First-in-human phase I clinical trial of RSO-021, a first-in class covalent inhibitor of mitochondrial peroxiredoxin 3 (PRX3), in patients with malignant pleural effusion due to mesothelioma and other advanced solid tumors (MITOPE)
Abstract
3019 Background: Malignant cells rely on buffering oxidative stress through mitochondrial PRX3. Oxidative stress is selectively lethal to cancer cells and may be leveraged therapeutically. RSO-021 is a naturally-occurring, sulfur-rich, cyclic oligopeptide of the thiopeptide class, which covalently inactivates PRX3, leading to catastrophic oxidative stress and cell death. We conducted a phase 1 study to explore safety and identify the maximum tolerated dose (MTD) of intra-pleural RSO-021 in patients with mesothelioma, or other predominantly pleural cancer, with pleural effusion. Methods: MITOPE was a multicenter trial of weekly intrapleural RSO-021 (90, 120, and 180 mg) with a 3 + 3 dose-escalation design. The primary objective was to assess RSO-021 safety/tolerability. Secondary objectives included establishing local and systemic pharmacokinetic profiles and early anti-tumor activity. We defined dose-limiting toxicity (DLT) as grade (G) ≥3 non-hematological AEs with exceptions for some manageable G3 AEs that resolved within 72 h and complicated G4 hematological AEs or those lasting >7 days. We also studied inflammatory and pharmacodynamic markers in local/systemic samples. Efficacy was assessed using mRECIST 1.1 (mesothelioma) and RECIST 1.1 (other tumors). Results: Of 15 patients treated (90 mg/wk, n=7; 120 mg/wk, n=6; 180 mg/wk, n=2), 12 (80%) had ≥3 prior anti-cancer regimens; 12 (80%) had mesothelioma. See table for AE and efficacy data. The commonest all-grade…
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