Background: A proprietary in vivo target discovery screen identified creatine kinase-B (CKB) as a cancer driver in KRAS mutant (KRAS-mut) CRC. CKB promotes tumor growth and survival under hypoxia. CKB generates the energetic metabolite phospho-creatine (PCr), which is imported into cells through the creatine transporter, SLC6A8. PCr generates intracellular ATP that enables tumoral survival. RGX-202-01 is a small molecule inhibitor of SLC6A8 that depletes intracellular PCr and ATP, resulting in apoptosis. In a completed Phase 1a study, RGX-202-01 monotherapy demonstrated objective anti-tumor activity in the relapsed/refractory KRAS-mut CRC setting without dose-limiting toxicity. The objectives of this ongoing Phase 1b study are to evaluate safety, PK/PD, and efficacy of RGX-202-01 in combination with standard-of-care (SOC) FOLFIRI + BEV in second-line CRC, a setting where SOC therapy results in an ORR and mPFS of approximately 15% and 6 months, respectively. Methods: Subjects with advanced CRC who had disease progression after receiving a first line oxaliplatin-containing regimen were eligible. The dose expansion phase of the study was restricted to CKB-expressing CRC tumors. As of 01-14-2022, 16 patients (pts) have been enrolled. 8 pts were enrolled in 2 dose escalation cohorts of RGX-202-01: 2400mg BID (4 pts) and 3000mg BID (4 pts) combined with FOLFIRI and BEV. 8 pts were enrolled in the dose expansion phase of the study and received RGX-202-01 3000mg BID combined with FOLFIRI and BEV Results: No DLTs were observed and the MTD was not reached in the dose escalation phase. Grade 3 TRAEs were observed in 25% of pts. Most common TRAEs were GI in nature. There were no Grade 4-5 TRAEs. PK analysis showed sustained RGX-202-01 drug exposures in both escalation cohorts above target levels (IC₅₀). Serum and urine creatine measurements indicated robust SLC6A8 target inhibition. 9 pts had KRAS-mut CRC, and all were evaluable for RECIST 1.1 response. 4 of these pts had cPR,1 patient had uPR and 4 pts had SD as best response (ORR 56%, DCR 100%). 5 of these pts remain on therapy ranging from 11-54 weeks and a patient with a cPR at 16 weeks followed by surgery with curative intent remains with NED at 24 weeks after surgery. Seven pts had KRAS WT CRC, of which 3 were evaluable (2 pts are pending 1^st scan assessment; 2 pts are off study and did not receive 1 full cycle of treatment). Of the 3 KRAS WT evaluable pts, all had SD as best response. 2 were on study for 38 and 24 weeks respectively and 1 is ongoing at 16 weeks. Conclusions: RGX-202-01 combined with FOLFIRI and BEV was well tolerated with no DLTs at the dose levels evaluated which induced potent inhibition of SLC6A8. Antitumor activity was noted in KRAS mutated colorectal cancer, consistent with preferential pre-clinical activity in RAS mutated tumors. Enrollment in the expansion phase continues. Clinical trial information: NCT03597581.