AZD5069 / AstraZeneca - LARVOL DELTA

Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - P1/2 | N=340 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Aug 2025

IO biomarker • Monotherapy • Trial completion date • Head and Neck Cancer • Oncology • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Overcoming Immunotherapy Resistance in Hepatocellular Carcinoma by Targeting Myeloid IL-8/ CXCR2 Signaling. (PubMed, Mol Ther) - "Single-cell RNA sequencing (scRNA-seq) were performed in advanced HCC patients with baseline and on-treatment biopsy after pembrolizumab in a Phase II clinical trial cohort...This myeloid IL-8/CXCR2 pathway was further elucidated in our ICB-resistant orthotopic mouse model using AZD5069, a clinically available CXCR2 antagonist...The association between myeloid IL-8 and ICB therapeutic outcome also extended to multiple cancer types. Collectively, our study not only suggests a potential non-invasive biomarker for patient stratification and monitoring of ICB response, but also provides a proof-of-concept for combinational immunotherapy to benefit patients who are non-responsive to ICB monotherapy."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CXCL8 • CXCR2

Convergent signaling via C/EBPβ regulates MDSC-intrinsic NLRP3 inflammasomes to drive inflammatory CAF polarization (AACRPanCa 2024) - "This was corroborated in vivo where ASC speck formation in intratumoral Ly6G+ gMDSCs was diminished in mice treated with CXCR2i AZD5069 and p38i peximetinib... CXCR2-p38 and TLR4 signaling converge on C/EBPβ to regulate gMDSC-intrinsic NLRP3 inflammasomes, which drives iCAF polarization in PDAC. The role of C/EBPβ activation as a central node in imparting myeloid checkpoint function in gMDSCs warrants further exploration."

Myeloid-derived suppressor cells • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ACTA2 • CAFs • CEBPB • CXCR2 • IL1B • IL1R1 • IL6 • MYD88 • NLRP3

Cell-specific nanoengineering strategy disrupts tolerogenic signaling from myeloid-derived suppressor cells to invigorate antitumor immunity in pancreatic cancer. (PubMed, bioRxiv) - "We conjugate a chemically modified small-molecule inhibitor of MDSC-surface receptor CXCR2 (AZD5069) with polyethylene glycol (PEG) and chemically graft AZD5069-PEG constructs onto amphiphilic polysaccharide derivatives to engineer CXCR2-homing nanoparticles (CXCR2-NP). Encapsulation of JAK2/STAT3i Ruxolitinib (CXCR2-NP Ruxo ) resulted in more durable attenuation in STAT3-regulated arginase activity from PMN-MDSCs and induction of cytolytic T-cell activity vs. free Ruxolitinib in-vitro and in-vivo . Cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC."

Journal • Myeloid-derived suppressor cells • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Neutropenia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CXCR2 • JAK2 • STAT3

Selective anti-CXCR2 receptor blockade by AZD5069 inhibits CXCL8-mediated pro-tumorigenic activity in human thyroid cancer cells in vitro. (PubMed, J Endocrinol Invest) - "Our findings confirm the involvement of the CXCL8/CXCR2-axis in promoting pro-tumorigenic effects in TC cells, further demonstrating its immunotherapeutic significance in human cancer."

Journal • Preclinical • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • CXCL8 • CXCR2 • TNFA

A microphysiological system reveals neutrophil contact-dependent attenuation of pancreatic tumor progression by CXCR2 inhibition-based immunotherapy. (PubMed, Sci Rep) - "Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CXCR2

CXCR2 perturbation promotes Staphylococcus aureus implant-associated infection. (PubMed, J Med Microbiol) - "To assess the role of CXCR2 induction or inhibition during infection, treatment groups received daily intraperitoneal doses of either Lipocalin-2 (Lcn2) or AZD5069, respectively...Interestingly, however, perturbation of CXCR2 expression or signalling both resulted in enhanced Cxcr2 transcription and elevated implant-associated bacterial burdens. Thus, CXCR2 appears finely tuned to efficiently recruit effector cells and mediate control of S. aureus biofilm-mediated infection."

Journal • Immune Modulation • Immunology • Infectious Disease • CXCR2 • LCN2

Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - P1/2 | N=340 | Active, not recruiting | Sponsor: AstraZeneca | Phase classification: P1b/2 ➔ P1/2 | Trial completion date: Dec 2023 ➔ Mar 2025

Combination therapy • Metastases • Monotherapy • Phase classification • Trial completion date • Head and Neck Cancer • Oncology • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance. (PubMed, Nature) - "To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This study provides the first clinical evidence that senescence-associated myeloid inflammation can fuel mCRPC progression and resistance to AR blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

A Comparative Inflammation-On-A-Chip with A Complete 3D Interface: Pharmacological Applications in COPD-Induced Neutrophil Migration. (PubMed, Adv Healthc Mater) - "We used the IoC model to evaluate the pharmacological effects of CXCR2 inhibitors (MK-7123, AZD5069, and SB225002) on the migration of neutrophil-like cells in the presence of plasma samples from patients with COPD. This is the first study to evaluate inhibitors of CXCR2-dependent NTEM in a comparative IoC model that mimics the physiological 3D microenvironment, consisting of an endothelial barrier, extracellular compartment, and inflammatory conditions. This IoC model will be useful to investigate COPD severity using patient samples, and will aid basic and translational research involving NTEM."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Combination Study of AZD5069 and Enzalutamide. (clinicaltrials.gov) - P1/2 | N=30 | Terminated | Sponsor: Institute of Cancer Research, United Kingdom | N=86 ➔ 30 | Trial completion date: Oct 2023 ➔ Nov 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2023 ➔ Sep 2022; Discontinuation of production of IMP

Combination therapy • Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Myeloid IL-8 enrichment associates with immunotherapy resistance in advanced hepatocellular carcinoma (EASL-ILC 2023) - "In this study, we analyzed the immune contexture of advanced HCC patients before and after pembrolizumab treatment to investigate the role of myeloid IL-8 in ICB-resistance mechanism and aim to intervene the IL-8 pathway through inhibition of its receptor by a clinical in-use CXCR2 antagonist...Therapeutic efficacy of CXCR2 pathway inhibition by AZD5069 in potentiating ICB response was evaluated in our ICB-resistant orthotopic mouse model which is generated by serial in vivo passaging of anti-PD-L1 residual tumor... We demonstrated the importance of myeloid IL-8/CXCR2 pathway in ICB-resistance from our advanced HCC cohort which paved way for IL-8 to become a novel prognostic target for immunotherapy. Blocking CXCR2 could reduce MDSC trafficking and overcome ICB-resistance in our pre-clinical HCC model, suggesting a promising combination regimen in future development."

IO biomarker • Metastases • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immune Modulation • Oncology • Solid Tumor • CXCL8 • CXCR2

REDUCED EXPRESSION OF THE CHEMOKINES CXCL2, CXCL3 AND CXCL8 PROVIDES A POTENTIAL MECHANISM PROMOTING IMMUNE EVASION FACILITATING AML RELAPSE FOLLOWING ALLOGENEIC HSCT (EHA 2023) - "Conversely, CXCR2 inhibition with AZD5069 led to reduced CD4 proliferation and PD-1 expression.Summary/ This study further highlights the importance of immune evasion in mediating AML relapse following AHSCT. This study further highlights the importance of immune evasion in mediating AML relapse following AHSCT. The chemokines CXCL2 and CXCL8 were identified as potential mediators of this process and may provide prospective targets to enhance the GvL effect to prevent or treat post-AHSCT relapse. Diagram Description automatically generated Chemokine, Acute myeloid leukemia, Allogeneic hematopoietic stem cell transplant"

IO biomarker • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD4 • CD8 • CXCL3 • CXCL8 • CXCR2 • PD-1

Gastric cancer mesenchymal stem cells via the CXCR2/HK2/PD-L1 pathway mediate immunosuppression. (PubMed, Gastric Cancer) - "Our findings reveal that blocking GCMSCs-derived IL-8/CXCR2 pathway decreasing PD-L1 expression and lactate production, improving antitumor efficacy of anti-PD-1 immunotherapy, may be of value for the treatment of advanced gastric carcinoma."

IO biomarker • Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • CXCL8 • CXCR1 • CXCR2 • HIF1A

Neutrophil-derived cathelicidin promotes cerebral angiogenesis after ischemic stroke. (PubMed, J Cereb Blood Flow Metab) - "Intracerebroventricular injection (ICV) of AZD-5069, the antagonist of CAMP receptor CXCR2, or knockdown of CXCR2 by shCXCR2 recombinant adeno-associated virus (rAAV) impeded angiogenesis and neurological recovery after MCAO. Administration of rCAMP promoted endothelial proliferation and angiogenesis and attenuated neurological deficits 14 days after MCAO. In conclusion, neutrophil derived CAMP represents an important mediator that could promote post-stroke angiogenesis and neurological recovery in the late phase after stroke."

Journal • Cardiovascular • CNS Disorders • Ischemic stroke • Vascular Neurology • CXCR2

A phase (Ph) I/II trial of the CXCR2 antagonist AZD5069 in combination with enzalutamide (ENZA) in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) (ESMO 2022) - P1/2 | "Conclusions The combination of AZD5069 and ENZA is tolerable and has antitumor activity in mCRPC. We provide clinical evidence for direct targeting of myeloid chemotaxis as a therapeutic strategy in mCRPC."

Clinical • Combination therapy • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CXCR2 • CYP3A4 • IL23A • NRG1

Phase 1b/2 Study (SCORES) assessing safety, tolerability, and preliminary anti-tumor activity of durvalumab plus AZD9150 or AZD5069 in patients with advanced solid malignancies and squamous cell carcinoma of the head and neck (SCCHN) (ESMO 2017) - P1b/2; "The selective Generation 2.5 antisense oligonucleotide STAT3 inhibitor AZD9150 (STATi), a small molecule CXCR2 inhibitor AZD5069 (CX2i), and CTLA4 inhibitor tremelimumab (T) are in evaluation.Initial ORR and DCR data suggest enhanced antitumor activity results from combining a PDL1 antagonist (D) with an agent targeting immunosuppression in the tumor microenviornment (STATi) compared to PDL1 monotherapy. The combination may prove to provide a tolerable and effective option for patients with recurrent/metastatic SCCHN in the naive and PDL1-pretreated setting and other solid tumor types being studied."

Clinical • Head and Neck Cancer • Prostate Cancer • Sarcoma

A phase 1b/2 study (SCORES) of durvalumab (D) plus danvatirsen (DAN; AZD9150) or AZD5069 (CX2i) in advanced solid malignancies and recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC): Updated results (ESMO 2018) - P1b/2; "These results suggest enhanced activity of DAN + D compared to CX2i + D or PD-L1 monotherapy in PD-L1 naive pts with RM-HNSCC and warrant further investigation. 1Cohen E, et al. Ann Oncol."

IO biomarker • P1/2 data • PD(L)-1 Biomarker • Head and Neck Cancer

A phase I/II study of the CXCR2 inhibitor, AZD5069, in combination with durvalumab, in patients (pts) with advanced hepatocellular carcinoma (HCC). (ASCO-GI 2023) - "The 2nd dose cohort opened to recruitment in September 2022. Exploratory studies (blood; pre- & on-treatment tumor and non-malignant liver biopsies) include biomarkers of CXCR2 inhibition (blood); proof-of-mechanism (tumor: expression of CXCR2, PD-L1, PD-1, CD8, CD4, CD66b, CD69); proof-of-mechanism (blood: ctDNA); drug-induced changes of mRNA expression, CXCR2 ligands & signalling pathway genes, T-cell and myeloid cell pathways, neutrophil-associated genes; predictive biomarkers (blood and tumour) include biomarkers of the CXCR2/PD-L1 immune axis; aberrant CXCR2 signalling pathways; proliferation biomarkers and CD10 (neutrophils), CD68 (macrophages), CD103 (T-regs); tumour mutational status."

Clinical • Combination therapy • IO biomarker • Metastases • P1/2 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CD4 • CD68 • CD69 • CD8 • CEACAM8 • CXCR2 • ITGAE • MME

Cell-specific nanoengineering strategy to disrupt tolerogenic signaling from myeloid-derived suppressor cells and invigorate antitumor immunity in pancreatic cancer (SITC 2022) - "Methods We chemically modified AZD5069—a small-molecule inhibitor of the gMDSC surface receptor CXCR2—by conjugating it with polyethylene glycol (PEG) to enhance aqueous solubility...We encapsulated hydrophobic STAT3i Ruxolitinib in NP CXCR2 nanoparticles and compared its effect on inhibition of Arg1 activity from gMDSCs and T-cell activation in-vitro and in-vivo...Conclusions Cell-specific delivery of payloads via CXCR2-homing nanoparticles represent a novel immunotherapeutic strategy to target tolerogenic signaling pathways in gMDSCs and invigorate antitumor immunity in PDAC. Ethics Approval All animal experiments were performed in accordance with the NIH animal use guideline and protocol 21-176 approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Miami."

IO biomarker • Myeloid-derived suppressor cells • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • CD8 • CXCR2 • IFNG • ITGAX • KRAS • LAMP1 • PDX1 • TGFB1

Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - P1b/2 | N=340 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Sep 2022 ➔ Dec 2023

Combination therapy • IO biomarker • Monotherapy • Trial completion date • Head and Neck Cancer • Oncology • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • STAT3

NOTCH1 driven metastasis in BRAF mutated colorectal cancer (ESMO 2022) - "Neutrophils were targeted in BPN mice with AZD5069 (CXCR2 inhibitor) +/- anti-PD1 antibody or vehicle control from 85 days post Cre induction (DPI)...Metastasis is reduced by neutrophil inhibition which synergises with anti PD1 therapy, supporting an actionable phenotype. The NAS identifies a poor prognostic patient group and future work will see if neutrophil targeted therapy could benefit these patients."

IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • CXCR2 • KRAS • NICD • NOTCH1 • TP53

CXCR2-targeting nanoparticles to abrogate tolerogenic signaling in myeloid-derived suppressor cells in pancreatic cancer | Poster Board #2712 (ACS-Fall 2022) - "We then chemically modified a surface receptor inhibitor of CXCR2 AZD5069 by conjugating it with polyethylene glycol to enhance aqueous solubility. Finally, co-culture of splenocyte-derived murine CD8+ T-cells with J774 treated with Ruxolitinib-NPCXCR2 showed significant improvement in T-cell IFN-γ release compared with free Ruxolitinib. Compartment-specific delivery of payloads targeting tolerogenic signaling in gMDSC via NPCXCR2 may represent a novel strategy to mitigate immunosuppression in PDAC."

Myeloid-derived suppressor cells • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Neutropenia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • CD8 • CXCR2 • IFNG

Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist. (PubMed, Cardiovasc Diabetol) - "These results show, for the first time, the effectiveness of a selective CXCR2 antagonist to improve insulin sensitivity, concomitantly preventing the progression towards LP characteristic of NAFLD/NASH. This represents a novel approach to target IR and developing LP under T2D-susceptible conditions using a single agent. Furthermore, our data extend the growing evidence in support of neutrophils as a leukocyte population that imprints and maintains a chronic inflammatory state in the progression of dysregulated metabolism in liver-specific co-morbid conditions."

Journal • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • CXCR2 • LGALS3

CXCR2 inhibition sensitises NASH-HCC to immunotherapy (EASL-ILC 2022) - "Here we aimed to sensitise NASH-HCC to anti-PD1 therapy by targeting neutrophils using a CXCR2 small molecule inhibitor (AstraZeneca-AZD5069)... CXCR2-inhibition induces multi-cellular reprogramming of the tumour immune microenvironment that promotes ICI treatment of HCC in the context of NASH."

Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immune Modulation • Immunology • Inflammation • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • CD8 • CXCR2 • GZMB • ITGAE