SX-682 / Syntrix - LARVOL DELTA

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

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

New P1 trial • Hematological Malignancies • Multiple Myeloma • Oncology

Reprogramming and selective recruitment of distinct neutrophil subpopulations restrain cancer metastasis* (AACRPanCa 2024) - P2 | "In both mouse models of liver and lung metastasis, small molecule inhibition of CXCR2 using SX-682 led to enrichment of CXCR2low neutrophils and reduced metastatic burden in TumorAg ON PDAC...Indeed, in a highly immune-resistant model of PDAC, 6419c5, the use of tumor-targeting listeria vaccine CRS-207 along with CXCR2 inhibition significantly reduced metastatic burden, whereas CXCR2 inhibitor or CRS-207 alone had no impact...Consistent with our mouse model results, IMC analysis revealed increased proportion of MPOhigh NOS2high neutrophils upon treatment, suggesting that induction of tumor antigen response results in an effective remodeling of the neutrophil compartment . Taken together, our results show that neutrophils may acquire anti-tumor properties under appropriate inflammatory conditions and that distinct subpopulations of neutrophils may be leveraged for the treatment of metastatic disease."

Clinical • IO biomarker • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • NOS2 • TP53

Targeting The CXCR1/2 Axis Inhibits Neutrophil Function, And Not Recruitment, in NSCLC (LUNG-SPORE 2024) - "Based on such reports, we have launched an investigator-initiated Phase II clinical trial combining the dual CXCR1/2 antagonist, SX-682, with pembrolizumab for non-small cell lung cancer (NSCLC) patients in the first line. Remarkably, these therapeutics do not impact the ability of neutrophils to phagocytose and kill ingested bacteria. Taken together, these results mechanistically explain why CXCR1/2 inhibition has been active in cancer but without infectious complications."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CXCR1 • CXCR2

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

Phase I/II Trial Investigating the Safety, Tolerability, Pharmacokinetics, Immune and Clinical Activity of SX-682 in Combination With BinTrafusp Alfa (M7824 or TGF-beta "Trap"/PD-L1) With CV301 TRICOM in Advanced Solid Tumors (STAT) (clinicaltrials.gov) - P1/2 | N=12 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Breast Cancer • Head and Neck Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CD4 • ER • HER-2 • PD-L1 • PGR

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. | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

An Update On The Phase I Study to Evaluate the Safety and Tolerability of SX-682 in Combination with Anti-PD1 as Maintenance Therapy for Unresectable Pancreatic Adenocarcinoma (SSO 2024) - P1 | "Here we present pre-clinical data demonstrating synergistic effect of CXC chemokine receptor-2 (CXCR2) inhibition and anti-PD1 as well as an update on the Phase-1 study (NCT04477343) evaluating SX-682, an oral CXCR1/2 inhibitor, and nivolumab as maintenance treatment for advanced PDAC...Following orthotopic injection, treatment with FOLFIRINOX was followed by maintenance SX-682 and anti-PD1 or 5-FU... Preclinical PDAC maintenance immunotherapy demonstrates increased survival. Clinical translation of this immunotherapy strategy is underway. At the time of submission there have been two DLTs."

Clinical • Combination therapy • IO biomarker • P1 data • Gastrointestinal Cancer • Hematological Disorders • Oncology • Pain • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRCA • CD8 • CXCR1

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=50 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • 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 completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Jan 2024 ➔ Jan 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

SYNERGY-201: Study of SX-682 Plus Enzalutamide in Men With Abiraterone-Resistant Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=53 | Not yet recruiting | Sponsor: Syntrix Biosystems, Inc.

Metastases • New P2 trial • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • 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 2024 ➔ Jan 2025 | Trial primary completion date: Jan 2024 ➔ Jan 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • CD4 • CD69 • CD8 • IRF2

SX-682 Treatment in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab (clinicaltrials.gov) - P1 | N=77 | Recruiting | Sponsor: Syntrix Biosystems, Inc. | Trial completion date: Dec 2023 ➔ Jun 2026 | Trial primary completion date: Jul 2023 ➔ Jun 2025

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=50 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P1/2 trial • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Study of SX-682 Alone and in Combination With Oral or Intravenous Decitabine in Subjects With Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=151 | Recruiting | Sponsor: Syntrix Biosystems, Inc. | N=64 ➔ 151 | Trial completion date: Mar 2024 ➔ Mar 2029 | Trial primary completion date: Aug 2023 ➔ Mar 2028

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Neoadjuvant Study of Tislelizumab and SX-682 for Resectable Pancreas Cancer (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • GZMB • TNFRSF9