SX-682 / Syntrix - LARVOL DELTA

SX-682 and Nivolumab for the Treatment of RAS-Mutated, MSS Unresectable or Metastatic Colorectal Cancer, the STOPTRAFFIC-1 Trial (clinicaltrials.gov) - P1/2 | N=51 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jan 2026 ➔ Jul 2026 | Trial primary completion date: Jan 2026 ➔ Jul 2026

Trial completion date • Trial primary completion date • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • BRAF

Safety and efficacy of first-in-class CXCR1/2 inhibitor SX-682 in combination with pembrolizumab (pem) in patients (pts) with metastatic melanoma (mMEL) with disease progression on anti–PD-1 therapy. (ASCO 2024) - P1 | "SX-682 combined with pem had a tolerable safety profile and activity reflected by objective responses and clinically meaningful disease control in heavily pretreated mMEL pts with progression on anti-PD-1 and anti–CTLA-4."

Clinical • Combination therapy • IO biomarker • Metastases • Hematological Disorders • Melanoma • Neutropenia • Oncology • Solid Tumor • BRAF • CD8 • CXCR1 • CXCR2

CXCR2 antagonism as a promising therapeutic approach for pulmonary fibrosis therapy. (PubMed, Biomed Pharmacother) - "In this study, we evaluated and compared the anti-inflammatory effects of four CXCR2 antagonists - DF2755A, AZD-5069, SX-682, and SCH527123 - in a murine model of bleomycin-induced lung injury. Importantly, DF2755A and SX-682 were particularly effective in mitigating fibrosis and chronic inflammatory changes when administered in both preventive and therapeutic schedules, even at later stages of disease progression. These findings underscore the potential of CXCR2 antagonism, especially with DF2755A, as a promising strategy to limit inflammation and fibrosis in experimental lung injury."

Journal • Fibrosis • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • CXCR2 • MPO

A phase I/II trial of a CXCR1/2 inhibitor in combination with anti-PD-1 for circulating tumor DNA (ctDNA) positive & refractoryRAS-mutated microsatellite stable (MSS) colorectal cancer (AACR 2023) - P1/2 | "The primary objectives are to determine safety profile, recommended phase 2 dose, clinical activity & 6m ctDNA clearance rate in CRC pts with MRD following 6m of SX-682 + Nivolumab on Arm B. Translational analyses include correlations of clinical outcomes with genomic and immune biomarkers from paired tissue and plasma samples. Clinical trial information: NCT04599140."

Circulating tumor DNA • Combination therapy • IO biomarker • P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CXCL3 • CXCR1 • CXCR2 • IRF2 • KRAS

SX-682 and Atezolizumab for the Treatment of Advanced or Metastatic, Recurrent Non-small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=32 | Not yet recruiting | Sponsor: University of Washington

Checkpoint inhibition • New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • CXCL8 • RET • ROS1

Syntrix-SX682-Melanoma-101: SX-682 Treatment in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab (clinicaltrials.gov) - P1 | N=77 | Active, not recruiting | Sponsor: Syntrix Biosystems, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2025 ➔ Aug 2026

Enrollment closed • Trial completion date • Trial primary completion date • Melanoma • Oncology • Solid Tumor

Phase I/II Study of the Combination Immunotherapy Regimen: SX-682, TriAdeno Vaccine, Retifanlimab and IL-15 Agonist N-803 (STAR15) for Metastatic Colorectal Cancer (mCRC) (clinicaltrials.gov) - P1/2 | N=60 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2028 ➔ Oct 2030 | Trial primary completion date: Oct 2025 ➔ Oct 2027

Trial completion date • Trial primary completion date • Colorectal Cancer • Oncology • Solid Tumor

Docetaxel synergizes with inhibition of the chemokine receptors CXCR1 and CXCR2 for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models (SITC 2025) - "Inhibition of CXCR1/2 with the clinical stage, small molecule inhibitor, SX-682, was evaluated in vitro and in vivo using human xenografts and murine models of HNSCC, both as a monotherapy and in combination with the taxane chemotherapy, docetaxel.Results Our initial analysis of HNSCC tissues via RNA in situ hybridization revealed that high levels of IL-8, CXCR1, and CXCR2 expression were present in HPV-negative compared to HPV-positive HNSCC tumors or cell lines. Additionally, in vivo treatment of a murine syngeneic model of HNSCC with CXCR1/2 inhibition plus docetaxel led to potent anti-tumor efficacy through a simultaneous decrease in suppressive CXCR2+ PMN-MDSC and an increase in cytotoxic CD8+ T cells in combination therapy treated tumors compared to the controls.Conclusions This study reports, for the first time, mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel chemotherapy exhibits synergy in models of HPV-negative HNSCC...."

IO biomarker • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • CXCL1 • CXCL8 • CXCR1 • CXCR2 • MIR200C • TUBB3

Dissecting myeloid-driven mechanisms of immunotherapy resistance in prostate cancer bone metastases (PCF 2025) - "In vivo studies showed that targeting Il1bhi-mNeu with a CXCR1/2 antagonist (SX-682) or adoptive transfer of these neutrophils into CRPC-bearing mice demonstrated that Il1bhi-mNeu are key drivers of ICI resistance in intraosseous CRPC... Our studies identify a distinct mediator of immunotherapy resistance in prostate cancer bone metastases. We demonstrate that mature inflammatory neutrophils (IL1Bhi-mNeu) are enriched in human mCRPC bone metastases and drive ICI resistance through IL-1R signaling. These findings suggest that targeting these cells and their signaling pathways could represent promising therapeutic strategies for overcoming ICI resistance in advanced prostate cancer."

IO biomarker • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • CXCR1 • IL1B • IL1R1 • SPP1

The Interleukin-8-CXCR1/2 Axis as a Therapeutic Target in Peritoneal Carcinomatosis. (PubMed, Curr Oncol) - "IL-8 targeting agents such as monoclonal antibodies (BMS-986253) and small-molecule inhibitors (SX-682, AZD5069, navarixin) have shown efficacy in mitigating tumor growth and improving the efficacy of immune checkpoint inhibitors. In this review, we discuss the influence of the IL-8/CXCR1/CXCR2 axis within the peritoneal immune environment in PC and highlight recent work using IL-8 or CXCR1/CXCR2 blockade as a therapeutic strategy for PC. Continued research into the peritoneal immune microenvironment and the development of targeted therapies are essential for improving the management and prognosis of PC, potentially enhancing antitumor immunity and patient outcomes."

Journal • Review • Oncology • Peritoneal Cancer • CXCL8 • CXCR1 • CXCR2 • IL6

Combined treatment with CDK4/6, CDK2, and CXCR1/2 inhibitors effectively halts the growth of BRAF wild-type melanoma tumors. (PubMed, Front Oncol) - "In this study, we evaluated the effectiveness of the CDK4/6 inhibitor, palbociclib, the CDK2 inhibitor, PF-07104091, the dual CXCR1 and CXCR2 (CXCR1/2) antagonist, SX-682, and the combination of these inhibitors for effective treatment of melanoma in preclinical models. This combination also decreased the percentage of CD8+ T cells that expressed PD-1 or TIM-3 and increased the ratio of MHCII+F4/80+ M1-like macrophages to CD206+F4/80+ M2-like macrophages. These data suggest that inhibiting CDK4/6 and CDK2, combined with antagonism of CXCR1/2, may be an effective treatment for BRAF wild-type melanoma tumors and NRAS mutant melanoma tumors that express Rb and are resistant to immune checkpoint inhibitors."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • BRAF • CCNA2 • CCND1 • CCNE1 • CD4 • CD8 • CXCR1 • CXCR2 • FOXP3 • HAVCR2 • IFNG • IL10 • MRC1 • NRAS • PD-1

SX-682 and Nivolumab for the Treatment of RAS-Mutated, MSS Unresectable or Metastatic Colorectal Cancer, the STOPTRAFFIC-1 Trial (clinicaltrials.gov) - P1/2 | N=51 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • BRAF

A Neoadjuvant Study of Tislelizumab and SX-682 for Resectable Pancreas Cancer (clinicaltrials.gov) - P2 | N=25 | Active, not recruiting | Sponsor: Lei Zheng | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

ASpiRE: Investigating SX-682 in Combination With Apalutamide in Metastatic Castration-resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=78 | Recruiting | Sponsor: Institute of Cancer Research, United Kingdom

New P1/2 trial • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Study to Evaluate the Safety and Tolerability of SX-682 in Combination With Nivolumab as a Maintenance Therapy in Patients With Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: University of Rochester | Trial primary completion date: Jan 2026 ➔ Jun 2026

Trial primary completion date • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Overcoming ICI resistance with CXCR1/2 antagonism in advanced HCC (AACR 2025) - "Finally, to understand the consequences of IL-8 inhibition via CXCR1/2 antagonism, we utilized a syngeneic murine HCC model (RIL-175 in female C57BL/6) treated with medicated SX-682 (anti-CXCR1/2) alone and in combination with intraperitoneal injections of anti-PD1+anti-VEGF. The final clinical cohort included 41 patients with advanced HCC. Patients were predominantly male (82.9%) with Barcelona Clinic Liver Cancer (BCLC) stage C disease (75.6%) who received treatment with atezolizumab + bevacizumab (51.2%)... Consistent with prior reports in other solid tumors, high plasma IL-8 concentration was associated with inferior survival on ICI based regimens in HCC. We hypothesize that IL-8 signaling promotes M2 macrophage polarization and in turn results in reduced effector T cell infiltration in the TiME. These results provide rationale for targeting the CXCR1/2 signaling axis in advanced HCC."

Metastases • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • AFP • CD8 • CXCL8 • CXCR1 • IL10 • IL6 • MRC1

Pygo2 deletion stimulates tertiary lymphoid structure formation and forms the cornerstone for a quadruple combination immunotherapy of prostate cancer (AACR 2025) - "Our study further consolidates Pygo2 as a valid and promising therapeutic target in combination immunotherapy of prostate cancer. The quadruple combination immunotherapy composed of Pygo2 inhibition, androgen deprivation therapy, SX682 and ICB demonstrates superior preclinical efficacy and should be further investigated for its clinical implications."

IO biomarker • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CXCR1 • IDO1 • PTEN • SMAD4

SX-682 in Combination With Carfilzomib, Daratumumab-Hyaluronidase, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=15 | Recruiting | Sponsor: Roswell Park Cancer Institute | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Multiple Myeloma • Oncology

A Study to Evaluate the Safety and Tolerability of SX-682 in Combination with Nivolumab As a Maintenance Therapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: University of Rochester | Suspended ➔ Recruiting

Enrollment open • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

SX-682 in Combination With Carfilzomib, Daratumumab-Hyaluronidase, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=15 | Not yet recruiting | Sponsor: Roswell Park Cancer Institute | Trial completion date: Nov 2029 ➔ Apr 2030 | Trial primary completion date: Nov 2026 ➔ Apr 2027

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

A Study to Evaluate the Safety and Tolerability of SX-682 in Combination with Nivolumab As a Maintenance Therapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1 | N=20 | Suspended | Sponsor: University of Rochester | Trial completion date: Dec 2025 ➔ Dec 2026 | Recruiting ➔ Suspended | Trial primary completion date: Jan 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Trial suspension • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

SX-682 and Nivolumab for the Treatment of RAS-Mutated, MSS Unresectable or Metastatic Colorectal Cancer, the STOPTRAFFIC-1 Trial (clinicaltrials.gov) - P1/2 | N=53 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jan 2025 ➔ Jan 2026 | Trial primary completion date: Jan 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • BRAF • CD4 • CD69 • CD8 • IRF2

Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models. (PubMed, J Exp Clin Cancer Res) - "This study reports, for the first time, mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel chemotherapy exhibits synergy in models of HPV-negative HNSCC. These findings provide rationale for the use of this novel combination approach to treat HPV-negative HNSCC patients and for future combination studies of CXCR1/2 inhibition, docetaxel, and immune-based therapies."

Journal • Preclinical • Head and Neck Cancer • Human Papillomavirus Infection • Infectious Disease • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • CXCL8 • CXCR1 • CXCR2 • MIR200C • TUBB3

SX-682 in Combination With Carfilzomib, Daratumumab-Hyaluronidase, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=15 | Not yet recruiting | Sponsor: Roswell Park Cancer Institute | Initiation date: Nov 2024 ➔ Feb 2025

Combination therapy • Trial initiation date • Hematological Malignancies • Multiple Myeloma • Oncology

SYNERGY-201: Study of SX-682 Plus Enzalutamide in Men with Abiraterone-Resistant Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=53 | Recruiting | Sponsor: Syntrix Biosystems, Inc. | Initiation date: Jun 2024 ➔ Nov 2024

Metastases • Trial initiation date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor