Background: Metabolic adaptation provides rapidly dividing cancer cells the flexibility to maintain homeostasis as nutrient supplies are continuously exhausted in the tumor microenvironment. Asparagine synthetase (ASNS) catalyzes ATP-dependent biosynthesis of the non-essential amino acid asparagine from aspartate and glutamine. Cells lacking ASNS, however, are auxotrophic for asparagine. Use of L-asparaginase (ASNase) to promote asparagine starvation in PDAC and other solid tumors with low ASNS levels is a rationale treatment strategy; however, aberrant RAS/MAPK signaling can circumvent effects of ASNase. Preclinical data shows that targeted inhibition of MAPK signaling along with ASNase is active against PDAC; however, this has not been tested in patients to date. Methods: CASPER is an open-label, phase IB, single-arm, dose-escalation study to evaluate the safety and tolerability of combining cala and cobi in patients with locally-advanced or metastatic PDAC. Participants receive cala and cobi at assigned dose level. The study uses a Bayesian Optimal Interval (BOIN) design to determine the maximum tolerated dose (MTD) for the combination of study agents. Up to 15 participants will be enrolled and treated, with a cohort of 3 participants assessed before a decision is made to escalate, de-escalate, or maintain the current dose level before initiating the next cohort. MTD is defined as the dose level where dose-limiting toxicity (DLT) probability is closest to the target toxicity rate of 30% after applying isotonic regression to the observed dose-level-specific DLT rate. Per BOIN, the dose level is escalated, maintained, or de-escalated based on comparisons of the observed DLT rate and pre-specified boundaries (0.236, 0.359). Starting in Cycle (C) 1, patients receive cobi (at assigned dose level) for Days (D) 1-14, and their assigned dose of cala on D1 of each 21-day cycle. If the combination of cala and cobi is tolerated and does not incur DLTs, participants will continue receiving their assigned dose of cala and cobi until evidence of disease progression, unacceptable toxicity, or study withdrawal. The DLT period starts on C1D1 and ends C2D21. Secondary endpoints include preliminary assessment of overall response rate (ORR), disease control rate (DCR), and mean levels of plasma ASNase. Paired tumor biopsies and serial blood will be used for exploratory objectives combining deep multi-omic analytics with clinical data. The trial is currently open with 1 patient enrolled at time of submission. Clinical trial information: NCT05034627.

* 21-day cycles, **Starting dose, *** % dose of target dose.