Background: mPAC has a poor prognosis, with a 5-year survival rate of 2.3%. CDK4/6 is often deregulated in mPAC due to loss of CDKN2A via homozygous deletion or epigenetic silencing, resulting in the loss of the p16INK4a protein that naturally inhibits CDK4/6. CDK4/6 inactivates the retinoblastoma protein (RB), allowing E2F family transcription factors to promote cell cycle progression. Inhibitors of CDK4/6 have been ineffective as single agents in part due to Ras-mediated activation of alternate signaling pathways including the PI3K-mTOR pathway. We have shown that co-inhibition of the CDK4/6 and mTOR pathways suppresses growth in mPAC patient-derived xenografts. We are investigating the activity of the combination of ribociclib (a CDK4/6 inhibitor) and everolimus (an mTOR inhibitor) in pts with mPAC. Methods: This is a phase I/II, single-arm, open-label study. Eligible pts are ≥ 18 years old, have histologically confirmed mPAC with progression on at least 1 prior 5-FU- and 1 gemcitabine-based regimen, an ECOG performance status of 0-1, normal bone marrow and hepato-renal function, and no concurrent anticancer therapy. Exclusion criteria are use of prior CDK or mTOR inhibitors or known CNS metastases. Pts in the phase I portion will be enrolled in a 3+3 design to find the recommended phase II dose (RP2D) of ribociclib with dose escalation and de-escalation levels. Pts in the phase II portion will receive ribociclib at the RP2D daily for 21 days out of a 28 cycle with everolimus 2.5 mg daily continuously. The phase II portion will use a Simon’s Minimax 2-stage design. Disease will be assessed by imaging every 8 weeks. Treatment will continue if it is tolerated and there is no disease progression. The primary endpoint of the phase II portion is progression free survival (PFS) at 8 weeks. Secondary endpoints are median PFS, median overall survival, best overall response rate by RECIST 1.1, and safety. Correlative studies include assessment of the pharmacodynamic effects on the RB pathway using pre- and on-treatment tumor biopsies, tumor sequencing, and analysis of circulating tumor DNA. Enrollment began in Q2 2017 with a goal accrual of 44 pts. Clinical trial information: NCT02985125