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Last Updated: 06/19/17

Information below provided by the Pharmaceutical Company.

AZD5069

Agent Description

Selective CXC chemokine receptor 2 (CXCR2) antagonist that inhibits the migration of CXCR2 + Myeloid-derived suppressor cells (MDSCs) to tumor microenvironment and may enhance immune-mediated tumor attack. It is currently being evaluated for safety and efficacy in human clinical trials.

Mechanism of Action

CXCR2 Antagonism

Classification

CXCR2 antagonist

Molecular Targets

CXCR2

Monograph

AZD5069 is a potent antagonist at the human CXCR2 receptor. The compound has been shown to mediate its interaction with CXCR2 through an allosteric site located on the intracellular surface of the receptor i.e., endogenous ligand interaction occurs at a site distal to the protein interface with AZD5069. AZD5069 demonstrated a CXCR2 selectivity of approximately 500-fold and 100-fold relative to its potency at the human CXCR1 and CCR2b receptors, respectively.

To establish a role for CXCR2 in pre-clinical tumor models, AZ13381758 (a surrogate compound with matched potency and similar structure) was tested in a transgenic model of pancreatic cancer. Pdx1-Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ (KPC) mice develop tumors that are similar to human pancreatic tumors in terms of histology and pathology, and are extremely aggressive, often metastatic and highly chemo-resistant, mimicking human pancreatic cancer. Treatment of KPC mice at an early stage with AZ13381758 either alone, or in combination with gemcitabine, reduced metastasis. At an advanced stage, AZ13381758 in combination with gemcitabine shows modest benefit; however, the combination with an anti-PD-1 antibody almost doubles the survival of the animals over controls.

Previously, long term evaluation of AZD5069 in patients with pulmonary disease (asthma, COPD, bronchiectasis) was associated with modest neutropenia, a favorably low frequency of infectious complications and good tolerability over 6 to 12 months at doses up to 45 mg BD. AZD5069 is currently in Phase 2 development in SCCHN, in combination with the anti-PD-L1 antibody durvalumab, and has shown manageable toxicity, good pharmacokinetics and proof of mechanism, along with early signals of efficacy.

Studies of Interest

Areas of interest:

  • Immunotherapy combinations in settings other than SCCHN and pancreatic cancer
  • Chemotherapy or radiation combinations - with mechanistic support for immune regulation in microenvironment
  • Window and translational studies - providing mechanistic insights into AZD5069/immunotherapy combinations

Areas NOT of interest:

  • Monotherapy studies
  • Combinations with PD-L1 therapy in SCCHN, breast cancer, pancreatic cancer
  • Combinations with PD-L1/CTLA-4 therapy in SCCHN
  • Combination with enzalutamide in CRPC

Information collaborator would like included in investigator proposals

N/A