AbstractBackground: Oncogenic mutations in PI3Kα are common driver events in ER+ breast cancer and other solid tumors. Alpelisib, a non-mutant selective PI3Kα inhibitor, is effective in ER+ breast cancer thus validating PI3Kα as a therapeutic target. Inhibition of wild-type PI3Kα results in toxicity including hyperglycemia which limits tolerability and drug exposure. RLY-2608, a novel, oral allosteric PI3Kα inhibitor, is uniquely designed to overcome these limitations via mutant- and isoform-selective PI3Kα inhibition for greater target coverage, improved tolerability, and antitumor activity. Initiated in December 2021, ReDiscover is the ongoing, first-in-human study to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of RLY-2608 monotherapy in PIK3CA-mutant advanced solid tumor patients (pts) and of RLY-2608 plus fulvestrant in pts with PIK3CA-mutant, HR+HER2-BC. At AACR 2023, dose escalation data for RLY-2608 was reported and demonstrated encouraging target inhibition and anti-tumor activity (including partial response), across PIK3CA genotypes with minimal impact on glucose homeostasis. To date, pts have received RLY-2608 at doses of 100–2000 mg/day, with no reported dose-limiting toxicities; the MTD has not been reached. These proof-of-mechanism data indicate that RLY-2608 is the first allosteric, pan-mutant selective PI3Kα inhibitor and that RLY-2608 has broad therapeutic potential in PIK3CA-driven cancers. Methods: Enrollment is ongoing in this global, multi-center, dose escalation/expansion study of RLY-2608 as a single agent in adults who have advanced solid tumors and are refractory, intolerant, or have declined standard therapy; and RLY-2608 in combination with fulvestrant in previously treated pts with HR+/HER2– MBC. Eligibility criteria include presence of PIK3CA mutation (blood or tumor) per local assessment, ECOG performance status 0–1, evaluable disease per RECIST 1.1 and no prior PI3K inhibitor (except in expansion combination group 2). RLY-2608 is administered on a continuous schedule with 4-week cycles. Adverse events (AEs) per CTCAE v5, PK, biomarkers (pAKT, mutant ctDNAs and insulin pathway markers) and anti-tumor activity are assessed serially. Dose escalation employs a Bayesian Optimal Interval design to identify the MTD and/or the recommended Phase 2 dose (RP2D). Following dose escalation, expansion cohorts will enroll patients with select PIK3CA-mutated solid tumors for treatment with RLY-2608 monotherapy and patients with HR+/HER2– MBC for treatment with RLY-2608 and fulvestrant. The primary endpoints are MTD/RP2D and AE profile for single agent and combination; key secondary endpoints are PIK3CA genotype in blood and tumor, PK, biomarkers, and overall response rate. ReDiscover (NCT05216432) is enrolling worldwide. For further information, contact clinicaltrials@relaytx.com. Funding source: This study is funded by Relay Therapeutics, Cambridge, MA, United States.Citation Format: Andreas Varkaris, Komal Jhaveri, Elena Garralda Cabanas, Lucia Sanz, Janice Kim, Cesar A. Perez, Erika Hamilton, Alexander I. Spira, Kari Wisinski, Angel Guerrero, Jason Henry, Jordi Rodon Ahnert, Gege Tan, Xiaoyan Li, Diana Hummel, Tamieka Hunter, Alison Timm, Ramin Samadani, Erika Puente-Poushnejad, Eunice Kwak, Brenton G. Mar, Alison M. Schram. First-in-human global study of RLY-2608, a pan-mutant and isoform selective PI3Kα inhibitor, as a single agent in patients with advanced solid tumors and in combination with fulvestrant in patients with advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-03.