E7386 in patients with advanced solid tumors: results from the dose-escalation part and an expansion part of a phase I study

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BACKGROUND: E7386 is an orally active inhibitor reported to block the CBP/β-catenin interaction. We present data from the dose-escalation and expansion part 1 of Study 103 (phase I) of E7386 in patients with advanced, unresectable, or recurrent (A/U/R) solid tumors. PATIENTS AND METHODS: This open-label study was conducted in Japan. In dose-escalation, eligible patients aged ≥20 years were diagnosed with A/U/R solid tumors with no alternative standard/effective therapies. In the expansion part, eligible patients were diagnosed with A/U/R colorectal cancer (two or more prior systemic anticancer therapies) or other gastrointestinal tumors (one or more prior systemic anticancer therapy). The primary objective was assessment of safety and tolerability. Secondary objectives were assessment of pharmacokinetic (PK) and antitumor activity. Efficacy was assessed by investigators using RECIST v1.1. RESULTS: Fifty-five enrolled patients (dose-escalation: n = 36; expansion: n = 19) received one or more dose of E7386. The most frequent tumor was colorectal cancer (dose-escalation: 55.6%; expansion: 84.2%). Over half of those enrolled received more than three prior systemic anticancer medications. In dose-escalation, dose-limiting toxicities (grade 3 decreased appetite) occurred in two patients [160 mg twice daily (b.i.d.) cohort]; the recommended dose was 120 mg b.i.d. Most patients (dose-escalation/expansion) experienced treatment-emergent adverse events (TEAEs; 97.2%/94.7%): the most frequent TEAEs were nausea (83.3%/84.2%) and vomiting (61.1%/73.7%). These were primarily low-grade in severity and well managed with antiemetics in patients receiving up to 120 mg b.i.d. No patients died due to TEAEs. In dose-escalation, two patients achieved partial response (PR): one with small bowel carcinoma (APC/KRAS/TP53 mutations); one with a desmoid tumor (APC mutation). No PRs were observed in the expansion part. PK exposure increased with doses (range: 10-160 mg b.i.d.) following single and repeat-dose administrations, although large inter-subject variability was observed. CONCLUSIONS: In heavily pretreated patients with advanced solid tumors, E7386 demonstrated a manageable safety profile and a dose-dependent PK profile. PRs were noted in patients with small bowel carcinoma or desmoid tumor.