338 Citation Format: Michael Cecchini, Cheng Quah, Shiyao Liu, Rachel Woloski, Akshata Udyavar, Marios Giannakis. ARC-3: Updated results of etrumadenant (AB928) + modified FOLFOX-6 (mFOLFOX-6) in metastatic colorectal cancer (mCRC) patients [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 CT129.

Background: The release of ATP from dying cancer cells in response to platinum-based chemotherapy increases extracellular immunosuppressive adenosine (A), which binds to and activates the A2a and A2b receptors on immune cells resulting in an ineffective anti-tumor immune response. Concomitant adenosine receptor blockade may therefore enhance the therapeutic efficacy of some chemotherapeutic agents. AB928, the first clinical-stage small molecule dual adenosine receptor antagonist, is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Methods: ARC-3 (NCT03720678) is a Phase 1/1b, open-label study in participants (pts) with advanced CRC. Phase 1 escalation identified AB928 150 mg orally once daily as the recommended dose in combination with standard mFOLFOX-6. Phase 1b expansion is ongoing and includes at least 15 and up to 40 pts. Eligible pts must have unresectable or mCRC, ECOG performance status 0-1, and at least one RECIST measurable lesion. Phase 1 eligibility included up to 5 lines of prior therapy; Phase 1b is similarly scoped. Exploratory biomarker analyses include immunohistochemistry of the adenosine axis, tumoral next gene sequencing, and tumor/blood immune correlates. Results: As of 27Dec19, 21 pts received AB928 150 mg + mFOLFOX-6: 7 in Phase 1 and 14 in Phase 1b. All previously treated pts (n=12) were FOLFOX- and/or FOLFIRI-experienced. Prior metastatic therapies range from 3 to 5 in Phase 1 escalation and 0 to 3 in Phase 1b expansion. Adverse events (AEs) reported in >30% of pts included fatigue, diarrhea, and thrombocytopenia. AEs related to AB928 occurred in 13 pts and were mostly mild to moderate. AB928-related Grade 3 AEs reported by 3 pts were diarrhea, AST increase, and neutropenia; there were no Grade 4-5 AB928-related AEs. Out of 15 evaluable pts, by investigator assessment, the disease control rate was 100% with 2 partial responses (13%; 1 confirmed, 1 pending confirmation) and 13 stable disease (87%). Of pts with stable disease, 6/13 (46%) had tumor shrinkage >15%. Median time on treatment was 15.4 (range: 1.7 - 40.6+) and 11.9 (range: 2.7 - 15.7+) weeks for Phase 1 and Phase 1b, respectively, with initiation of Phase 1b dosing on 09Sep19. Enrollment up to 40 pts is proceeding based on early efficacy gates; 15 pts are currently receiving study treatment. Conclusions: AB928 with mFOLFOX-6 has been well tolerated without significant evidence of additive toxicity in pts with mCRC. Combination treatment was associated with disease control in all evaluable pts, including those with microsatellite stable and RAS/BRAF mutated mCRC. Additional updates on the safety, clinical activity, and correlative biomarker results for all escalation/expansion pts will be presented. Citation Format: Michael Cecchini, Manuel Modiano, Fadi Braiteh, Olivia S. Gardner, Houston N. Gilbert, Daniel DiRenzo, Lisa Seitz, Matt J. Walters, Fangfang Yin, Rachel Woloski, Melissa C. Paoloni, Ki Y. Chung. Efficacy and safety of AB928 plus modified FOLFOX-6 (mFOLFOX-6) in participants with metastatic colorectal cancer (mCRC): Initial results at the recommended dose for expansion (ARC-3) [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 LB-387.

Background: Gut microbiome composition affects response to PD-1 blockade; and recent proof of concept studies suggest that gut microbiome manipulation is effective in reversing resistance to PD-1 blockade. VE800 is an oral live biotherapeutic consisting of 11 distinct non-pathogenic, non-toxigenic, commensal bacterial strains manufactured in lyophilized form. VE800 induces CD8+ T cell infiltrate into tumors; and significantly enhances anti-tumor activity of PD-1 blockade preclinically in multiple tumor models in a CD103+ dendritic cell and major histocompatibility (MHC) class I dependent fashion (Tanoue et al., 2019). Retrospective analysis of cancer patient's (pt) samples also suggests that greater VE800 strain abundance is associated with improved response to PD-1 blockade. The objective of this phase I study is to evaluate the safety, tolerability, and clinical activity of VE800 administered orally in combination with nivolumab in pts with select cancers. Methods: CONSORTIUM-IO (NCT04208958) is an open-label, first-in-human study evaluating VE800 and nivolumab combination in pts with anti-PD-1/PD-L1 relapsed/refractory melanoma, anti-PD-1/PD-L1 naïve gastric/gastroesophageal junction (GEJ) adenocarcinoma and anti-PD-1/PD-L1 naïve microsatellite-stable (MSS) colorectal cancer. Following a 5-day course of oral vancomycin 125mg QID, VE800 will be administered daily along with nivolumab (480mg Q4W). A single dose level of VE800 will be evaluated. In the interests of maximizing safety, a Simon 2-stage design will be used for each disease cohort. Although no dose-limiting toxicities (DLT) are expected, the first 3 pts will be enrolled serially 1 week apart; and safety data of the first 6 pts will be reviewed prior to further accrual. Pts will continue to receive VE800/nivolumab combination until disease progression or unacceptable toxicity. Primary endpoints include safety, tolerability; and clinical activity by objective response rate (ORR) per RECIST v1.1. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS); and metagenomic strain-level analysis of degree/duration of VE800 strain colonization. Exploratory endpoints include tumor and blood immunophenotyping, serum/stool metabolomics and global changes in fecal microbiome composition. CONSORTIUM-IO is currently actively enrolling pts. Citation Format: Diwakar Davar, Judy S. Wang, Michael Cecchini, Zev Wainberg, Martin Gutierrez, Anita Turk, Rose Szabady, Jason Norman, Bernat Olle, Bruce Roberts, Dmitri Bobilev. Consortium-IO: A safety and efficacy study of VE800 in combination with nivolumab in previously treated patients with select advanced metastatic cancers [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 CT246.

Background: Hyperclustering of death receptor 5 (DR5) and subsequent induction of apoptosis, which normally occurs upon binding of its ligand TRAIL, can be mimicked by agonistic antibodies (Abs). However, clinical efficacy of conventional DR5 Abs has been disappointing. To improve antibody-mediated DR5 clustering on cancer cells, we utilized the HexaBody® antibody technology. This antibody platform is based on the discovery that IgG molecules can organize into hexamers through intermolecular Fc-Fc interactions upon binding to membrane-bound targets. HexaBody molecules are IgG1 Abs with a single point mutation in the Fc domain that enhances hexamerization. HexaBody-DR5/DR5 is a 1:1 mixture of two non-competing anti-DR5 HexaBody molecules that induces potent caspase-dependent apoptosis through hexamer-dependent hyperclustering of DR5 on the cell surface. We previously showed that HexaBody-DR5/DR5 induced superior potency compared to conventional DR5 antibodies in vitro and in vivo. Methods: To obtain preclinical proof-of-concept for targeting specific solid tumors using HexaBody-DR5/DR5, we performed a patient-derived xenograft (PDX) mouse clinical trial (1 mouse per group design) using a large number of colorectal (CRC) (100), gastric (19), urothelial (13), non-small cell lung cancer (NSCLC) (90), and triple-negative breast cancer (TNBC) (20) PDX models. Results: HexaBody-DR5/DR5 showed potent anti-tumor activity (tumor stasis or tumor regression) in a substantial proportion of the CRC (36%), gastric (42%) and urothelial (54%) models. Additional in vivo studies comparing single vs multiple dosing demonstrated that maximal anti-tumor activity was already achieved after a single dose of HexaBody-DR5/DR5. A Phase 1/2 clinical trial to determine the RP2D and assess clinical safety of HexaBody-DR5/DR5 in cancer patients is currently ongoing (NCT03576131), from which a case study will be presented. Conclusions: Potent anti-tumor activity of HexaBody-DR5/DR5 was observed in large and diverse panels of CRC, gastric and urothelial PDX models, providing preclinical rationale for the clinical evaluation of HexaBody-DR5/DR5 in these indications. Citation Format: Marije B Overdijk, Michael Cecchini, Kristin Strumane, Marcel Brandhorst, Andreas Lingnau, Paul W.H.I. Parren, Merete Ellekilde-Pedersen, Ulf Forssmann, Tahamtan Ahmadi, A. Kate Sasser, Janine Schuurman, Esther C.W. Breij, Patricia LoRusso. HexaBody-DR5/DR5 (GEN1029) shows potent preclinical antitumor activity in a variety of patient-derived xenograft (PDX) tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C025. doi:10.1158/1535-7163.TARG-19-C025