Phase 1 camonsertib (ATR kinase inhibitor) plus SBRT re-irradiation in recurrent HNSCC

This Phase 1 NCI-sponsored study tests safety, tolerability, and the recommended Phase 2 dose of camonsertib—Repare Therapeutics’ oral ATR (ataxia telangiectasia and Rad3-related) kinase inhibitor—given concurrently with stereotactic body radiation therapy (SBRT) re-irradiation for recurrent or unresectable head and neck squamous cell carcinoma arising in a previously irradiated field. The design is dose-escalation followed by dose-expansion, with camonsertib taken once daily on the day of and the day after each SBRT fraction; SBRT is delivered twice weekly for 4–5 fractions over ~3 weeks, with imaging (PET/CT or CT) and blood sampling for PK and exploratory biomarkers (including ATM/TP53 alterations, HPV status, tumor mutational load, and ctDNA). The scientific angle is radiosensitization: ATR blockade can impair replication-stress and DNA-damage checkpoint signaling, potentially increasing tumor vulnerability to high-dose hypofractionated radiation in a difficult re-irradiation setting. Today’s care for unresectable, previously irradiated locoregional recurrence is typically limited to re-irradiation approaches (SBRT or other techniques) when feasible plus systemic therapy such as PD-1 inhibitors (pembrolizumab or nivolumab) and/or chemotherapy or cetuximab, with modest control rates and significant toxicity constraints—making a “radiation + DNA damage response inhibitor” strategy clinically relevant.