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    Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours

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    Authors
    Middleton, M. R.
    Dean, Emma J
    Evans, T. R. J.
    Shapiro, G. I.
    Pollard, J.
    Hendriks, B. S.
    Falk, M.
    Diaz-Padilla, I
    Plummer, R.
    Affiliation
    Department of Oncology, University of Oxford, Oxford, UK.
    Issue Date
    2021
    
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    Abstract
    Background: 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.
    Citation
    Middleton 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.
    Journal
    British Journal of Cancer
    URI
    http://hdl.handle.net/10541/624100
    DOI
    10.1038/s41416-021-01405-x
    PubMed ID
    34040175
    Additional Links
    https://dx.doi.org/10.1038/s41416-021-01405-x
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41416-021-01405-x
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