SX-682

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.

P1, N=15, Not yet recruiting, Roswell Park Cancer Institute | Initiation date: Nov 2024 --> Feb 2025

P2, N=53, Recruiting, Syntrix Biosystems, Inc. | Initiation date: Jun 2024 --> Nov 2024

P1, N=15, Not yet recruiting, Roswell Park Cancer Institute

P1/2, N=12, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

P2, N=53, Recruiting, Syntrix Biosystems, Inc. | Not yet recruiting --> Recruiting

P1/2, N=50, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P1, N=20, Recruiting, University of Rochester | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=53, Not yet recruiting, Syntrix Biosystems, Inc.

P1/2, N=53, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=77, Recruiting, Syntrix Biosystems, Inc. | Trial completion date: Dec 2023 --> Jun 2026 | Trial primary completion date: Jul 2023 --> Jun 2025

P1/2, N=50, Not yet recruiting, National Cancer Institute (NCI)

P1, N=151, Recruiting, Syntrix Biosystems, Inc. | N=64 --> 151 | Trial completion date: Mar 2024 --> Mar 2029 | Trial primary completion date: Aug 2023 --> Mar 2028

P2, N=25, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.

P2, N=25, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: May 2026 --> Sep 2026 | Trial primary completion date: May 2026 --> Sep 2026

Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR.

We also investigated the effect of adding SX682, a small-molecule inhibitor of CXCR1/2 known to reduce MDSC trafficking to tumor microenvironment, to our therapeutic approach...Treatment with HMGN1, FSL-1, R848, and anti-CTLA4 antibody increased the number of infiltrating CD4+ and CD8+ effector/memory T cells in both tumors and draining lymph nodes and triggered the generation of 4T1-specific cytotoxic T lymphocytes (CTLs) in the draining lymph nodes. Thus, we developed a potentially curative immunotherapeutic regimen consisting of HMGN1, FSL-1, R848, plus a checkpoint inhibitor for TNBC, which does not rely on the administration of chemotherapy, radiation, or exogenous tumor-associated antigen(s).

P1/2, N=12, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Oct 2021 --> Feb 2023

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.

P2, N=25, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2026 --> May 2026 | Initiation date: Dec 2022 --> May 2023 | Trial primary completion date: Dec 2026 --> May 2026

Here, we present pre-clinical data demonstrating a 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, in combination with nivolumab as maintenance treatment for advanced PDAC...Following orthotopic injection, treatment with FOLFIRINOX was followed by 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 has been one DLT.

P2, N=30, Recruiting, University of Washington | Not yet recruiting --> Recruiting | Initiation date: Apr 2023 --> Dec 2022

All pts were transfusion-dependent and all had failed prior HMA and 24% lenalidomide. SX-682 is a novel therapy in HMA failure MDS with dual activity against LSCs and MDSCs. SX-682 was well tolerated with encouraging efficacy with a biologically effective oral dose selected at 200 mg BID. An expansion cohort in both lower and higher risk MDS pts is ongoing and will additionally include HMA naïve patients.

P2, N=25, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

P2, N=30, Not yet recruiting, University of Washington

P1/2, N=12, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> May 2024 | Trial primary completion date: Dec 2025 --> Oct 2021

Here we present pre-clinical data demonstrating synergistic effect of CXC chemokine receptor-2 (CXCR2) inhibition and anti-PD1 as well as a Phase-1 study ( NCT04477343) evaluating SX-682, an oral CXCR1/2 inhibitor, and nivolumab as maintenance treatment for advanced PDAC... Preclinical PDAC maintenance immunotherapy demonstrates increased survival. Clinical translation of this immunotherapy strategy is underway. At the time of submission there have been no DLTs, and paired tumor biopsies have shown decreased immunosuppressive cell populations within the TME.

P1/2, N=8, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P1/2, N=8, Suspended, National Cancer Institute (NCI) | N=105 --> 8 | Recruiting --> Suspended

Combined SHP2(SHP099)/CXCR1/2(SX682) inhibition depleted a specific cluster of S100a8/9high gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in NSCLC patients.

P1/2, N=53, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2024 --> Jan 2024 | Trial primary completion date: Oct 2024 --> Jan 2024

The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted.

P1/2, N=105, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Treatment of tumor-bearing mice with a CXCR2 antagonist (SX-682) also inhibited tumor growth, reduced intratumoral MDSCs, and increased intratumoral B1b cells expressing CXCL11, leading to an increase in activated CD8+ T cells in the tumor. Depletion of B220+ cells or depletion of CD8+ T cells reversed the tumor inhibitory properties in CXCR2myeΔ/Δ mice. These data revealed a mechanism by which loss of CXCR2 signaling in myeloid cells modulates antitumor immunity through decreasing MDSCs and enriching CXCL11-producing B1b cells in the TME, which in turn increases CD8+ T-cell recruitment and activation in tumors.

Tumor-bearing mice treated with a combination of anti-PD1 and SX-682 (CXCR1/2 inhibitor) displayed relocation of lymphocytes from the tumor periphery into a malignant tumor, which was associated with induction of IFN-γ-responsive genes. These results suggest that neutrophil antagonism may represent a viable secondary therapeutic strategy to enhance ICI treatment outcomes.

P1/2, N=105, Not yet recruiting, National Cancer Institute (NCI)

CXCR1/2 blockade combined with immune checkpoint inhibition and first line chemotherapy significantly enhanced survival in our PDAC mouse model. Thus, CXCR1/2 inhibition with SX-682 represents a promising target for clinical intervention in PDAC. Research Funding: URMC Department of Surgery.

CXCR1/2 blockade combined with immune checkpoint inhibition and first line chemotherapy significantly enhanced survival in our PDAC mouse model. Thus, CXCR1/2 inhibition with SX-682 represents a promising target for clinical intervention in PDAC. Research Funding: URMC Department of Surgery.