Fig. 1: Study rationale.
A Schematic of ATR function. ATR phosphorylates CHK1, on Serine 345, after DNA damage or replication stress. Activated CHK1 causes a predominantly G2 cell cycle arrest. Ceralasertib prevents ATR activating CHK1. B Schematic for tumor selectivity. Normal cells have intact G1 and G2 cell cycle checkpoints, most tumor cells have impaired G1 checkpoint control and will, therefore, be more at risk from G2 checkpoint inhibition when combined with DNA damage. C Study schema for drug and radiation dosing, PD sampling, response and toxicity assessments. Blue boxes: lead-in and post-radiotherapy ceralasertib; green boxes: radiotherapy treatments, grey outline: weekend with ceralasertib and no radiotherapy. D Schema for escalation of ceralasertib and radiotherapy (RT) doses. RT dose in Gy, (2 Gy fractions); ceralasertib dose in mg BD. E Late toxicities identified through medical notes review, AE reporting or LENT-SOMA assessment, compared with radiation dose-volume parameters. All indicated participants received ceralasertib 80 mg BD and 30 Gy in 15 fractions radiation. Density indicates length of available follow-up for that participant, and color indicates toxicity grade. Dmax maximum point dose, Dmean mean organ dose, VxGy volume of organ receiving x Gy, D10cc dose to most irradiated 10 cc of organ. Source data are provided online.
