Abstract 1251P
Background
Berzosertib (M6220) is a selective ATR protein kinase inhibitor. Preclinical studies in esophageal cancer cell lines show that combining M6220 with cisplatin increased tumour cell kill in vitro and caused tumour growth delay in combination with radiation in vivo. The A1 cohort of CHARIOT (NCT03641547) tested the feasibility of combining Berzosertib with radiation in esophageal cancer. Primary objective: establish recommended phase II dose (RP2D) in combination with palliative RT; secondary objectives: safety, toxicity and efficacy.
Methods
Design-Single arm, open label, phase I dose escalation trial using TiTE-CRM. Key inclusion/exclusion - Adenocarcinoma or Squamous carcinoma of thoracic oesophagus, not suitable for radical treatment, tumour length ≤15cm, no stent in-situ, life expectancy of ≥12 weeks, ECOG 0-1, without prior irradiation to mediastinum/upper abdomen. Radiation dose was 35gy/15 fractions/3 weeks. Six dose levels were tested (table), with a target dose-limiting toxicity (DLT) rate of 25% during an observation window of 24 weeks. Table: 1251P
| Treatment schedule | Berzosertib Dose | Participants commencing treatment | Participants Receiving full dose |
| 1 | 140mg/m2 day 2,9,16 | 3 | 3 |
| 2 | 140mg/m2 day 2,5,9,12,16 | 1 | 1 |
| 3 | 140mg/m2 day 2,5,9,12,16,19 | 1 | 1 |
| 4 | 240mg/m2 day 2,9,16 | 1 | 1 |
| 5 | 240mg/m2 day 2,5,9,12,16 | 1 | 1 |
| 6 | 240mg/m2 day 2,5,9,12,16,19 | 9 | 4* |
* 4/9 received all 6 infusions; 4/9 received 5 infusions and 1/9 received 4 infusions
Results
Between Dec 2018 and Jan 22, 16 patients were recruited from 4 UK centres. All completed final (week 12) visit. No DLTs were reported during the trial. The TiTE-CRM recommended dose escalation for each dose level until the maximum. This was the RP2D at trial end. Ten Grade 3 adverse events [rash (n=4), one each of oesophagitis, lymphoedema, hyponatremia, lymphopenia, constipation, RIG displacement] were reported. Seven deaths were reported (6 disease related; 1 – cause not documented).
Conclusions
Berzosertib plus radiotherapy was well tolerated in patients with advanced oesophageal cancer and warrants investigation in future trials evaluating efficacy.
Clinical trial identification
NCT03641547.
Editorial acknowledgement
Legal entity responsible for the study
University of Oxford.
Funding
Cancer Research UK & Merck KGaA (Funder ID: 10.13039/100009945).
Disclosure
All authors have declared no conflicts of interest.