Cb-839, Panitumumab, And Irinotecan In Ras Wildtype (Wt) Metastatic Colorectal Cancer (Mcrc): Phase I Results

574Background: Epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) are approved in RAS WT mCRC; however, patients (pts) will develop resistance to these agents. Alterations in glutamine (Gln) metabolism play a critical role in cancer cell growth. In cancers such as CRC, EGFR and Gln cooperate to provide signals and fuel for mitogen activated protein kinase-dependent cell growth. Our in vitro data show that Gln abrogates EGFR inhibition, and blockade of Gln transport restores sensitivity. We also observed a greater antitumor response in vivo with EGFR mAb plus CB-839, an inhibitor of a rate-limiting enzyme of Gln metabolism, than either agent alone. We designed a phase I/II study (NCT03263429) to evaluate CB-839 + panitumumab + irinotecan in anti-EGFR refractory RAS WT mCRC. Methods: Dose escalation used a Bayesian continual reassessment method targeting a 25% toxicity probability. CB-839 (600 mg or 800 mg twice daily [BID]) were evaluated with panitumumab (6 mg/kg) and irinotecan (180 mg/...