A first-in-human, open-label multicentre Phase 1 study of the orally administered E7386 in patients with selected advanced neoplasms

Background We present data from the Phase 1 open-label Study 101 of E7386, an oral protein-protein interaction inhibitor reported to block the CBP/β-catenin interaction, in patients with solid tumours. Methods Eligible patients (across the UK and US) aged ≥18 years had advanced/recurrent solid tumours (dose-escalation) or CTNNB1 -mutated hepatocellular carcinoma (dose-expansion). Primary objectives were to assess safety/tolerability and determine the recommended Phase 2 dose (RP2D) of E7386. Results Thirty-eight patients received study drug (dose-escalation: n = 32; expansion: n = 6; dose-range: 5–120 mg twice daily [BID]); 60.5% received ≥3 prior anticancer medications. Dose-limiting toxicities (grade-2 lethargy and grade-2 decreased appetite) occurred in 1 patient (20 mg BID cohort). The RP2D was determined as 120 mg BID. Most (94.7%) patients experienced treatment-related adverse events (TRAEs), most frequently nausea (65.8%) and vomiting (60.5%), which were primarily grade 1/2 and well-managed with antiemetics. No grade 4/5 TRAEs were noted. Pharmacokinetic exposure increased with increasing dose, although large intersubject variability was observed. No objective responses were noted; stable disease (SD) was observed in 36.8% of patients, including SD ≥ 23 weeks in 18.8% of patients (dose-escalation). Conclusions E7386 demonstrated a manageable safety profile, a dose-dependent pharmacokinetic profile, and some disease stabilisation in heavily pretreated patients with advanced solid tumours. Trial registration NCT03264664 https://clinicaltrials.gov/study/NCT03264664 .