Trial in progress: A phase 2 study of CTX-009 in adult patients with metastatic colorectal cancer who have received two or three prior systemic chemotherapy regimens.

Abstract

TPS281 Background: CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Patients with unresectable locally advanced and unresectable metastatic colorectal cancer (CRC) are sequentially treated with various combinations or single agent courses of cytotoxic chemotherapy agents including 5-fluorouracil and its orally administered family members (capecitabine, TAS-102) oxaliplatin, and irinotecan, as well with targeted therapies such as bevacizumab or aflibercept (anti-VEGF), cetuximab or panitumumab (anti-EGFR), or multitargeted tyrosine kinase inhibitors (regorafenib). In subsets of patients who have had multigene panel testing done and whose tumors have been identified as having mutations that drive their disease such as defective mismatch repair, HER-2 overexpression, or NTRK fusions specific treatments with respectively PD-1 or PD-L1 inhibitors, traztuzumab or larotrectinib or entrectinib can also be used effectively. Despite the approval of multiple new agents in the past two decades, the goals of therapy are generally palliative although some patients will have long disease-free intervals when they respond to therapy. In the cases of patients whose disease has progressed, or who have not tolerated 2 or 3 prior lines of therapy, the expectation for tumor response with the available treatments are less than 5% and the median overall survival is approximately 6 months (for 3rd line therapy) or less (for 4th line therapy). In a Phase 1 study with CTX-009, responses have been seen in patients with colorectal cancers who were treated in the 4th line setting. Since CTX-009 targets tumor induced neoangiogenesis, and monoclonal antibodies that target vascular endothelial growth factor (VEGF) has been shown to extend the lives of patients with advanced colorectal cancer, testing of CTX-009 in the setting of advanced treatment refractory colorectal cancer is justified. Methods: CTX-009 is being evaluated in an open label study in patients with previously treated metastatic CRC. This study is designed as an adaptive Simon Two Stage study, with approximately 37 patients to be enrolled into Stage 1. If criteria are met to move to Stage 2, an additional 47 patients will be enrolled, for a total of approximately 84 patients. To move to stage 2 of the study, 3 or more Complete or Partial Responses must be confirmed via RECIST 1.1. Patients will be treated in 28-day cycles, with CTX-009 administration on Day 1 and 15. The primary objective of the study is to assess the efficacy of CTX-009, as measured by Overall Response Rate (ORR). The study is currently activating sites with first patient in expected in 2022. Clinical trial information: NCT05513742 .