SX-682 and Nivolumab for the Treatment of RAS-Mutated, MSS Unresectable or Metastatic Colorectal Cancer, the STOPTRAFFIC-1 Trial

PRIMARY OBJECTIVE: I. To determine the safety profile of CXCR1/2 Inhibitor SX-682 (SX-682) alone and in combination with nivolumab in subjects with refractory RAS mutated microsatellite stable (MSS) metastatic colorectal cancer (mCRC), including the maximum dose that can be administered until adverse effects prevent further dose increases (i.e., the maximum tolerated dose \[MTD\] or recommended phase 2 dose), and the dose-limiting toxicity (DLT). SECONDARY OBJECTIVES: I. Evaluate the efficacy of SX-682 in combination with nivolumab on the basis of the objective response rate (ORR), the duration of response, and the rate of progression. II. Characterize the single-dose and multidose pharmacokinetic (PK) profile of SX-682. EXPLORATORY OBJECTIVES: I. Assess overall survival (OS). II. Explore potential biomarkers associated with pharmacodynamic and clinical response to SX-682 alone and combined with nivolumab, where the biomarker measures include, but are not limited to, tumor CMS4, gene expression, deoxyribonucleic acid (DNA) mutations (KRAS, NRAS and BRAF mutation status via ribonucleic acid \[RNA\] and DNA sequencing), IRF2 (interferon regulatory factor 2) expression, lymphocyte clonality (via sequencing), myeloid-derived suppressor cell (MDSCs), regulatory T-cells (Tregs) and CD69/CD8 T cells, and in the circulation, circulating tumor DNA (ctDNA), T- and B-cell subpopulations, neutrophils, the neutrophil-to-lymphocyte ratio (NLR), MDSCs, Tregs, the CD4:CD8 ratio, chemokines and cytokines. OUTLINE: This is a phase I, dose-escalation study of CXCR1/2 Inhibitor SX-682, followed by a phase II study. MONOTHERAPY STAGE: Patients receive SX-682 orally (PO) twice daily (BID) on days 1-21 in the absence of disease progression or unacceptable toxicity. COMBINATION STAGE: Patients receive SX-682 PO BID on days 1-56 and nivolumab intravenously (IV) over 30 minutes on days 1 and 29. Treatment repeat every 56 days weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After completion of study, patients with no have tumor response are followed up every 3 weeks for 90 days, and patients with tumor response every 3 months for up to 6 months.