ATR inhibitor promise for advanced solid tumours dimmed by liver toxicity

Gartisertib, an oral inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), for patients with advanced solid tumours is well tolerated at lower doses, according to the results of a phase I study. However, unexpected liver toxicity prevents dose escalation and, in turn, limits the drug’s antitumour activity.

The multicentre phase I study included 97 patients who were grouped into four according to the gartisertib regimen they received: group A (dose escalation; gartisertib twice weekly; n=42), group A2 (dose escalation; gartisertib once daily or twice daily; n=26), group B1 (dose escalation; gartisertib + carboplatin; n=16), and group C (dose expansion; n=13).

The median age of the patients was 58.5 years in group A, 63.0 years in group A2, 61.0 years in group B1, and 61.0 years in group C. Between 47.6 percent and 69.2 percent of patients continued gartisertib treatment until disease progression or death. Treatment was discontinued in 52.4 percent of patients in group A, 46.2 percent in group A2, 43.8 percent in group B1, and 30.8 percent in group C. Treatment duration was ≤6 weeks for most patients.

The maximum tolerated dose and recommended phase II dose (RP2D) were not established for cohorts A or B1. In cohort A2, the RP2D for gartisertib was 250 mg once daily.

Gartisertib was generally well-tolerated, but all patients had an unexpected increase in blood bilirubin, which prevented further dose escalation. Gartisertib and its metabolite M26 were shown to inhibit UGT1A1-mediated bilirubin glucuronidation in human liver microsomes.

Biomarker status did not predict prolonged partial response (n=1) and stable disease >6 months (n=3) with gartisertib.

The development of the drug was subsequently discontinued.