Phase IB trial of the BMI-1 inhibitor unesbulin plus neoadjuvant paclitaxel-carboplatin in advanced ovarian cancer

Preclinical studies with BMI-1 inhibitor Unesbulin (PTC596) demonstrated enhanced anti-cancer activity. This trial was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy, and recommended phase 2 dose (RP2D) of Unesbulin combined with Paclitaxel (P) and Carboplatin (C) in advanced OC. The trial utilized a 3 + 3 design to determine the safety, maxium tolerated dose (MTD), and RP2D of Unesbulin + paclitaxel and carbplatin (PC) for 3 cycles, followed by surgery and 3–7 cycles of Unesbulin + PC. Blood samples were collected to estimate PK parameters. RNA was extracted and analyzed from pre- and post-therapy tumor samples. Unesbulin tablets were escalated up to 300 mg po twice weekly with PC with no DLTs. The most commonly reported treatment emergent adverse events (TEAEs) were those associated with PC and included nausea and fatigue (48%), neutropenia (44%), vomiting (36%), diarrhea (28%) and anemia (20%). Most common grade 3 or higher TEAE included neutropenia (40%) and neutropenic fever (12%). Among 18 patients with measurable disease, the objective response rate before surgery was 61%. Unesbulin was detectable post-dose through 96 h, reaching T max at 4 h. C max and AUC 0-24 h increased with the dose. RNA expression analysis revealed increased mitochondrial dysfunction, Granzyme A signaling, sirtuin signaling, antigen processing, and a concomitant decrease in oxidative phosphorylation (OP), complex I biogenesis, and NET signaling. The study demonstrates that unesbulin + PC is feasible and safe. Exploratory data showed the critical role of BMI-1 in regulating cellular bioenergetics and modulating the immune response, supporting BMI-1 inhibition as a potential therapeutic strategy. Dose escalation was halted based on the sponsor’s declaration of 300 mg PO twice weekly as the optimal combination dose, and the expansion cohort was not enrolled due to the company’s de-prioritization of the asset. This trial is registered with ClinicalTrials.gov, NCT03206645, on 2017-07-02.