Abstract

Background

The replication stress response is a novel anti-cancer drug target. ATR is a central kinase in this response, and is also critical for the intra-S and G2/M cell cycle arrest after DNA damage.  Multiple lines of preclinical evidence show that ATR inhibition may be effective when there is deficiency of the DNA damage response or high levels of replication stress.  ATR inhibition in combination with radiotherapy leads to mitotic catastrophe.

Method

We report preliminary data from an ongoing phase I study of AZD6738.  Patients with advanced solid tumours were eligible.  Patients suitable for palliative radiotherapy were entered into the radiotherapy combination, where AZD6738 is dose-escalated in combination with 20 Gy in 10 fractions. Monotherapy dose escalation completed in July 2016, and expansion cohorts are ongoing. Radiation combination dose-escalation is ongoing. We present the data from the two completed cohorts.

Results

The maximum-tolerated dose of AZD6738 is 160 mg BD.  The most common treatment-related adverse events were fatigue, anaemia and thrombocytopenia.  Dose-limiting toxicities were elevation of GGT (n=1, G3), thrombocytopenia (n=1 G3, with epistaxis; n=2 G4), pancytopenia (n=1, G4), elevated amylase (n=1, G3), anaemia (n=2, G3) and photosensitivity (n=1, G3). Monotherapy expansion cohorts are testing alternative dosing schedules to mitigate cumulative toxicity. So far, there have been 2 confirmed partial responses in the monotherapy cohort. 

Nine patients in 2 cohorts have been treated in combination with radiotherapy 20 Gy in 10 fractions.  20 mg and 40 mg BD have been well tolerated. DLT has not been encountered yet and the combination is associated with clinical activity (3 partial response, 5 stable disease, 1 progressive disease).

Conclusion

AZD6738 monotherapy is tolerable and associated with clinical responses. Expansion cohorts will allow assessment of tumour DNA damage response.  AZD6738 in combination with radiotherapy is a promising combination. This ongoing study will define RP2D for the combination.