Background: Autophagy, a catabolic process to resupply nutrients and recycle damaged organelles, is activated by cancer cells to survive hypoxia, limited nutrients, or chemotherapy. The RAS family of oncoproteins are the most commonly mutated oncoproteins in human cancer and require autophagy for tumor growth and survival. RAS activates signaling through the mitogen-activated protein kinase (MAPK) pathway that is responsible for regulating cell survival. ULK1/2 are kinases that receive and process input from nutrient and stress sensors to initiate autophagy. Inhibition of the MAPK pathway releases tonic inhibition of ULK1/2 and triggers autophagy as a survival mechanism, suggesting that ULK1/2 may provide a promising therapeutic target. DCC-3116 is a potent and selective ULK inhibitor that showed preclinical antitumor activity in combination with the MAPK kinase inhibitor trametinib (Smith et al. 2019 AACR-NCI-EORTC Poster). Here, we describe the Phase 1 study of DCC-3116 monotherapy and combination therapy with trametinib in patients with RAS or RAF mutant advanced or metastatic solid tumors. Methods: This is a Phase 1/2, multicenter, open-label, first-in-human study evaluating safety, tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of DCC-3116 as a single agent and in combination with trametinib (NCT04892017). The study consists of single agent and combination dose escalation cohorts and expansion of combinations with demonstrated safety. Single-agent oral DCC-3116 will be administered twice daily (BID) in escalating cohorts in 28-day cycles until the recommended Phase 2 dose (RP2D) is determined. Subsequently, the single-agent RP2D or one level below the maximum tolerated dose (MTD) will be administered in combination with trametinib. Participants in the dose escalation phase must be ≥18 years with a histologically confirmed diagnosis of advanced or metastatic solid tumor with a documented RAS or RAF mutation, have progressed despite standard therapies, and have received ≥1 prior anticancer therapy. In the dose expansion phase, DCC-3116 will be given BID with trametinib in 28-day cycles to participants with pancreatic ductal adenocarcinoma, non-small cell lung cancer, colorectal cancer, or melanoma (Cohorts 1–4, respectively). Primary outcomes are incidence of adverse events, identification of MTD, and objective response rate per RECIST v1.1. Secondary outcomes include duration of response, clinical benefit rate, time to response, progression-free survival, and pharmacokinetic/pharmacodynamic attributes. Participants in dose expansion cohorts must be ≥18 years and meet cohort-specific criteria including histologically confirmed diagnoses, documented mutation status, and number of prior lines of systemic therapy. This study is recruiting and plans to enroll up to 130 participants. Clinical trial information: NCT04892017.