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CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to
S R Javed1, S Lord1, S El Badri1
1Department of Oncology, University of Oxford, Oxford, UK.
Background:
Berzosertib (M6620) is a highly potent (IC50 = 19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine.
Methods:
Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks).
Results:
No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m2) was determined as the recommended phase II dose (RP2D) for A1. Seven DLTs in two patients in A2. The RP2D of berzosertib was 140 mg/m2 once weekly. The most common grade ≥3 treatment-related AEs were neutropenia and thrombocytopenia. No treatment-related deaths were reported.
Conclusions:
Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting.
Clinical Trials Identifier:
EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547.
Insights
Berzosertib, an ATR inhibitor, is safe and well-tolerated with radiotherapy in esophageal cancer and with chemotherapy in advanced cancers. Further phase 2 studies are recommended.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Berzosertib is a potent and selective ATR inhibitor.
- This study evaluated berzosertib in esophageal cancer with radiotherapy and advanced solid tumors with chemotherapy.
Purpose of the Study:
- To assess the safety, preliminary efficacy, and tolerance of berzosertib.
- To determine the recommended phase II dose (RP2D) for berzosertib in combination regimens.
Main Methods:
- Single-arm, open-label dose-escalation trial.
- 16 patients in the esophageal cancer cohort (A1) and 18 in the advanced solid tumor cohort (A2).
- Time-to-Event Continual Reassessment Method used for dose escalation.
Main Results:
- RP2D for berzosertib with RT in A1 was 240 mg/m²; no dose-limiting toxicities (DLTs) observed.
- RP2D for berzosertib with cisplatin and capecitabine in A2 was 140 mg/m² weekly; 7 DLTs in 2 patients.
- Most common grade ≥3 adverse events included rash, neutropenia, and thrombocytopenia; no treatment-related deaths.
Conclusions:
- Berzosertib combined with RT is feasible and well-tolerated in esophageal cancer.
- Berzosertib with cisplatin and capecitabine is well-tolerated in advanced cancer.
- Further investigation in a phase 2 setting is warranted.
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