The ATR Inhibitor Elimusertib in Combination with Cisplatin in Patients with Advanced Solid Tumors: A California...

The ataxia telangiectasia and Rad3-related kinase inhibitor elimusertib synergizes with cisplatin preclinically. We evaluated the clinical feasibility of combining elimusertib with cisplatin.

Patients with advanced solid tumors who had received <300 mg/m2 of prior cisplatin, and for whom cisplatin-based treatment was deemed appropriate, were enrolled according to a standard 3 + 3 design, starting elimusertib at 20 mg orally twice daily on days 2 and 9, with cisplatin 60 mg/m2 intravenously on day 1 of a 21-day cycle. Primary objectives were the determination of the maximum tolerated dose and safety. Secondary objectives included the assessment of elimusertib pharmacokinetics and preliminary efficacy.

Fifteen patients were enrolled. Dose level -2 (elimusertib 20 mg once on day 2 and cisplatin 30 mg/m2 on days 1 and 8) was deemed the maximum tolerated dose; dose-limiting toxicities (DLT) including creatinine increase, hypokalemia, febrile neutropenia, neutropenia, syncope, and thrombocytopenia, required dose de-escalation. Although the four patients with the highest elimusertib exposure all experienced hematologic DLTs within 1 week, they also received a higher day 1 cisplatin dose, precluding a definitive association of elimusertib exposure with DLT occurrence. Of 10 evaluable patients, one (10%) with clear-cell ovarian cancer had a partial response, whereas five (50%) had stable disease.

Cisplatin combined with elimusertib was associated with hematologic toxicity requiring significant dose de-escalation. Elimusertib pharmacokinetics was consistent with prior studies. Only modest activity was observed. Further clinical evaluation of elimusertib plus cisplatin is not warranted.

Preclinical data suggest synergy between cisplatin and the ataxia telangiectasia and Rad3-related inhibitor elimusertib, leading to this phase Ib trial in advanced solid tumors evaluating feasibility. The results do not support further examination of the combination due to DLTs observed in the absence of robust efficacy.