A phase 1b study of E7386, a CREB-binding protein (CBP)/β-catenin interaction inhibitor, in combination with lenvatinib in patients with advanced hepatocellular carcinoma.

4075 Background: E7386, a novel oral anticancer agent, inhibits β-catenin binding to its transcriptional co-activator, CBP, thus modulating Wnt/β-catenin signaling. The objectives of the dose-escalation part in this phase 1b study were to assess safety, tolerability, pharmacokinetics (PK), biomarkers, and preliminary efficacy of E7386 combined with lenvatinib in patients with advanced hepatocellular carcinoma (HCC) or other solid tumors. Here, we present the results from the HCC subpart. Methods: In cycle 0, E7386 was administered orally in escalating doses once daily (QD) or twice daily (BID) for 5 or 6 consecutive days. From cycle 1 day 1, E7386 QD or BID, combined with daily oral lenvatinib (8 mg in patients with body weight of <60 kg or 12 mg in patients with body weight ≥60 kg), were administered on a continuous schedule in 28-day cycles in the HCC subpart. Adverse events (AEs) were graded using CTCAE v5.0. Prophylactic antiemetics were not allowed during the dose-limiting toxicities (DLT) evaluation period but were permitted after the occurrence of nausea and vomiting. Tumor response was assessed by investigators using mRECIST (Lencioni and Llovet, 2010). PK and biomarker analyses were conducted using samples collected at defined time points. Results: As of the cutoff date (9 December 2022), 25 patients had been treated in the HCC subpart with E7386 dose ranges from 10 to 80 mg QD and from 60 to 120 mg BID. Among 3 patients in the E7386 120 mg BID cohort, grade 3 maculopapular rash (in 1 patient) and grade 5 acute kidney injury (in 1 patient) DLTs were observed. No DLTs were observed in other cohorts. The most common treatment-emergent AEs (TEAEs; any grade) across all cohorts were nausea (n=19; 76.0%), vomiting (n=15; 60.0%), constipation (n=13; 52.0%), palmar-plantar erythrodysesthesia syndrome (n=12; 48.0%), diarrhea (n=11; 44.0%), and proteinuria (n=10; 40.0%). The most common grade ≥3 TEAEs (≥5% of patients) were proteinuria (n=5; 20.0%) and aspartate aminotransferase level increased (n=2; 8.0%). Nausea and vomiting were well controlled by a 5HT3 antagonist. Among the 25 treated patients, 9 (36.0%) partial responses (PRs) were observed, including 3 PRs in 10 patients who had received lenvatinib as a prior regimen. C max and AUC for E7386 increased with increasing E7386 dose. Conclusions: E7386 100 mg BID, in combination with lenvatinib (8 or 12 mg based on bodyweight) QD, was determined as the recommended phase 2 dose, and was deemed tolerable and manageable with antiemetic administration. The combination showed promising activity in patients with HCC, including those pretreated with lenvatinib. Clinical trial information: NCT04008797 .