Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours
AuthorsMiddleton, M. R.
Dean, Emma J
Evans, T. R. J.
Shapiro, G. I.
Hendriks, B. S.
AffiliationDepartment of Oncology, University of Oxford, Oxford, UK.
MetadataShow full item record
AbstractBackground: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. Methods: We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. Results: Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. Conclusions: Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs.
CitationMiddleton MR, Dean E, Evans TRJ, Shapiro GI, Pollard J, Hendriks BS, et al. 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 May 26.
JournalBritish Journal of Cancer
- Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours.
- Authors: Shapiro GI, Wesolowski R, Devoe C, Lord S, Pollard J, Hendriks BS, Falk M, Diaz-Padilla I, Plummer R, Yap TA
- Issue date: 2021 Aug
- Population pharmacokinetics of ATR inhibitor berzosertib in phase I studies for different cancer types.
- Authors: Terranova N, Jansen M, Falk M, Hendriks BS
- Issue date: 2021 Feb
- Effect of Cisplatin and Gemcitabine With or Without Berzosertib in Patients With Advanced Urothelial Carcinoma: A Phase 2 Randomized Clinical Trial.
- Authors: Pal SK, Frankel PH, Mortazavi A, Milowsky M, Vaishampayan U, Parikh M, Lyou Y, Weng P, Parikh R, Teply B, Dreicer R, Emamekhoo H, Michaelson D, Hoimes C, Zhang T, Srinivas S, Kim WY, Cui Y, Newman E, Lara PN Jr
- Issue date: 2021 Oct 1
- Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors.
- Authors: Yap TA, O'Carrigan B, Penney MS, Lim JS, Brown JS, de Miguel Luken MJ, Tunariu N, Perez-Lopez R, Rodrigues DN, Riisnaes R, Figueiredo I, Carreira S, Hare B, McDermott K, Khalique S, Williamson CT, Natrajan R, Pettitt SJ, Lord CJ, Banerji U, Pollard J, Lopez J, de Bono JS
- Issue date: 2020 Sep 20
- Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.
- Authors: Konstantinopoulos PA, Cheng SC, Wahner Hendrickson AE, Penson RT, Schumer ST, Doyle LA, Lee EK, Kohn EC, Duska LR, Crispens MA, Olawaiye AB, Winer IS, Barroilhet LM, Fu S, McHale MT, Schilder RJ, Färkkilä A, Chowdhury D, Curtis J, Quinn RS, Bowes B, D'Andrea AD, Shapiro GI, Matulonis UA
- Issue date: 2020 Jul