Br J Cancer: berzosertib + gemcitabine + cisplatin combined treatment of advanced solid tumors

Chemotherapy drugs, including platinum drugs and gemcitabine, induce a potentially fatal DNA damage response (DDR) in cancer cells, which is part of the standard treatment for many cancers
.

However, chemotherapeutic drug resistance can lead to poorer clinical outcomes in patients

Chemotherapy drugs, including platinum drugs and gemcitabine, induce a potentially fatal DNA damage response (DDR) in cancer cells, which is part of the standard treatment for many cancers

DDR top adjustment factor is ATM (ataxia capillary blood vessel dilation mutated kinases), and the ATR (ataxia telangiectasia and Rad3 related protein kinase), ATR reaction is mainly single exposure stranded DNA, as these are usually single stranded DNA Produced by DNA damage and replication stress, ATM corresponds to DNA double-strand breaks
.

Blood vessel

Previous studies have shown that inhibition of ATR is a potential cancer treatment target.

In these cancers, DNA damaging chemotherapy has been used as a standard treatment, but further research is still needed

Berzosertib (M6620, VX-970) is a highly effective and selective ATR inhibitor
.

This study aims to evaluate the efficacy of multiple escalating doses of berzosertib + gemcitabine + cisplatin in patients with drug-resistant/refractory advanced solid tumors

Berzosertib (M6620, VX-970) is a highly effective and selective ATR inhibitor

Related research design drawings

Related research design drawings

The results showed that a total of 52 patients received berzosertib + gemcitabine treatment, while the other eight patients received berzosertib + gemcitabine + cisplatin combination therapy
.

The researchers found that four patients treated with berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLT), while the berzosertib + gemcitabine + cisplatin treatment group had a total of three DLTs

The researchers determined that the recommended dose for Phase 2 (RP2D) was: berzosertib 210mg/m ² (days 2 and 9) + gemcitabine 1000mg/m ² (days 1 and 8); they did not determine berzosertib+ gemcitabine + cis RP2D with platinum combination therapy
.

Further studies have shown that neither gemcitabine nor cisplatin will affect the pharmacokinetics of berzosertib

Berzosertib plasma concentration-time curve

Berzosertib plasma concentration-time curve

All in all, the results of the study revealed that patients with advanced solid tumors tolerated the berzosertib+gemcitabine combination therapy well and showed preliminary efficacy
.

Patients with advanced solid tumors tolerated berzosertib+gemcitabine combination therapy well and showed preliminary efficacy
.

Patients with advanced solid tumors tolerated berzosertib+gemcitabine combination therapy well and showed preliminary efficacy
.

Original source:

Middleton, MR, Dean, E.
, Evans, TRJ 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 (26 May 2021 ).

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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