A phase Ia/Ib trial of the DNA-PK inhibitor M3814 in combination with radiotherapy (RT) in patients (pts) with advanced solid tumors: Dose-escalation results.

2518Background: DNA-dependent protein kinase (DNA-PK), regulates one of the major pathways responsible for repair of DNA double-strand breaks. The combination of RT and DNA-PK inhibition (DNA-PKi) has been shown to be synergistic in preclinical studies. The purpose of this phase I trial is to explore the safety, tolerability, pharmacokinetic (PK) profile, and clinical activity of M3814 administered together with RT (Arm A) and chemo-RT (CRT; Arm B). Results for Arm A are reported. Methods: Pts with tumors or metastases in the head and neck region or thorax in need of palliative RT (30 Gy in 10 factions) are enrolled in the dose escalation part Ia of Arm A to receive M3814, starting dose 100 mg. Dose escalation is aided by a Bayesian logistic regression model. Dose-limiting toxicity (DLT) is evaluated up to 3 weeks after RT. Rich PK sampling is taken during treatment. Tumor evaluation is performed every 6 weeks up to 6 months and every third month thereafter. Results: 16 pts had been enrolled, 100 mg (N = ...