Phase 1b SX-682 CXCR1/2 chemokine-receptor inhibitor plus proton CSI for leptomeningeal metastases

Memorial Sloan Kettering Cancer Center is running a Phase 1b, open-label study testing SX-682 (a small-molecule CXCR1/CXCR2 inhibitor that blocks IL-8–axis neutrophil/MDSC trafficking and related tumor-promoting inflammation) together with proton craniospinal irradiation (pCSI), an external-beam radiation approach treating the full neuraxis while reducing exit dose versus photons. The primary aim is safety/tolerability of the combination, with secondary evaluation of anti-tumor activity in leptomeningeal disease (LMD) from melanoma or non-small cell lung cancer (NSCLC). Participants receive SX-682 200 mg orally twice daily up to cycle 3 alongside pCSI to 30 Gy (RBE) delivered in 3 Gy (RBE) daily fractions. The scientific angle is pairing immunomodulatory microenvironment control (CXCR1/2 blockade) with comprehensive neuraxis radiation in a setting where drug delivery and durable control are difficult. Today, care for LMD is individualized and often involves focal or involved-field radiation to symptomatic sites, selected use of craniospinal irradiation (in specialized centers), and tumor-specific systemic therapy when feasible (targeted therapy or immunotherapy when appropriate), but outcomes remain poor—so this trial probes whether pCSI plus myeloid-trajectory suppression can improve CNS-compartment control without prohibitive toxicity.