Project Grant R44CA278187

A PHASE 2, SINGLE-ARM STUDY OF THE CXCR1/2 INHIBITOR SX-682 PLUS ENZALUTAMIDE IN MEN WITH ABIRATERONE-RESISTANT METASTATIC CASTRATION RESISTANT PROSTATE CANCER (MCRPC) - PROSTATE CANCER (PC) IS THE SECOND LEADING CAUSE OF CANCER-RELATED DEATH AMONG AMERICAN MEN, AND THE VAST MAJORITY OF THESE DEATHS ARE DUE TO METASTATIC, CASTRATION-RESISTANT PC (MCRPC). ANDROGEN SUPPRESSION THERAPY (AST) IS USED TO TREAT PC PATIENTS, WHICH COMPRISE OF: (1) ANDROGEN DEPRIVATION THERAPY (ADT) WITH LHRH AGONISTS OR ANTAGONISTS; (2) BLOCKING CYP17-MEDIATED ANDROGEN SYNTHESIS WITH ABIRATERONE; AND (3) ANDROGEN RECEPTOR (AR) ANTAGONISTS SUCH AS ENZALUTAMIDE AND OTHERS. WHILE AR CAN SIGNIFICANTLY PROLONG OVERALL SURVIVAL (OS) OF PATIENTS WITH VARIOUS STAGES OF PC, ACQUIRED RESISTANCE TO EITHER IS INEVITABLE, AFTER WHICH LIMITED TREATMENT OPTIONS EXIST. ONLY ABOUT 35% OF MEN RESPOND TO ENZALUTAMIDE AFTER DEVELOPING RESISTANCE TO ABIRATERONE [1]. THERE IS THEREFORE A SIGNIFICANT UNMET NEED FOR NEW MCRPC TREATMENTS THAT ACT ORTHOGONALLY AND SYNERGISTICALLY WITH EXISTING AST TO INCREASE AND PROLONG ITS EFFICACY IN MCRPC. THE CHEMOKINE RECEPTOR ISOFORMS CXCR1 AND CXCR2 (CXCR1/2) ARE VALIDATED AS ORTHOGONAL THERAPEUTIC TARGETS IN MCRPC. TUMOR-SECRETED CXCR1/2 LIGANDS SUCH AS CXCL6 AND CXCL8 (IL-8) MEDIATE RESISTANCE TO ASTS, EXERTING PROTUMORIGENIC EFFECTS BY BINDING SURFACE CXCR1/2 ON TAMS [2], MDSCS [3-8] AND AR NEGATIVE (AR-) NEUROENDOCRINE (NE) CANCER CELLS [9] IN THE PC TME. MDSCS ARE SIGNIFICANTLY ELEVATED IN PATIENT BIOPSIES WITH CRPC VS. PRE-ADT [3], AS IS EXPRESSION OF CXCL6 [7] AND CXCL8 [5, 10]. HIGHER PATIENT BASELINE SERUM CXCL8 PRE-ADT WAS PROGNOSTIC FOR SHORTER OS AND TIME TO CRPC INDEPENDENT OF DOCETAXEL, DISEASE BURDEN, AND TIME OF METASTASES [11]. CIRCULATING MDSCS POSITIVELY CORRELATED WITH CLINICAL STAGE, AND INVERSELY WITH OS (MEDIAN OS OF 19 VS. 55 MONTHS WITH HIGH VS. LOW MDSCS) [12, 13]. WE HYPOTHESIZE THAT COMBINING CXCR1/2 BLOCKADE WITH STANDARD OF CARE (ENZALUTAMIDE) IN MCRPC PATIENTS PROGRESSING ON FIRST-LINE ABIRATERONE WILL AFFORD ENHANCED EFFICACY VS. HISTORICAL STANDARD OF CARE EFFICACY IN THE SAME POPULATION. SX-682 IS A CLINICAL-STAGE, SMALL-MOLECULE CXCR1/2 INHIBITOR VALIDATED IN NUMEROUS PUBLISHED PRE-CLINICAL CANCER MODELS INCLUDING MCRPC, AND WHICH EXHIBITS ACTIVITY IN PATIENTS WITH MELANOMA, PANCREATIC ADENOCARCINOMA AND MYELODYSPLASTIC SYNDROMES. THROUGH EXECUTION OF THE SPECIFIC AIMS, WE WILL ADVANCE SX-682 THROUGH CRITICAL PROOF-OF-CONCEPT (POC) EFFICACY TESTING IN THE FIRST EVER PHASE 2 ONE-ARM, OPEN-LABEL TRIAL IN MCRPC OF A CXCR1/2 INHIBITOR WITH ENZALUTAMIDE IN PATIENTS FAILING ABIRATERONE. THE TRIAL WILL ENROLL 53 EVALUABLE PATIENTS WITH MCRPC DIAGNOSIS WITH (A) ANY HISTOLOGY, (B) MEASURABLE DISEASE AT ENROLLMENT, AND (C) CURRENTLY ON OR PREVIOUSLY ON ABIRATERONE WITH PREDNISONE AND WITH RISING PSA (A RISING PSA REQUIRES AT LEAST 3 MEASUREMENTS OBTAINED AT LEAST 1 WEEK APART SHOWING INCREASE FROM NADIR WITH THE LAST LEVEL ABOVE 2 NG/ML). THE PRIMARY ENDPOINT IS CLINICAL BENEFIT (CB), WHEREIN CB IS A COMPOSITE ENDPOINT DEFINED AS 1) RECIST 1.1 CR OR PR, 2) CONFIRMED PSA50 DECLINE, OR 3) PROLONGED STABLE DISEASE BY RECIST/PCWG3 CRITERIA FOR = 6 MONTHS. IF SUCCESSFUL, SX-682 WOULD BE A HIGHLY VALUABLE NEW ADDITION TO THE EXISTING MCRPC TREATMENT LANDSCAPE.