Improving Neoadjuvant Chemoradiotherapy For Rectal Cancer With Crlx101, A Nanoparticle-Drug Conjugate, With A Camptothecin Payload.

645 Background: There has been great interest in developing novel agents and strategies to improve chemoradiotherapy (CRT) for locally advanced rectal cancer. Irinotecan, a camptothecin (CPT) analogue, held high potential, but the combination was clinically infeasible due to severe gastrointestinal toxicities. CRLX101, a dynamically tumor targeted nanoparticle-drug conjugate differentially delivers CPT into cancer cells and appears to durably suppress HIF-1α as well as topoisomerase 1, but with less gastrointestinal toxicities than irinotecan. We therefore hypothesized that the addition of CRLX101 to CRT may further improve the therapeutic index in this setting. Methods: CRLX101 was evaluated using murine flank xenograft models (SW480 and HT29) of colorectal cancer alone or in combination with radiotherapy (XRT) and/or 5-FU and compared to CPT plus CRT. Skin toxicity and hematologic toxicity were also studied. In addition, a Phase Ib/II clinical trial (LCCC1315) evaluating the addition of CRLX101 to CRT i...