CASPER: A Phase I trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer

Asparagine synthetase (ASNS) catalyzes the biosynthesis of asparagine from aspartate and glutamine. Cells lacking ASNS, however, are auxotrophic for asparagine. Use of L-asparaginase to promote asparagine starvation in solid tumors with low ASNS levels, such as pancreatic ductal adenocarcinoma (PDAC), is a rationale treatment strategy. However, tumor cell resistance to L-asparaginase has limited its clinical utility. Our preclinical studies show that RAS/MAPK signaling circumvents L-asparaginase-induced tumor killing, but L-asparaginase and MEK inhibition potentiated tumor killing; suggesting that this combination may provide meaningful clinical benefit to patients with PDAC. This Phase I trial (NCT05034627) will evaluate the safety and tolerability of the MEK inhibitor, cobimetinib, in combination with pegylated L-asparaginase, L calaspargase pegol-mknl, in patients with locally-advanced or metastatic PDAC. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis. The majority (50–80%) of PDAC lack asparagine synthetase and ability to synthesize asparagine; and are dependent on extracellular sources of asparagine. Use of L-asparaginase to promote asparagine starvation in solid tumors can be exploited as a rationale treatment strategy. Under conditions of nutrient stress, aberrant RAS/MEK/ERK signaling induces ATF4 and in turn, asparagine synthetase to bolster intracellular biosynthesis of asparagine. Targeted inhibition of RAS/MEK/ERK signaling along with an L-asparaginase has the potential to provide meaningful clinical benefit to patients with advanced PDAC. There is no prior research that has provided a safety profile for a MEK inhibitor in combination with L-asparaginase. This Phase IB trial will evaluate the safety and tolerability of the MEK inhibitor, cobimetinib, in combination with the pegylated L-asparaginase, L calaspargase pegol-mknl, in patients with locally-advanced or metastatic PDAC. The trial uses a Bayesian optimal interval design to assess the maximum tolerated dose for combining cobimetinib and calaspargase pegol-mknl. The primary end point estimates the incidence of dose limiting toxicities associated with combination regimen of cobimetinib and calaspargase pegol-mknl. Secondary objectives estimate the preliminary objective response rate and clinical benefit rate. Adults with locally-advanced or metastatic PDAC that have progressed on, been intolerant to, or refused systemic therapy that is consistent with institutional standards (e.g., Gemcitabine-based, or FOLFIRINOX). A maximum of 15 patients will be enrolled in cohorts of 3 to receive their assigned dose of calaspargase pegol-mknl and cobimetinib. Up to 6 core-needle biopsies at baseline and on Cycle 2 Day 14.