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 I clinical study for safety, tolerability, pharmacokinetics, 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 and 7-day off) in dose escalation at seven dose levels (30–360 mg) following the classic “3 + 3” design. Results: Twenty-five patients (colorectal cancer, 23 patients; male sex, 48%, and median age, 58 years) were treated with basroparib. Dose-limiting toxicities and fatal treatment-related adverse events were not observed. The most commonly reported treatment-related adverse events were fatigue and nausea with mild/moderate severity. Basroparib pharmacokinetics increased less than proportionally with dose increase up to 300 mg. Among 17 patients evaluated for response, four (23.5%) had stable disease with a duration of up to 2.5 months and relative higher drug exposure compared with others. The dose of 360 mg was determined to be the maximum tolerated dose and recommended phase II dose. Conclusions: Basroparib was shown to be a safe and well-tolerated tankyrase-selective inhibitor with preliminary antitumor activity warranting further investigation. Significance: Tankyrase in the active β-catenin–dependent (canonical) Wnt signaling pathway has been a desirable but difficult target because of safety concerns. We developed a tankyrase-selective inhibitor, basroparib, and successfully introduced it in a first-in-human study. This study demonstrated a favorable safety profile and modest antitumor activity for basroparib and suggests that basroparib may play a role when combined with other rational targeted therapies.

Patient demographic and baseline characteristics (N = 25).

Treatment duration of all enrolled patients. Note: “▲” marks patients with RCC. “Stable Disease (SD)” and “Progressing Disease (PD)” evaluations are based on target lesions only in this graph. C1D1, cycle 1 day 1.

Summary of stable disease patients data.

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 I clinical study for safety, tolerability, pharmacokinetics, 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 and 7-day off) in dose escalation at seven dose levels (30–360 mg) following the classic “3 + 3” design.Results:Twenty-five patients (colorectal cancer, 23 patients; male sex, 48%, and median age, 58 years) were treated with basroparib. Dose-limiting toxicities and fatal treatment-related adverse events were not observed. The most commonly reported treatment-related adverse events were fatigue and nausea with mild/moderate severity. Basroparib pharmacokinetics increased less than proportionally with dose increase up to 300 mg. Among 17 patients evaluated for response, four (23.5%) had stable disease with a duration of up to 2.5 months and relative higher drug exposure compared with others. The dose of 360 mg was determined to be the maximum tolerated dose and recommended phase II dose.Conclusions:Basroparib was shown to be a safe and well-tolerated tankyrase-selective inhibitor with preliminary antitumor activity warranting further investigation.Significance:Tankyrase in the active β-catenin–dependent (canonical) Wnt signaling pathway has been a desirable but difficult target because of safety concerns. We developed a tankyrase-selective inhibitor, basroparib, and successfully introduced it in a first-in-human study. This study demonstrated a favorable safety profile and modest antitumor activity for basroparib and suggests that basroparib may play a role when combined with other rational targeted therapies.

Summary of AEs related to basroparib.