Moon, Jee‐Young

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 .

Purpose: Periocular inverted papilloma (IP) is a rare, locally aggressive tumor with a propensity for recurrence and malignant transformation. Historically treated via wide excision, this study examines the characteristics and management of periocular IP, comparing those confined to the nasolacrimal system with those invading the orbit. Methods: An Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant retrospective, comparative case series was conducted in patients with IP of the orbit or nasolacrimal system across 15 clinical sites. Results: Of 25 patients, 22 met inclusion criteria with 9 limited to the nasolacrimal system and 13 invading the orbit. Mean age was 60.4 years, 55% were women, all were unilateral. Mean follow-up was 48 months. Rates of smoking, dust and/or aerosol exposure, human papillomavirus (HPV) status, and inflammatory polyps were elevated compared to rates in the general population (45%, 18%, 18%, and 14%, respectively). Bony erosion on computed tomography scans was statistically significantly associated with orbit-invading IP (p = 0.002). Treatment involved all confined IP undergoing surgery alone while 39% of orbit-invading IP also received radiation therapy and/or chemotherapy (p = 0.054). Orbit-invading IP was more likely to be excised with wide margins than IP confined to the nasolacrimal system (85% vs. 22%, p = 0.007). Overall rates of malignancy, recurrence, and patient mortality from IP were found to be 27%, 23%, and 9%, respectively. Conclusions: IP invading the orbit typically requires aggressive therapy, while IP confined to the nasolacrimal system may be treated more conservatively. Using risk factors, characteristics, and outcomes, a treatment algorithm was created to guide management.