Background: Effective therapies are limited for advanced metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) who have progressed after 1^st line gemcitabine-based chemotherapy (Gem). FOLFOX has clinical benefit in Gem-refractory PDAC pts. A phase 1 trial demonstrated promising activity with pegilodecakin (PEG; pegylated IL-10) and FOLFOX in Gem-refractory PDAC pts, providing rationale for the phase 3 trial (SEQUOIA; NCT02923921). Methods: SEQUOIA is a randomized phase 3 study of FOLFOX alone or with PEG in Gem-refractory PDAC pts. Pts were randomized 1:1, excluding pts with prior surgery and radiation, and received FOLFOX (dI-Leucovorin [400 mg/m²], oxaliplatin [85 mg/m²] followed by bolus 5-FU [400 mg/m²], and a 46-48 hr infusion of 5-FU [2400 mg/m²]) on day 1 of a 14-day cycle up to 12 cycles. PEG + FOLFOX arm received PEG (0.4 mg/d if ≤80kg and 0.8mg/d if > 80 kg) on Days 1-5 then Days 8-12 + FOLFOX. Pts could continue PEG monotherapy (0.8mg/d if ≤ 80 kg and 1.6 mg/d if > 80 kg) after FOLFOX discontinuation. Primary objective was OS. Secondary objectives included PFS, ORR per RECIST 1.1, and safety. Assuming OS HR of 0.74, the study was powered to 85% at 2-sided α = 0.05 with ~566 pts to detect superiority of PEG + FOLFOX. Results: As of Sept 9, 2019, 567 pts were randomized to PEG + FOLFOX (283) or FOLFOX (284). The majority (94.7%) had 1^st line Gem+nab paclitaxel. The mOS was similar between FOLFOX + PEG arm [5.8 months] and FOLFOX arm [6.3 months] with HR = 1.045 (95% CI [0.863, 1.265], p = 0.6565). No statistical difference was observed for PFS, mPFS was 2.1 months in both arms with HR = 0.981, (95% CI [0.808, 1.190], p = 0.8144). ORR was 4.6% on the PEG+FOLFOX arm and 5.6% on the FOLFOX arm. Grade ≥3 adverse events that were 5% higher on the PEG+FOLFOX arm included thrombocytopenia (25.2% vs. 3.6%), anemia (16.2% vs. 4.0%), neutropenia (29.5% vs. 22.7%), and fatigue (17.6% vs. 10.8%). Conclusions: The addition of PEG to FOLFOX did not improve efficacy (OS, PFS, ORR) in advanced PDAC pts who have progressed after 1st line Gem-containing therapy. Safety findings were consistent with previous data observed from PEG + chemotherapy; toxicity was manageable and tolerable. Clinical trial information: NCT02923921