Abstract Purpose: The pathogenesis of colorectal cancer is largely driven by mutations of the tumor suppressor gene APC (Adenomatous Polyposis Coli) that lead to aberrant activation of the β-catenin-dependent (canonical) Wnt signaling pathway. We evaluated basroparib, a tankyrase-selective inhibitor targeting the Wnt/β-catenin signaling pathway, in a first-in-human phase 1 clinical study for safety, tolerability, pharmacokinetics (PK) and efficacy in patients with advance-stage solid tumors. Patients and Methods: Patients enrolled to this open-label, multicenter study (NCT04505839) were treated with basroparib capsules orally once daily in 28-day cycles (21-day on, 7-day off) in dose escalation at 7 dose levels (30 to 360 mg) following classic “3+3” design. Results: Twenty-five patients (colorectal cancer, 23 patients; male sex, 48%, median age, 58.0 years) were treated with basroparib. Dose-limiting toxicities and fatal treatment related adverse events (TRAEs) were not observed. The most commonly reported TRAEs were fatigue and nausea with mild/moderate severity. STP1002 pharmacokinetics increased less-than-proportionally with dose increase up to 300 mg. Among 17 patients evaluated for response, 4 (23.5%) had stable disease with duration of up to 2.5 months and relative higher drug exposure compare to others. 360 mg was determined to be the maximum tolerated dose and recommended phase 2 dose. Conclusions: Basroparib (STP1002) was shown to be a safe and well-tolerated tankyrase-selective inhibitor with preliminary anti-tumor activity warranting further investigation.
Lieu et al. (Thu,) studied this question.