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A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in
Howard A Burris1, Jordan Berlin2, Tobias Arkenau3
1Sarah Cannon Research Institute, Nashville, TN, USA. howard.burris@scri.com.
Background:
Gartisertib is an oral inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a key kinase of the DNA damage response. We aimed to determine the safety and tolerability of gartisertib ± carboplatin in patients with advanced solid tumours.
Methods:
This phase I open-label, multicenter, first-in-human study comprised four gartisertib cohorts: A (dose escalation [DE]; Q2W); A2 (DE; QD/BID); B1 (DE+carboplatin); and C (biomarker-selected patients).
Results:
Overall, 97 patients were enroled into cohorts A (n = 42), A2 (n = 26), B1 (n = 16) and C (n = 13). The maximum tolerated dose and recommended phase II dose (RP2D) were not declared for cohorts A or B1. In cohort A2, the RP2D for gartisertib was determined as 250 mg QD. Gartisertib was generally well-tolerated; however, unexpected increased blood bilirubin in all study cohorts precluded further DE. Investigations showed that gartisertib and its metabolite M26 inhibit UGT1A1-mediated bilirubin glucuronidation in human but not dog or rat liver microsomes. Prolonged partial response (n = 1 [cohort B1]) and stable disease >6 months (n = 3) did not appear to be associated with biomarker status. Exposure generally increased dose-dependently without accumulation.
Conclusion:
Gartisertib was generally well-tolerated at lower doses; however, unexpected liver toxicity prevented further DE, potentially limiting antitumour activity. Gartisertib development was subsequently discontinued.
Clinicaltrials:
GOV: NCT02278250.
Insights
Gartisertib, an ATR inhibitor, showed general tolerability but unexpected liver toxicity halted further development. This liver toxicity, linked to bilirubin glucuronidation inhibition, limited its potential antitumour activity in advanced solid tumours.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Gartisertib is an oral inhibitor targeting ataxia telangiectasia and Rad3-related protein (ATR), a key kinase in DNA damage response pathways.
- This study evaluated the safety and tolerability of gartisertib, alone and in combination with carboplatin, in patients with advanced solid tumours.
Purpose of the Study:
- To determine the safety and tolerability profile of gartisertib in patients with advanced solid tumours.
- To establish the recommended phase II dose (RP2D) for gartisertib monotherapy and in combination with carboplatin.
Main Methods:
- A phase I, open-label, multicenter, first-in-human study involving four cohorts: dose escalation (Q2W and QD/BID), dose escalation with carboplatin, and biomarker-selected patients.
- Safety and tolerability were assessed, including dose-limiting toxicities and adverse events.
- Pharmacokinetic analysis was performed to evaluate dose-dependency and accumulation.
Main Results:
- 97 patients were enrolled across cohorts. The RP2D for gartisertib monotherapy was established at 250 mg QD in cohort A2.
- Unexpected increased blood bilirubin across all cohorts, attributed to gartisertib and metabolite M26 inhibiting UGT1A1-mediated bilirubin glucuronidation, precluded further dose escalation.
- While generally well-tolerated at lower doses, liver toxicity limited further development, with limited evidence of antitumour activity associated with biomarker status.
Conclusions:
- Gartisertib demonstrated general tolerability at lower doses but was associated with significant liver toxicity due to UGT1A1 inhibition.
- This unexpected toxicity limited further dose escalation and potentially antitumour efficacy, leading to the discontinuation of gartisertib development.
- The study highlights the importance of investigating drug metabolism and its impact on toxicity, even in early-phase trials.
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