A Dose Expansion Study of SX-682 Alone and in Combination with Decitabine in MDS Patients

Myelodysplastic syndromes (MDS) are genetically and morphologically diverse hematopoietic neoplasms that arise from a small pool of mutant clones within hematopoietic stem and progenitor compartments [1-9]. MDS is a pre-leukemic syndrome to acute myeloid leukemia (AML). Only four drugs have received regulatory approval for MDS, with the two hypomethylating agents (HMAs) azacitidine and decitabine (iv and oral with cedazuridine) each with suboptimal response rates (~15-20% for CR+PR) and of limited durability, typically 1-2 years [10]. Once these agents fail, there is no second-line treatment. Prognosis after failure is dismal, with median survival at <6 months for higher-risk patients, and <18 months for lower-risk patients [11]. That MDS is frequently characterized by relapse or failure to achieve durable remission, indicates that current treatments do not adequately eradicate the disease-initiating stem cells. Clearly there is a significant unmet need for a new MDS treatment in the frontline and HMA-relapsed/refractory (HMA-RR) settings that eradicates leukemic stem cells and normalizes cytopenias. Chemokine receptors CXCR1 and CXCR2 (CXCR1/2) and its ligands (CXCL 1, 2, 3, 5, 7 and CXCL8) are elevated in the bone marrow and plasma of patients with AML and MDS where they drive mutant stem cell growth and correlate with reduced survival [12-16], transfusion dependence [17] and HMA resistance [14]. CXCR1/2 on MDSCs are pivotal in their recruitment to the bone marrow where they kill hematopoietic progenitors and impair anti-leukemic immune surveillance [18-20]. Dual CXCR1/2 blockade is therefore a preclinically validated multi-prong strategy to attack (1) mutant stem cells, (2) the immunosuppressive marrow microenvironment and (3) hematopoiesis-killing MDSCs, and (4) are implicated in de novo and acquired HMA-resistance. SX-682 is a clinical-stage, small-molecule CXCR1/2 inhibitor that is in multiple trials in which it exhibits activity in metastatic melanoma, pancreatic ductal adenocarcinoma, and as a single-agent in HMA- RR MDS (NCT04245397), where it arrests unrestrained outgrowth of stem and progenitor compartments and alters the mutant stem and progenitor architecture and inflammatory niche. The specific aims of this proposal encompass adding additional cohorts to our ongoing MDS trial that will test SX-682 alone and together with oral or intravenous decitabine in the frontline and HMA-RR settings and the preparation of SX-682 study drug to support clinical evaluation. Our hypothesis is that de novo or acquired resistance to HMA involves the CXCR1/2 axis, and that adding SX-682 to decitabine will provide efficacy better than either agent alone. The primary objective is to show preliminary clinical evidence of improved outcomes in patients treated with SX-682 and decitabine compared to historical data for either agent alone. If successful, SX-682 added to decitabine would transform the MDS treatment landscape.