Dose-exposure-response model between an ATR inhibitor and peripheral monocytes
Alienor Berges1, S. Y. Amy Cheung1, Andrew Pierce1, Nathan Standifer1, Graham Ross1, Simon Smith1, Brunella Felicetti1, Christine Stephens1, Kevin Harrington2, Magnus Dillon2 Jean-Charles Soria3, Simon J Hollingsworth1
1. AstraZeneca R & D, Cambridge, UK; 2. Royal Marsden Hospital, London, UK; 3. Institut Gustave Roussy, Paris, France
Introduction: AZD6738 is a potent, selective inhibitor of the ATR protein kinase, currently being tested in patients with solid malignancies. Thrombocytopenia is one of the main dose-limiting toxicity [1]. In order to support dose and schedule selection, we utilised emerging phase I data and modelled the relationship between dose, plasma exposure and peripheral blood cell counts.
Methods: We assessed blood cell counts (neutrophils, platelets, erythrocytes monocytes or lymphocytes) from patients of AZD6738 dosed alone (continuous doses from 40 to 480mg), or in combination with the PARP-1 inhibitor, olaparib 300mg bd, or the PD-L1 inhibitor, durvalumab 1500mg Q4W (intermittent doses up to 320mg). Individual time profiles were plotted to show any trend during AZD6738 treatment and exposure-PD correlation plots were generated using specific PK parameters and change from baseline in cell counts. The correlation plots were compared across blood cells and the differential effect of AZD6738 between two cells of interest was modelled.
Results: Monocytes were found to be the most sensitive cells, with a decrease up to 80% from the 160mg dose. This decrease was not observed with either single agent olaparib or durvalumab. Upon cessation of dosing, monocyte levels return to baseline values within 14 days. A decrease in the other blood cells counts was noticed at 480mg and to a lesser extent. These results were consistent across studies.
An Emax model characterised well the correlation between the decreases of monocyte over platelets as a function of AZD6738 Cmax values, and predicted a response plateau at 13ug/mL. Beyond this value (reached between 320-480mg), the gain of monocyte decrease (considered as target exposure), versus safety was considered minimal.
Conclusion: This analyses allowed predicting AZD6738 dose with the maximum cell type-specific differential effects during the study. This modelling and process is expected to be refined on a regular basis, with the integration of further trial data.
Reference:
[1] Cheung et al 2017 Page meeting