Abstract 5515: Neoadjuvant chemoradiotherapy for rectal cancer with CRLX101, an investigational nanoparticle-drug conjugate with a camptothecin payload

Abstract

Abstract Background: There has been great interest in developing novel agents and strategies to improve chemoradiotherapy (CRT) for locally advanced rectal cancer. Irinotecan, a campothecin (CPT) analogue, held high potential, but the combination was clinically infeasible due to severe gastrointestinal toxicities. CRLX101, is an investigational nanoparticle drug conjugate (NDC). Preclinical experiments showed that CRLX101 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 rectal CRT (5-FU + XRT) may further improve the therapeutic index in this setting. Methods: Synergy with CRLX101 in combination with either XRT or CRT was studied in vitro (SW480 and HT29 colorectal cancer cell lines) and in vivo (murine flank xenograft models). Skin toxicity and hematologic toxicity were also characterized. In order to test the synergy hypothesis in the clinic, a Phase Ib/II clinical trial (LCCC1315) evaluating the addition of CRLX101 to CRT in the neo-adjuvant treatment of rectal cancer is currently underway. A standard 3 + 3 design is being employed for the phase Ib with a CRLX101 starting dose of 12 mg/m2 in the first cohort escalating to the CRLX101 monotherapy MTD of 15 mg/m2 in the second. The primary phase 2 end-point is the pathological complete response (pCR) rate from treatment. Results: CRLX101 was found to be as potent as camptothecin in vitro. We have demonstrated that CRLX101 functions by inhibition of both DNA repair and HIF-1α signaling. The addition of CRLX101 to radiotherapy increased and prolonged the number of γH2AX foci, even at 24 hours post radiotherapy. We also confirmed that CRLX101 decreased HIF-1α and its downstream targets VEGF and carbonic anhydrase IX in mice bearing HT29 xenografts. Our findings were further validated in vivo: we demonstrated that both CRLX101+5FU+XRT and CRLX101+XRT delayed tumor growth more than other regimens (p-values < 0.05). More importantly, we found CRT with CRLX101+5FU is significantly more effective than CRT with oxaliplatin+5FU (25 days to double tumor volume vs. 11 days), a regimen that has been extensively studied clinically. Preclinical toxicity studies demonstrated that the addition of CRLX101 did not increase hematologic or skin toxicities. In the ongoing clinical trial, none of the first 6 patients enrolled have experienced dose-limiting toxicities, and 1 out of 3 patients who underwent surgery had a pCR. The other 2 patients had extensive treatment response with minimal residual tumor. Conclusions: Preclinical data suggests that CRLX101 improves the therapeutic index of CRT for rectal cancer. Preliminary clinical data is encouraging, and supports further clinical assessment of CRLX101+5FU+XRT in patients with locally advanced rectal cancer. Citation Format: XI TIAN, Minh Nguyen, Henry Foote, Kyle T. Wagner, Hanna K. Sanoff, Autumn J. McRee, Bert H. O'Neil, Benjamin F. Calvo, William A. Blackstock, Joel E. Tepper, Edward Garmey, Scott Eliasof, Andrew Z. Wang. Neoadjuvant chemoradiotherapy for rectal cancer with CRLX101, an investigational nanoparticle-drug conjugate with a camptothecin payload. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5515. doi:10.1158/1538-7445.AM2015-5515