A First-in-Human, Phase I, Multicenter, Open-Label, Dose-Escalation Study of PCA062: An Antibody-Drug Conjugate...

This first-in-human (FIH), phase I, multicenter, open-label study was conducted to characterize the safety, tolerability, pharmacokinetics, and preliminary efficacy, and to establish the MTD/recommended dose for expansion (RDE) of PCA062 in patients with solid tumors. Adult patients with any solid tumor type and having a documented P-cadherin-positive tumor were enrolled; exceptions to P-cadherin positivity requirement were head and neck squamous cell carcinomas (HNSCC) and esophageal squamous cell carcinoma (ESCC). Dose escalation was guided by an adaptive Bayesian logistic regression model with escalation with overdose control to determine the MTD/RDE. Forty-seven patients were treated at 10 different dose levels of PCA062, ranging from 0.4 to 5.0 mg/kg every 2 weeks administered as a 1-hour intravenous infusion. All enrolled patients discontinued the treatment; primary reason for discontinuation was progressive disease (78.7%). All 47 patients experienced at least one AE, of which 32 patients had a grade ≥3 AE and 37 patients experienced AEs suspected to be study drug related. The MTD of PCA062 was 3.6 mg/kg every 2 weeks and thrombocytopenia was reported as a DLT that was attributed to the known toxicities of the DM1 payload with no P-cadherin-related toxicities. Pharmacokinetics was proportional, and no patients developed antidrug antibodies, suggesting adequate exposure at the doses tested. One patient of 47 achieved a partial response and there was no correlation between tumor P-cadherin expression and clinical efficacy. Because of limited antitumor activity at the MTD level, Novartis has terminated clinical development of PCA062 (NCT02375958).