Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours.
Br J Cancer
; 125(4): 520-527, 2021 08.
Article
en En
| MEDLINE
| ID: mdl-34040174
ABSTRACT
BACKGROUND:
Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin.METHODS:
Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W).RESULTS:
Thirty-one patients received berzosertib (90-210 mg/m2) and cisplatin (40-75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2 (days 2 and 9) and cisplatin 75 mg/m2 (day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy.CONCLUSIONS:
Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting. CLINICAL TRIALS IDENTIFIER NCT02157792.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Pirazinas
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Protocolos de Quimioterapia Combinada Antineoplásica
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Cisplatino
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Isoxazoles
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Neoplasias
Tipo de estudio:
Clinical_trials
Límite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Br J Cancer
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos