Abstract C057: A phase I study to access the safety and efficacy of valecobulin (CKD-516), oral vascular disruption agent, in combination with irinotecan in patients with previously treated metastatic colorectal cancer

Background: Tumor neovascularization is a critical step for tumor growth and results in structurally and functionally abnormal tumor blood vessels. Vascular disrupting agents (VDAs) destroy established tumor vessels, subsequently causing tumor ischemia and necrosis. Valecobulin is an orally available VDA that acts as an inhibitor of tubulin polymerization. Thus valecobulin affects the central regions that are often resistant to conventional chemotherapy agents. Valecobulin combined with irinotecan showed significantly improved anti-cancer activity in colorectal cancer (CRC) bearing mouse models. On the basis of this background, we conducted a phase I dose-finding study of valecobulin in combination with biweekly irinotecan in CRC patient who had failed standard therapies including irinotecan basis regimen. Methods: Patients with metastatic CRC refractory to previous chemotherapy including one irinotecan containing regimen were enrolled in dose escalation cohort (Part A, traditional 3+3 design) and expansion cohort (Part B). The primary objective was to determine the recommended dose of expansion cohort in Part A, and to evaluate the antitumor activity and safety in Part B. All patient received valecobulin 5, 7, 9, or 11 mg/m2 PO on Day 1-5 and Day 8-12 (5 days of treatment followed by 2 days of rest) in combination with irinotecan 120 (Level 1-4) or 150 mg/m2 IV (Level 5) on Day 1 (14 days treatment cycle). Adverse events (AEs) and antitumor activity were evaluated using CTCAE V4.03 and RECIST V 1.1, each other. Results: A total 16 patients were enrolled to Part A, and 23 patients to Part B. Of 39 patients(≥19 years), 26(66.8%) were male, median age was 59 years(30-74). Past treatment history showed that most patients have already received 2nd (n=10; 25.6%), 3rd(n=12; 30.8%) or 4th line (n=13; 33.3%) chemotherapy. There was no dose limited toxicity until Level 5 and valecobulin 11 mg/m2 and irinotecan 120 mg/m2 (Level 4) was determined to the recommended dose of Part B according to reduction trend in whole treatment period. Among total 39 patients, the median progression-free survival was 126 days (95% CI: 83-175) and the overall survival was 361 days (95% CI: 240-526). PR was observed in 1 patient (2.9%) and SD was 26 (76.5%) among evaluable 34 patients. Common grade 3/4 AEs (>10%) regardless of cause included neutrophil decrease 51.3%, diarrhea 30.7% and vomiting 15.4%. The major cardiovascular events which were other VDAs’ common toxicity, were not observed. There were no treatment-related deaths. Conclusions Valecobulin in combination with irinotecan demonstrated a manageable safety profile and preliminary antitumor activity in chemotherapy refractory metastatic colorectal cancer. Citation Format: Tae Won Kim, Jeong Eun Kim, Hyeong-Seok Lim, Young Suk Park, Won Ki Kang, Sang Joon Shin, Joong Bae Ahn, Sae-Won Han, Tae-You Kim. A phase I study to access the safety and efficacy of valecobulin (CKD-516), oral vascular disruption agent, in combination with irinotecan in patients with previously treated metastatic colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C057. doi:10.1158/1535-7163.TARG-19-C057