- |||||||||| AZD5069 / AstraZeneca
Journal: CXCR2 perturbation promotes Staphylococcus aureus implant-associated infection. (Pubmed Central) - Apr 7, 2024
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.
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, danvatirsen (AZD9150) / AstraZeneca, Flamingo Therapeutics, AZD5069 / AstraZeneca
Phase classification, Trial completion date, Combination therapy, Monotherapy, Metastases: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - Jan 9, 2024
P1/2, N=340, Active, not recruiting,
Thus, CXCR2 appears finely tuned to efficiently recruit effector cells and mediate control of S. aureus biofilm-mediated infection. Phase classification: P1b/2 --> P1/2 | Trial completion date: Dec 2023 --> Mar 2025
- |||||||||| Xtandi (enzalutamide capsule) / Pfizer, Astellas, AZD5069 / AstraZeneca
Enrollment change, Trial completion date, Trial termination, Trial primary completion date, Combination therapy, Metastases: Combination Study of AZD5069 and Enzalutamide. (clinicaltrials.gov) - Jul 13, 2023
P1/2, N=30, Terminated,
This IoC model will be useful to investigate COPD severity using patient samples, and will aid basic and translational research involving NTEM. 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
- |||||||||| AZD5069 / AstraZeneca
Journal: Neutrophil-derived cathelicidin promotes cerebral angiogenesis after ischemic stroke. (Pubmed Central) - May 17, 2023
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.
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, AZD5069 / AstraZeneca
A phase I/II study of the CXCR2 inhibitor, AZD5069, in combination with durvalumab, in patients (pts) with advanced hepatocellular carcinoma (HCC). (Available On Demand; Poster Board No. N20) - Dec 13, 2022 - Abstract #ASCOGI2023ASCO_GI_630;
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.
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, danvatirsen (AZD9150) / AstraZeneca, Flamingo Therapeutics, AZD5069 / AstraZeneca
Trial completion date, Combination therapy, Monotherapy, IO biomarker, Metastases: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - Oct 7, 2022
P1b/2, N=340, Active, not recruiting,
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. Trial completion date: Sep 2022 --> Dec 2023
- |||||||||| Jakafi (ruxolitinib) / Novartis, Incyte, AZD5069 / AstraZeneca
Cell-specific nanoengineering strategy to disrupt tolerogenic signaling from myeloid-derived suppressor cells and invigorate antitumor immunity in pancreatic cancer (253ABC) - Oct 6, 2022 - Abstract #SITC2022SITC_1532;
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.
- |||||||||| AZD5069 / AstraZeneca
NOTCH1 driven metastasis in BRAF mutated colorectal cancer (Poster Area, Hall 4) - Jul 28, 2022 - Abstract #ESMO2022ESMO_2042;
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.
- |||||||||| AZD5069 / AstraZeneca
CXCR2 inhibition sensitises NASH-HCC to immunotherapy (Poster Area) - May 12, 2022 - Abstract #EASLILC2022EASL_ILC_1884;
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.
- |||||||||| AZD5069 / AstraZeneca, Tecentriq (atezolizumab) / Roche
Journal: CXCR2 Small-Molecule Antagonist Combats Chemoresistance and Enhances Immunotherapy in Triple-Negative Breast Cancer. (Pubmed Central) - May 7, 2022
Moreover, CXCR2 inhibition improved the efficacy of the immunotherapeutic drug "atezolizumab" where the combined inhibition of CXCR2 and PDL1 in TNBC in vitro coculture showed an additive effect in cytotoxicity. Altogether, the current study suggests CXCR2 inhibitors as a promising approach to improve TNBC treatment if used in combination with chemotherapy and/or immunotherapy.
- |||||||||| Xtandi (enzalutamide capsule) / Pfizer, Astellas, AZD5069 / AstraZeneca
Enrollment closed, Combination therapy, Metastases: Combination Study of AZD5069 and Enzalutamide. (clinicaltrials.gov) - Mar 21, 2022
P1/2, N=86, Active, not recruiting,
Altogether, the current study suggests CXCR2 inhibitors as a promising approach to improve TNBC treatment if used in combination with chemotherapy and/or immunotherapy. Recruiting --> Active, not recruiting
- |||||||||| Kineret (anakinra) / SOBI, AZD5069 / AstraZeneca, reparixin (DF 1681Y) / Dompe
A therapeutically actionable pro-tumoral axis of cytokines involving interleukin-8, TNFα and IL-1β (Section 12) - Mar 9, 2022 - Abstract #AACR2022AACR_6309;
In keeping with these findings, both TNFα and IL-1β induce functional IL-8 release from all tested human tumor cell lines representing a variety of tissue origins, as well as from primary organoids and fresh human cancer explants. In all these cases, including xenografted human tumors, IL-8 induction could be blunted by the pharmacological blockade of TNFα or IL-1β.
- |||||||||| AZD5069 / AstraZeneca
Journal: CXCR2 Mediates Distinct Neutrophil Behavior in Brain Metastatic Breast Tumor. (Pubmed Central) - Feb 16, 2022
We further demonstrate that abrogation of NETs formation using Neutrophil Elastase Inhibitor (NEI) significantly decreases the influx of neutrophils towards BrM but not to their parental tumor, suggesting that CXCR2 activation could be used by the brain metastatic tumors as a mechanism to program the tumor-infiltrating TANs into a pro-NETotic state, so as to assume a unique spatial distribution that assists in the subsequent migration and invasion of the metastatic tumor cells. This new perspective indicates that CXCR2 is a critical target for suppressing neutrophilic inflammation in brain metastasis.
- |||||||||| AZD5069 / AstraZeneca
CXCR2 inhibition sensitises to anti-PD1 therapy in NASH-HCC ([VIRTUAL]) - Jan 30, 2022 - Abstract #LCS2022LCS_111;
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.
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, danvatirsen (AZD9150) / AstraZeneca, Flamingo Therapeutics, AZD5069 / AstraZeneca
Trial completion date, Combination therapy, Monotherapy, IO biomarker, Metastases: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - Nov 23, 2021
P1b/2, N=340, Active, not recruiting,
We then propose that the manipulation of neutrophils may have therapeutic potential in NASH-HCC. Trial completion date: Sep 2021 --> Sep 2022
- |||||||||| Xtandi (enzalutamide capsule) / Pfizer, Astellas, AZD5069 / AstraZeneca
Enrollment change, Combination therapy, Metastases: Combination Study of AZD5069 and Enzalutamide. (clinicaltrials.gov) - May 3, 2021
P1/2, N=86, Recruiting,
Funding Has not received any funding. N=49 --> 86
- |||||||||| AZD5069 / AstraZeneca
CXCR2 blockade disrupts tumor trafficking of MDSC to potentiate immunotherapy efficacy () - Dec 12, 2020 - Abstract #IDDF2020IDDF_139;
Therapeutic efficacy of CXCR2 blockade was conducted in an orthotopic mouse model using AZD5069 (100 or 150 mg/kg) which is a CXCR2 antagonist currently undergoing clinical trials and in combination with anti-PD-L1 antibody (10F.9G2)...Conclusions Our data demonstrated the intricate link between IL-8/CXCR2 axis and MDSC trafficking to TME, providing insight into the immunosuppression mechanism in HCC. Targeting IL-8/CXCR2 chemotaxis pathway may potentiate ICB responsiveness, serving as a novel potential therapeutic option for effectively combined immunotherapy in liver cancer.
- |||||||||| Xtandi (enzalutamide capsule) / Pfizer, Astellas, AZD5069 / AstraZeneca
Trial completion date, Trial primary completion date, Combination therapy, Metastases: Combination Study of AZD5069 and Enzalutamide. (clinicaltrials.gov) - Nov 16, 2020
P1/2, N=49, Recruiting,
Targeting IL-8/CXCR2 chemotaxis pathway may potentiate ICB responsiveness, serving as a novel potential therapeutic option for effectively combined immunotherapy in liver cancer. Trial completion date: Aug 2021 --> Oct 2023 | Trial primary completion date: Jun 2020 --> Jan 2023
- |||||||||| AZD5069 / AstraZeneca
Journal: Distinct Spatio-Temporal Dynamics of Tumor-Associated Neutrophils in Small Tumor Lesions. (Pubmed Central) - Oct 22, 2020
Selective pharmacological blockade of CXCR2 receptors using AZD5069 profoundly inhibited recruitment of TAN into peritumoral regions, while intratumoral infiltration was only transiently attenuated and rebounded at later time points. Our findings unravel distinct spatial dynamics of TAN that are partially and differentially regulated via the CXCR2 signaling pathway.
- |||||||||| Xtandi (enzalutamide capsule) / Pfizer, Astellas, AZD5069 / AstraZeneca
Enrollment open, Combination therapy, Metastases: Combination Study of AZD5069 and Enzalutamide. (clinicaltrials.gov) - Jun 4, 2020
P1/2, N=49, Recruiting,
Funding: Has not received any funding. Active, not recruiting --> Recruiting
- |||||||||| AZD5069 / AstraZeneca, AZD4721 / AstraZeneca
Journal: Plasma protein binding as an optimisable parameter for acidic drugs. (Pubmed Central) - Apr 22, 2020
Here we detail the approaches and lessons learned at AstraZeneca during the optimisation of acidic CXCR2 antagonists for the oral drug treatment of inflammatory diseases, resulting in discovery and clinical testing of AZD5069 and AZD4721, orally bioavailable acidic molecules with PPB of <1%, human hepatocyte intrinsic clearance values < 5 µl/min/106 cells and predicted human Vss < 0.3 L/kg, resulting in effective half-lives in man of 4 and 17 h respectively. SIGNIFICANCE STATEMENT: Provided that pharmacological potency is high enough, modulation of plasma protein binding can form part of a viable strategy in drug discovery to optimise effective half-life of drug candidates in humans.
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, danvatirsen (AZD9150) / AstraZeneca, Flamingo Therapeutics, AZD5069 / AstraZeneca
Trial completion date, Combination therapy, Monotherapy, PD(L)-1 Biomarker, IO biomarker, Metastases: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - Apr 9, 2020
P1b/2, N=339, Active, not recruiting,
SIGNIFICANCE STATEMENT: Provided that pharmacological potency is high enough, modulation of plasma protein binding can form part of a viable strategy in drug discovery to optimise effective half-life of drug candidates in humans. Trial completion date: Feb 2020 --> Aug 2021
- |||||||||| Xtandi (enzalutamide capsule) / Pfizer, Astellas, AZD5069 / AstraZeneca
Enrollment closed, Combination therapy, Metastases: Combination Study of AZD5069 and Enzalutamide. (clinicaltrials.gov) - Apr 9, 2020
P1/2, N=49, Active, not recruiting,
Trial completion date: Feb 2020 --> Aug 2021 Recruiting --> Active, not recruiting
- |||||||||| AZD5069 / AstraZeneca, danirixin (GSK1325756) / GSK
Review, Journal: NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma. (Pubmed Central) - Dec 23, 2019
Clinical validation of this type could lead to novel therapeutics for multiple CXCR2-related NETopathologies. In this Review, we discuss the emerging role of NETs in the clinicopathobiology of COPD and severe asthma and provide an outlook on how novel NET-stabilizing therapies via CXCR2 blockade could be leveraged to disrupt NETopathic inflammation in disease-specific phenotypes.
- |||||||||| Xtandi (enzalutamide capsule) / Pfizer, Astellas, AZD5069 / AstraZeneca
Enrollment open, Trial completion date, Combination therapy, Metastases: Combination Study of AZD5069 and Enzalutamide. (clinicaltrials.gov) - Oct 1, 2019
P1/2, N=49, Recruiting,
In this Review, we discuss the emerging role of NETs in the clinicopathobiology of COPD and severe asthma and provide an outlook on how novel NET-stabilizing therapies via CXCR2 blockade could be leveraged to disrupt NETopathic inflammation in disease-specific phenotypes. Not yet recruiting --> Recruiting | Trial completion date: Dec 2020 --> Aug 2021
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, danvatirsen (AZD9150) / AstraZeneca, Flamingo Therapeutics, AZD5069 / AstraZeneca
Enrollment closed, Combination therapy, Monotherapy, PD(L)-1 Biomarker, IO biomarker, Metastases: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - Jul 8, 2019
P1b/2, N=337, Active, not recruiting,
Not yet recruiting --> Recruiting | Trial completion date: Dec 2020 --> Aug 2021 Recruiting --> Active, not recruiting
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, danvatirsen (AZD9150) / AstraZeneca, Flamingo Therapeutics, AZD5069 / AstraZeneca
Trial completion date, Trial primary completion date, Combination therapy, Monotherapy, PD(L)-1 Biomarker, IO biomarker, Metastases: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - Mar 11, 2019
P1b/2, N=465, Recruiting,
Recruiting --> Active, not recruiting Trial completion date: Oct 2019 --> Apr 2020 | Trial primary completion date: Oct 2019 --> Apr 2020
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, danvatirsen (AZD9150) / AstraZeneca, Flamingo Therapeutics, AZD5069 / AstraZeneca
Enrollment change, Trial completion date, Trial primary completion date, Combination therapy, Monotherapy, PD(L)-1 Biomarker, IO biomarker, Metastases: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - Feb 22, 2018
P1b/2, N=465, Recruiting,
Recruiting --> Active, not recruiting N=257 --> 465 | Trial primary completion date: Aug 2018 --> Oct 2019 | Trial completion date: Aug 2018 --> Oct 2019
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, danvatirsen (AZD9150) / AstraZeneca, Flamingo Therapeutics, AZD5069 / AstraZeneca
Enrollment change, Combination therapy, Monotherapy, PD(L)-1 Biomarker, IO biomarker, Metastases: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - Dec 14, 2017
P1b/2, N=257, Recruiting,
N=257 --> 465 | Trial primary completion date: Aug 2018 --> Oct 2019 | Trial completion date: Aug 2018 --> Oct 2019 N=147 --> 257
- |||||||||| Xtandi (enzalutamide capsule) / Pfizer, Astellas, AZD5069 / AstraZeneca
New P1/2 trial, Combination therapy, Metastases: Combination Study of AZD5069 and Enzalutamide. (clinicaltrials.gov) - Jun 7, 2017
P1/2, N=49, Not yet recruiting,
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, danvatirsen (AZD9150) / AstraZeneca, Flamingo Therapeutics, AZD5069 / AstraZeneca
Trial primary completion date, Combination therapy, Monotherapy, PD(L)-1 Biomarker, IO biomarker, Metastases: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - Dec 8, 2016
P1b/2, N=147, Recruiting,
Recruiting --> Active, not recruiting | N=26 --> 19 | Trial primary completion date: Jul 2017 --> Nov 2017 Trial primary completion date: Sep 2017 --> May 2018
- |||||||||| Imfinzi (durvalumab) / AstraZeneca, danvatirsen (AZD9150) / AstraZeneca, Flamingo Therapeutics, AZD5069 / AstraZeneca
Phase classification, Combination therapy, Monotherapy, PD(L)-1 Biomarker, IO biomarker, Metastases: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - Jun 15, 2016
P1b/2, N=147, Recruiting,
Trial primary completion date: Sep 2017 --> May 2018 Phase classification: P1/2 --> P1b/2
|
