CHARIOT: a Phase I Study of Berzosertib with Chemoradiotherapy in Oesophageal and Other Solid Cancers Using Time to Event Continual Reassessment Method

Overview

Journal Br J Cancer

Specialty Oncology

Date 2023 Dec 21

PMID 38129525

Authors

S R Javed

S Lord

S El Badri

R Harman

J Holmes

F Kamzi

T Maughan

D McIntosh

S Mukherjee

A Ooms

G Radhakrishna

P Shaw

M A Hawkins

Affiliations

Soon will be listed here.

Abstract

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/m) 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/m 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.

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References

Allum W, Blazeby J, Griffin S, Cunningham D, Jankowski J, Wong R . Guidelines for the management of oesophageal and gastric cancer. Gut. 2011; 60(11):1449-72. DOI: 10.1136/gut.2010.228254. View

van Hagen P, Hulshof M, van Lanschot J, Steyerberg E, van Berge Henegouwen M, Wijnhoven B . Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012; 366(22):2074-84. DOI: 10.1056/NEJMoa1112088. View

Blackford A, Jackson S . ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Mol Cell. 2017; 66(6):801-817. DOI: 10.1016/j.molcel.2017.05.015. View

Fokas E, Prevo R, Pollard J, Reaper P, Charlton P, Cornelissen B . Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012; 3:e441. PMC: 3542617. DOI: 10.1038/cddis.2012.181. View

Pires I, Olcina M, Anbalagan S, Pollard J, Reaper P, Charlton P . Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. Br J Cancer. 2012; 107(2):291-9. PMC: 3394988. DOI: 10.1038/bjc.2012.265. View

Leszczynska K, Dobrynin G, Leslie R, Ient J, Boumelha A, Senra J . Preclinical testing of an Atr inhibitor demonstrates improved response to standard therapies for esophageal cancer. Radiother Oncol. 2016; 121(2):232-238. PMC: 5154234. DOI: 10.1016/j.radonc.2016.10.023. View

Wong R, Malthaner R, Zuraw L, Rumble R . Combined modality radiotherapy and chemotherapy in nonsurgical management of localized carcinoma of the esophagus: a practice guideline. Int J Radiat Oncol Biol Phys. 2003; 55(4):930-42. DOI: 10.1016/s0360-3016(02)04278-5. View

Crosby T, Hurt C, Falk S, Gollins S, Staffurth J, Ray R . Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/- cetuximab in oesophageal cancer. Br J Cancer. 2017; 116(6):709-716. PMC: 5355926. DOI: 10.1038/bjc.2017.21. View

Hulshof M, Geijsen E, Rozema T, Oppedijk V, Buijsen J, Neelis K . Randomized Study on Dose Escalation in Definitive Chemoradiation for Patients With Locally Advanced Esophageal Cancer (ARTDECO Study). J Clin Oncol. 2021; 39(25):2816-2824. DOI: 10.1200/JCO.20.03697. View

10.

Conroy T, Galais M, Raoul J, Bouche O, Gourgou-Bourgade S, Douillard J . Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014; 15(3):305-14. DOI: 10.1016/S1470-2045(14)70028-2. View

11.

Penniment M, De Ieso P, Harvey J, Stephens S, Au H, OCallaghan C . Palliative chemoradiotherapy versus radiotherapy alone for dysphagia in advanced oesophageal cancer: a multicentre randomised controlled trial (TROG 03.01). Lancet Gastroenterol Hepatol. 2017; 3(2):114-124. DOI: 10.1016/S2468-1253(17)30363-1. View

12.

Deng W, Lin S . Advances in radiotherapy for esophageal cancer. Ann Transl Med. 2018; 6(4):79. PMC: 5890036. DOI: 10.21037/atm.2017.11.28. View

13.

Pabla N, Huang S, Mi Q, Daniel R, Dong Z . ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. J Biol Chem. 2007; 283(10):6572-83. DOI: 10.1074/jbc.M707568200. View

14.

Wengner A, Siemeister G, Lucking U, Lefranc J, Wortmann L, Lienau P . The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage-Inducing or Repair-Compromising Therapies in Preclinical Cancer Models. Mol Cancer Ther. 2019; 19(1):26-38. DOI: 10.1158/1535-7163.MCT-19-0019. View

15.

Reaper P, Griffiths M, Long J, Charrier J, MacCormick S, Charlton P . Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol. 2011; 7(7):428-30. DOI: 10.1038/nchembio.573. View

16.

van Bijsterveldt L, Durley S, Maughan T, Humphrey T . The Challenge of Combining Chemo- and Radiotherapy with Checkpoint Kinase Inhibitors. Clin Cancer Res. 2020; 27(4):937-962. DOI: 10.1158/1078-0432.CCR-20-3358. View

17.

Fisher O, Lord S, Falkenback D, Clemons N, Eslick G, Lord R . The prognostic value of TP53 mutations in oesophageal adenocarcinoma: a systematic review and meta-analysis. Gut. 2016; 66(3):399-410. PMC: 5534764. DOI: 10.1136/gutjnl-2015-310888. View

18.

Murai K, Dentro S, Ong S, Sood R, Fernandez-Antoran D, Herms A . p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition. Nat Commun. 2022; 13(1):6206. PMC: 9584949. DOI: 10.1038/s41467-022-33945-y. View

19.

Middleton M, Dean E, Evans T, Shapiro G, Pollard J, Hendriks B . Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. Br J Cancer. 2021; 125(4):510-519. PMC: 8368196. DOI: 10.1038/s41416-021-01405-x. View

20.

Shapiro G, Wesolowski R, Devoe C, Lord S, Pollard J, Hendriks B . Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours. Br J Cancer. 2021; 125(4):520-527. PMC: 8367944. DOI: 10.1038/s41416-021-01406-w. View