Phase 2 trial of CBX-12 for metastatic chemotherapy-refractory microsatellite stable colorectal cancer (ETCTN 10707).

Abstract

TPS259 Background: Despite currently approved therapies, most patients with metastatic colorectal cancer (mCRC) progress through all approved treatments and eventually succumb to their disease. Thus, novel therapies for chemotherapy-refractory mCRC are desperately needed. Inhibition of the DNA unwinding enzyme TOP1 is a well-characterized and clinically successful treatment strategy for mCRC. CBX-12 is a novel peptide-drug conjugate comprised of an exatecan warhead linked to a pH-Low Insertion Peptide (pHLIP). The principle behind this targeting mechanism is based on the Warburg effect, in which tumors establish a low pH extracellular environment. The pHLIP moiety of CBX-12 preferentially forms a unidirectional, transmembrane alpha helix in a low-pH extracellular environment. Thus, CBX-12 delivers its exatecan cytotoxic warhead preferentially into tumor cells. In mouse xenograft models, CBX-12 inhibited the HCT116 CRC xenograft model more potently than an equimolar dose of free exatecan. The phase 1 study of CBX-12 reported cytopenias as the predominant AEs and confirmed responses in several solid tumors including mCRC. Methods: This is a single-arm, phase 2 trial, with a Simon 2-stage design assessing CBX-12 for the treatment of chemotherapy-refractory mCRC. The primary objective is efficacy determined by RECIST v1.1 response rate. Secondary and exploratory objectives include evaluating the PK and PD as well as the progression-free survival (PFS) on CBX-12. Key inclusion criteria include: age ≥18 years, ECOG performance status ≤1, histologically or cytologically confirmed mCRC that is MSS/pMMR based on CLIA-approved testing, and progression on 2 or more lines of chemotherapy. This design requires 17 patients for stage 1, with termination if 1 or fewer objective responses are seen out of 17. If 2 or more patients out of 17 responds, then an additional 18 patients will be enrolled for stage 2. If 5 out of the total of 35 patients (14%) respond, then the trial would be declared successful. Correlative studies will include tumor plus peripheral blood PK to evaluate effectiveness of CBX-12 tumor targeting, ctDNA, and several tumor PD markers including TOP1-DNA trapping, SLFN11 expression, DNA damage, and apoptosis. The trial opened to enrollment on 8/21/25. Clinical trial information: NCT06730100 .