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. 2024;20(37):2915-2925.
doi: 10.1080/14796694.2024.2395235. Epub 2024 Oct 8.

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

Charles D Lopez  1   2 , Adel Kardosh  1   2 , Emerson Y Chen  1 , Guillaume Pegna  1 , Alexander Guimaraes  2   3 , Bryan Foster  4 , Brian Brinkerhoff  4 , Shaun M Goodyear  1   2 , Jeong-Youn Lim  5 , Erin Taber  1 , Brindha Rajagopalan  1 , Exodus Edmerson  1 , Johnson Vo  1 , Katherine Nelson  1 , Anna Jackson  1 , Tasha Gingerich  1 , Anne Fahlman  1 , Christopher Lessenich  1 , Francesca Fennell  1 , Diane Ventura  1 , Preeyam Roy  1 , Dove Keith  2 , Brett Sheppard  2   6 , Jonathan R Brody  2   6 , Gordon B Mills  2   7 , Ze'ev A Ronai  8 , Rosalie C Sears  2   9
Affiliations

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

Charles D Lopez et al. Future Oncol. 2024.

Abstract

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.

Keywords: L-asparaginase; MEK inhibition; calaspargase pegol-mknl; cobimetinib; drug resistance; metabolic reprogramming; pancreatic cancer.

Plain language summary

[Box: see text].

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Conflict of interest statement

CDL received grants or has contracts with Taiho, Roche, AstraZeneca, Servier and AACR. AK has provided consulting support for Exelixis, Astellas Pharma, Astex Pharmaceuticals, and Genentech, and research support from Natera. EYC has received honorarium from Horizon CME and has provided research support for Taiho Oncology. AG, GP, BF, BB, SMG, JYL, ET, BR, EE, JV, KN, AJ, TG, AF, CL, FF, DV, PR, DK, and BS have no conflict of interests. JRB: reports grants from Code Bio and personal fees from Ideaya Biosciences; personal fees from Springer (co-editor), Taylor & Francis (co-editor); and nonfinancial support and other support from Perthera, LLC; and is the co-owner of Faster betterMedia LLC. GBM: SAB/Consultant: AstraZeneca, BlueDot, Chrysallis Biotechnology, Ellipses Pharma, ImmunoMET, Infinity, Ionis, Lilly, Medacorp, Nanostring, PDX Pharmaceuticals, Signalchem Lifesciences, Tarveda, Turbine, Zentalis Pharmaceuticals; Stock/Options/Financial: Catena Pharmaceuticals, ImmunoMet, SignalChem, Tarveda, Turbine; Licensed Technology: HRD assay to Myriad Genetics, digital spatial profiling patents with Nanostring. ZAR: is the founder of and a Scientific Advisor to Pangea Biomed. RCS: SAB/Consultant for Rappta Therapeutics; sponsored research from Cardiff Oncology and AstraZeneca. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1.
Figure 1.
Exploiting asparagine auxotrophy in pancreatic cancer cells. Depletion of extracellular asparagine by L-asparaginase (to aspartate) can reduce cancer cell growth in tumors auxotrophic for asparagine. However, aberrant RAS/MEK/ERK signaling can sustain ASNS expression, thus limiting the efficacy of this strategy. Inhibition of MEK signaling reduces ATF4 transcriptional factor levels and subsequent expression of ASNS, thereby sensitizing cancer cells to asparagine starvation and reducing tumor cell growth and survival. Figure previously presented in a ASCO Gastrointestinal cancer Symposium 2023 poster. ASNS: Asparagine synthetase.
Figure 2.
Figure 2.
CASPER trial study design. (A) CASPER is a Phase IB study to evaluate the safety and tolerability calaspargase pegol-mknl and cobimetinib in patients with locally-advanced or metastatic PDAC. Pre- and on-treatment biopsies, and serial blood collection will be used toward deep analysis of the tumor and immune microenvironments to better inform on treatment response. (B) Flowchart for CASPER trial conduct using the BOIN design. Figure previously presented in a ASCO Gastrointestinal cancer Symposium 2023 poster. BOIN: Bayesian optimal interval.
See this image and copyright information in PMC

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