Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a dearth of effective therapeutic options. Over 90% of PDAC harbor activating mutations in the KRAS oncoprotein, which in turn leads to activation of downstream effector proteins in the the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling cascade serving to promote tumor cell survival, growth and metastasis. Unfortunately, single agent treatment with MAPK-inhibitors have had limited therapeutic efficacy in patients with PDAC owing to development of various tumor-cell intrinsic resistance mechanisms, including upregulation of autophagy. Hydroxychloroquine is an antimalarial drug that functions to inhibit autophagy by inhibiting acidification of lysosomes. Previously published preclinical data suggest combination therapy with binimetinib, a MEK 1/2 inhibitor, and hydroxychloroquine leads to enhanced killing of PDAC cells in vitro and in vivo. Methods: This is a single arm, single center phase I trial of binimetinib plus hydroxychloroquine in patients with metastatic pancreatic cancer harboring a KRAS mutation. All patients will receive binimetinib at a fixed dose of 45mg PO twice daily (14-day cycles) while hydroxychloroquine will be dosed at 400mg PO twice daily (14-day cycles) and dose escalated using a Bayesian optimal interval design with a target toxicity rate of 0.3. Key eligibility criteria include histologically confirmed metastatic pancreatic adenocarcinoma, prior treatment with at least one line of systemic therapy and a documented KRAS mutation. An estimated 24 patients will be enrolled in the first phase of this study and up to 15 patients in the dose expansion cohort. The primary endpoint of this study is to determine the maximum tolerated dose (MTD) of hydroxychloroquine when combined with a fixed dose of binimetinib. Key secondary endpoints include safety and toxicity profile, response rate, progression free survival (PFS) and overall survival (OS). This study is ongoing and has enrolled 10 patients at the time of submission. Clinical trial information: NCT04132505.