BET inhibitor OPN-2853 in advanced solid tumors and lymphoma: results from the phase 1b PLX124-01 trial

OPN-2853 (formerly PLX2853, now dubbed zavabresib) is a potent, oral inhibitor of all four members of the bromodomain and extraterminal (BET) proteins, involved in epigenetic regulation across multiple cancers. This study aimed to determine the recommended Phase 2 dose (RP2D) of OPN-2853 and collect safety, pharmacokinetic and pharmacodynamic data in adults with advanced relapsed/refractory solid tumors or non-Hodgkin lymphoma (NHL).

This was a first-in-human, open-label, Phase 1b study. Primary endpoints included RP2D, pharmacokinetics and safety. Secondary and exploratory endpoints were efficacy and pharmacodynamics.

Forty-nine patients were enrolled. The RP2D was determined at 80 mg oral once daily (QD). The most common adverse events were nausea (n = 17 [24.7%], all < Grade 3) and fatigue (n = 12 [24.5%], n = 3 Grade 3). No OPN-2853-related deaths occurred. Three patients (6.1%) experienced dose-limiting toxicities: Grade 4 thrombocytopenia at 120 mg QD [n = 2] and a Cycle 1 dose reduction (Grade 3 fatigue with Grade 2 cheilitis and nausea [n = 1]). OPN-2853 has a short half-life (< 3 h). For pharmacodynamic response, gene expression changes in whole blood RNA-seq analysis were observed for up to 9 h. Of the 36 patients (73.4%) with at least one post-baseline assessment, 1 patient (2.8%) achieved a complete response with 18-month progression-free survival (PFS) and 1 patient (2.8%) achieved a partial response (PFS of 5.2 months). Another patient (2.8%) achieved an unconfirmed PR.

OPN-2853 was well tolerated at the RP2D in patients with advanced solid tumors and NHL, with modest clinical activity including two confirmed objective responses.