Abstract A133: CASPER: A Phase Ib trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer
Lyndsey Sandow, Adel Kardosh, Emerson Y. Chen, Guillaume Pegna, Alexander Guimaraes, Bryan Foster, Brian Brinkerhoff, Shaun Goodyear, Jeong-Youn Lim, Emile Latour, Erin Taber, Brindha Rajagopalan, Johnson Vo, Katherine Nelson, Anna Jackson, Abby Keller, Lillian Raley, Katherine Jaffe, Jieun Park, Tasha Gingerich, Christopher Lessenich, Diane Ventura, Preeyam Roy, Dove Keith, Brett Sheppard, Jonathan Brody, Gordon Mills, Rosalie Sears, Charles D. LopezAbstract
Background:
A hallmark of PDAC is its ability to reprogram metabolism. A majority of PDAC tumors (50-80%) express low levels of asparagine synthetase (ASNS) rendering them dependent on extracellular asparagine. L-asparaginase (ASNase) depletes systemic asparagine to restrict tumor cell growth, but clinical trials of ASNase in PDAC have only shown marginal improvements despite low ASNS expression and auxotrophy for asparagine. Preclinical studies suggest that MEK/ERK signaling limits ASNase efficacy as targeted inhibition of MEK signaling in combination with ASNase synergizes to reduce tumor growth in PDAC mouse models; however, this strategy has not been tested in patients.
Methods:
CASPER is an open-label, phase Ib, single-arm dose escalation study evaluating calaspargase pegol-mnkl (cala) plus cobimetinib (cobi) in patients with locally advanced or metastatic PDAC after progression on first line therapy (NCT05034627). A Bayesian optimal interval (BOIN) design was used to find the maximum tolerated dose (MTD) targeting a 30% dose-limiting toxicity (DLT) rate. Up to 15 patients were planned for enrollment. The primary endpoint was the incidence of DLTs during Cycle 1 (21 days) to find the MTD. Starting in cycle 1, patients received cobi (DL1 40 mg, DL2 60mg, DL3 60mg) for days 1-14, and cala (DL1 750 U/m2, DL2 1000 U/m2, DL3 1500 U/m2) on day 1 of each 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal. Secondary endpoints included overall response rate (ORR) and disease control rate (DCR) per RECIST v1.1, and plasma ASNase activity. Paired tumor biopsies and serial blood were collected for exploratory objectives with integrated multi-omic analytics.
Results:
A total of 20 patients were consented and 15 patients were treated: 4 at DL1, 7 at DL2, and 4 at DL3. Thirteen patients were DLT evaluable: 4 at DL1, 6 at DL2 and 3 at DL3. Both DLTs occurred at DL3 (66.7%): Grade 2 rash (n=1) and Grade 3 fatigue/dizziness (n=1). No DLTs were observed in DL1 or DL2. The MTD was established at DL2. Seven SAEs occurred in 6 patients; 1 was possibly related to study drug (syncope, DL2). Grade ≥ 3 treatment emergent adverse events occurred in 4 (26%) patients: nausea (n=1), syncope (n=1), hyponatremia (n=1) and fibrinogen decrease (n=1). Only nausea was study related. Cala infusion reactions occurred in 2 patients (13.3%) leading to treatment discontinuation. Median treatment duration was 49 days (range 14-176). Among the 8 efficacy evaluable patients, no OR were observed. There was one minor response (12.5%) and stable disease was achieved in 3 patients (37.5%). Plasma ASNase enzyme activity increased with continued dosing, reaching mean levels of 0.139 IU/mL at C1D15 and 0.188 IU/mL at C2D15.
Conclusion:
We establish DL2 as the MTD for cala and cobi in advanced PDAC. Sustained plasma ASNase activity demonstrated pharmacodynamic target engagement. Disease stabilization and a minor response were observed in heavily pretreated patients, supporting further evaluation of this targeted combination in PDAC.
Citation Format:
Lyndsey Sandow, Adel Kardosh, Emerson Y. Chen, Guillaume Pegna, Alexander Guimaraes, Bryan Foster, Brian Brinkerhoff, Shaun Goodyear, Jeong-Youn Lim, Emile Latour, Erin Taber, Brindha Rajagopalan, Johnson Vo, Katherine Nelson, Anna Jackson, Abby Keller, Lillian Raley, Katherine Jaffe, Jieun Park, Tasha Gingerich, Christopher Lessenich, Diane Ventura, Preeyam Roy, Dove Keith, Brett Sheppard, Jonathan Brody, Gordon Mills, Rosalie Sears, Charles D. Lopez. CASPER: A Phase Ib trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A133.