Phase 1 clinical trial of the ataxia telangiectasia and Rad3‐related inhibitor berzosertib with irinotecan in patients with advanced solid tumors (ETCTN 9938)

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ABSTRACT Background Ataxia telangiectasia and Rad3‐related (ATR) inhibition with berzosertib potentiates the efficacy of irinotecan in preclinical models. The authors hypothesize that this combination is well tolerated, modulates the DNA damage response to irinotecan, and is associated with clinical activity in advanced solid tumors. Methods In this phase 1 study (NCT02595931), berzosertib 60–270 mg/m 2 was administered with irinotecan 180 mg/m 2 every 2 weeks in a 4‐week cycle. The primary end point was determination of the maximum tolerated dose and recommended phase 2 dose (RP2D). Antitumor activity, pharmacokinetics, and pharmacodynamics were secondary end points. Results Sixty‐three patients were enrolled, the majority with colorectal cancer (49%) or pancreatic cancer (21%). Median number of prior lines of therapy was four (range, 2–7). Two dose‐limiting toxicities, both febrile neutropenia, occurred among 45 patients treated with berzosertib 270 mg/m 2 and irinotecan 180 mg/m 2 . The most common treatment‐related grade ≥3 toxicities were lymphopenia (30%), neutropenia (29%), and anemia (25%). Two partial responses occurred in patients with pancreatic cancer and ataxia telangiectasia mutated (ATM) alterations: 32% decrease in an ATM E11828/ATM K1109* tumor lasting 15.8 months and 57% decrease in an ATM R3008H/germline ATM R1882* tumor lasting 13.6 months. Induction of DNA damage markers γH2AX and pNBS1 was observed in one tumor biopsy obtained post berzosertib and irinotecan combination treatment compared with post irinotecan alone. Conclusion Berzosertib 270 mg/m 2 and irinotecan 180 mg/m 2 was the RP2D. The combination is associated with manageable side effects and promising disease activity in ATM mutant solid tumors.

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