Safety and Tolerability of Berzosertib, an Ataxia-Telangiectasia–Related Inhibitor, and Veliparib, an Oral Poly (ADP-ribose) Polymerase Inhibitor, in Combination With Cisplatin in Patients With Refractory Solid Tumors

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PURPOSE We conducted a phase I trial of the combination of cisplatin with the ataxia-telangiectasia–related protein kinase inhibitor berzosertib and the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib, with the objective of creating a DNA damage response (DDR)–impaired, BRCA null–like phenotype to potentiate the antitumor activity of cisplatin. PATIENTS AND METHODS In this open label, 3 + 3 trial design, cisplatin and berzosertib were administered intravenously on day 1 (D1) and D8, and D2 and D9, respectively, together with twice-daily oral veliparib on D1-D3 and D8-D10 in 21-day cycles. Previous platinum and PARPi therapy were permitted. A pharmacodynamic study compared tumor nuclear DDR biomarker response on C1D1 and C1D9 at the combination maximum tolerated dose (MTD). RESULTS Fifty-three patients enrolled with 46 evaluable for response (41 with measurable disease). The MTD and recommended phase II dose (RP2D) were determined to be cisplatin 40 mg/m 2 once daily on D1/D8, berzosertib 210 mg/m 2 once daily on D2/D9, and veliparib 200 mg twice a day on D1-D3 and D8-D10. Three patients achieved confirmed partial responses (PRs; 3/41, 7.3%); two patients experienced unconfirmed PRs. Median time on study was four cycles (range, 1-25), and 35 patients (66.0%) required at least one dose reduction. The most common grade 3/4 adverse events were myelosuppressive (anemia [37.7%], thrombocytopenia [32.1%], leukopenia [24.5%], neutropenia [22.6%], lymphopenia [20.8%]); no new safety signals were observed. Adding berzosertib to veliparib/cisplatin increased the frequency of RAD51-positive tumor cells in BRCA -wildtype biopsy specimens. CONCLUSION This combination shows antitumor activity, including in patients with and without homologous recombination–compromised tumors and those previously treated with platinum. Adding berzosertib further increases the DDR response elicited by combination cisplatin/veliparib treatment in BRCA -wildtype patients, indicating increased replication stress at the RP2D/MTD.

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