Background: Oleclumab is a human mAb that binds to CD73 and inhibits production of immunosuppressive adenosine. This is a first-in-human study to investigate the safety, efficacy, and pharmacodynamics of oleclumab alone or in combination with durvalumab in patients (pts) with advanced panc or MSS-CRC. Methods: A 3+3 dose-escalation design was followed in which pts received one of 4 escalating doses of oleclumab IV with or without durvalumab 10 mg/kg IV Q2W until disease progression, followed by study expansion with high dose of oleclumab plus durvalumab 10 mg/kg Q2W. AEs and tumor response (RECIST v1.1) were assessed. Free soluble CD73 and cell surface CD73 on lymphocytes were measured by ELISA and flow cytometry, respectively. Tumoral CD73 was centrally assessed by an in situ enzyme assay and IHC. Results: The initial dose-escalation and PD exploration enrolled 42 monotherapy and 24 combination pts with no reported DLTs. The minimum target serum concentration was exceeded at the top 2 doses. Sustained decrease in free soluble CD73 and CD73 on peripheral T cells was demonstrated across all doses and pts. Decreased CD73 enzymatic activity was observed in all evaluable frozen tumor biopsy samples (n = 4) 20 days after treatment with the top 2 doses of oleclumab. Treatment with oleclumab alone decreased tumoral CD73 expression (5/9) while increasing CD8+ TILs in all 5 samples. Subsequently, durva + oleclumab highest dose was selected for expansion in 2-5L CRC (21 pts) and 2-3L panc (20 pts). The most commonly reported TRAEs in combo expansion were diarrhea (8.7%), pyrexia (8.7%), fatigue (6.5%), and increases in ALT (6.5%), AST (6.5%), and ALP (6.5%). PR was observed for 1/21 CRC (5L) and 2/20 panc (2 and 3L) pts; SD was observed in 2/21 CRC and 3/20 panc pts. Duration of treatment for subjects with disease control was 84-322 days (CRC) and 28-232 days (panc). Treatment is ongoing for 1 CRC (322 days) and 2 panc pts (140 and 182 days). Conclusions: Treatment with oleclumab and durvalumab had a manageable safety profile and PD consistent with mechanism of action. Combination therapy has encouraging clinical activity in panc and potentially in CRC pts. Clinical trial information: 02503774.