Study Explores First-in-Class CXCR1/2 Inhibitor SX-682 After HMA Failure in MDS

SX-682 is a first-in-class oral dual allosteric inhibitor of CXCR1/2 chemokine receptors, which are involved in recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs) and growth of leukemic stem cells (LSCs). The agent has dual activity against LSCs and MDSCs in patients with myelodysplastic syndromes (MDS) who have experienced hypomethylating agent (HMA) failure, according to a study presented at the 64th American Society of Hematology Annual Meeting & Exposition. The research indicates that SX-682 was effective and well tolerated at a dose of 200 mg twice daily.

The current phase I study involved five groups of patients (N=17; median age, 76 years) who had MDS and HMA failure and were transfusion-dependent. The breakdown of patients’ scores on the International Prognostic Scoring System was low (n=1), intermediate-1 (n=10), intermediate-2 (n=5), and high (n=1).

Patients received different doses twice daily in six continuous 28-day cycles. The researchers then assessed response at the end of cycles one, three, and six, as well as every third cycle after that in patients who continued treatment. After initiation of SX-682, MDSCs and LSCs lessened. The study found no maximum-tolerated dose, and no patients discontinued use due to adverse events. Adverse events were more common in patients who received 200-mg or 400-mg doses and were often related to neutrophils, but that effect reversed when the drug was stopped.

The authors, led by David A. Sallman, MD, of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida, found that overall response rates increased significantly at the 200-mg dose level, and that dose provided the most rapid and deep reduction in blasts.

The researchers are planning an expansion cohort in both lower- and higher-risk patients with MDS, as well as those who are HMA-naïve.

Reference

Sallman DA, DeZern AE, Gayle AA, et al. Phase 1 results of the first-in-class CXCR1/2 inhibitor SX-682 in patients with hypomethylating agent failure myelodysplastic syndromes. Abstract #855. Presented at the 64th American Society of Hematology Annual Meeting, December 10-13, 2022; New Orleans, Louisiana.