Phase I crossover study of DNA‐protein kinase inhibitor peposertib in healthy volunteers: Effect of food and pharmacokinetics of an oral suspension

Abstract

Peposertib is an orally administered inhibitor of DNA‐dependent protein kinase. We evaluated the effect of food on its pharmacokinetics, and examined the pharmacokinetics of an oral suspension (OS) of disintegrated tablets, in a phase I, open‐label, crossover three‐period study (NCT04702698). Twelve healthy volunteers were randomized to one of six treatment sequences. They received a single dose of peposertib 100 mg as film‐coated tablets under fasted or fed conditions (“tablet fasted” or “tablet fed”) or as an OS under fasted conditions (“OS fasted”), with washout between treatments. Using healthy volunteers was possible because, despite its mechanism of action being suppression of DNA repair, peposertib has shown no genotoxic effect in animals. A mild food effect was observed with peposertib tablets. Fed‐to‐fasted ratios were: area under the curve from time 0 to time t (AUC0–t), 123.81% (90% confidence interval [CI]: 108.04, 141.87%); AUC from zero to infinity (AUC0–∞), 110.28% (90% CI 100.71, 120.77%); and maximum concentration (Cmax) 104.47% (90% CI: 79.15, 137.90%). Cmax was delayed under fed conditions (median time to maximum concentration [Tmax] was 3.5 h [tablet fed] vs. 1 h [tablet fasted]). OS‐to‐tablet (fasted) ratios were: AUC0–t, 124.83% (90% CI: 111.50%, 139.76%); AUC0–∞, 119.05% (90% CI: 104.47, 135.67%); and Cmax 173.29% (90% CI: 135.78, 221.16%). Median Tmax was 0.5 h (OS fasted) versus 1 h (tablet). All treatments were well‐tolerated in healthy volunteers. Peposertib tablets can be taken with or without food; if combined with chemotherapy or radiotherapy, the delay in Cmax must be considered to optimize the chemo‐ or radiosensitizing effect. The peposertib OS form represents an alternative route of administration in patients with specific cancers causing dysphagia. However, the OS form should be part of future dose optimization strategies in relevant settings.

Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors

“…Although PK findings in Part FE were inconclusive, a subsequent study in healthy volunteers showed only a mild food effect. 43 In biomarker analyses, disease control was not associated with baseline PD-L1 or DNA-PK levels; however, within the few assessable patients in Part B, a potential association between disease control and Ki-67 expression, a proliferation and prognostic marker for multiple cancers, was observed in tumor cells. 44 …”

Peposertib, a DNA-PK Inhibitor, Enhances the Anti-Tumor Efficacy of Topoisomerase II Inhibitors in Triple-Negative Breast Cancer Models

“…The discovery of the key role of DNA-PK in DNA damage repair highlighted the potential of DNA-PK inhibitors, such as peposertib, to block DNA repair and, therefore, enhance the efficacy of DNA-damaging agents [8]. Peposertib is a potent, selective and orally bioavailable DNA-PK inhibitor, which, in both preclinical models and clinical trials, strongly potentiates the anti-tumor effects of ionizing radiation and DNA DSB-inducing agents, including anthracyclines [8][9][10]. The combination potential of peposertib with various DNA-damaging treatment modalities, including pegylated liposomal doxorubicin (PLD), is currently being evaluated in early-stage clinical studies (e.g., NCT04092270).…”