TPS465 Background: Treatment options for PDAC are limited; thus, new therapies that can improve outcomes and extend survival are needed. PDAC is associated with high infiltration by tumor-associated macrophages (TAMs) that inhibit antitumor T-cell activity. Blocking colony-stimulating factor 1 receptor (CSF-1R) signaling—which supports the recruitment, differentiation, and maintenance of immunosupressive macrophages in tumors—may lead to depletion of TAMs and upregulation of T-cell checkpoints. Cabira, a humanized IgG4 monoclonal antibody, binds to CSF-1R and blocks its signaling, a key determinant of TAM activation and survival. By reducing TAMs and promoting a proinflammatory microenvironment, cabira may stimulate T-cell responses, thereby sensitizing PDAC to therapy with nivo (anti‒PD-1). In a phase 1a/b study cabira + nivo was tolerable and showed evidence of on-target tumor immune modulation and durable clinical benefit in heavily pretreated patients (pts) with advanced PDAC (Wainberg et al. J Immunother Cancer. 2017 [abst O42]; Carleton et al. J Clin Oncol. 2018 [abst 3020]). Here we describe a randomized, open-label, phase 2 study evaluating the safety and efficacy of cabira + nivo ± chemo in advanced PDAC. Methods: Pts aged ≥18 y with locally advanced/metastatic PDAC that progressed on/after first-line chemo (gemcitabine [gem] or 5-fluorouracil [5-FU] based) will be enrolled. Pts with active/suspected autoimmune disease, uncontrolled/significant cardiovascular disease, or prior exposure to select immune cell–modulating antibodies are not eligible. Depending on prior chemo received, pts will be randomized to 1 of 4 arms (n≈40 each): cabira + nivo; cabira + nivo + gem/nab-paclitaxel; cabira + nivo + oxaliplatin/5-FU/leucovorin; or investigator’s choice of standard-of-care chemo. Endpoints include median progression-free survival (primary), overall survival rate, objective response rate, median duration of response, pharmacokinetics, and safety. In a completed preliminary safety cohort, 12 pts were treated with cabira + nivo + chemo and monitored for 4 wk; competitive enrollment is open, with 32 pts enrolled. (NCT03336216, NCT02526017) Clinical trial information: NCT03336216.