A first-in-human phase I study of TAS0728, an oral covalent binding inhibitor of HER2, in patients with advanced solid tumors with HER2 or HER3 aberrations

Abstract

TAS0728 is an oral covalent binding inhibitor of human epidermal growth factor receptor 2 (HER2). A first-in-human open-label, dose-escalation, phase I study (NCT03410927) was initiated to investigate the safety and dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of TAS0728 in adults with advanced solid tumors with HER2 or HER3 overexpression, amplification or mutation. In total, 19 patients received TAS0728 at escalating doses from 50 to 200 mg BID for 21-day cycles. Following escalation of the dose to 200 mg BID, a total of two DLTs were observed, both cases of Grade 3 diarrhea (lasting >48 h and not responsive to aggressive antidiarrheal treatment). Following de-escalation of the dose to 150 mg BID, another DLT of Grade 3 diarrhea was observed in one patient. Additionally, at 150 mg BID, one patient had a fatal cardiac arrest after receiving 1 cycle (21 days) of TAS0728. The etiology of the cardiac arrest event was not clear, however causal relationship to TAS0728 could not be excluded due to the temporal association observed. Partial responses were observed in 2 of 14 patients evaluable for TAS0728 treatment response. The study was stopped due to unacceptable toxicity during the dose-escalation as the overall risk-benefit ratio no longer favored the dose level being tested, therefore the MTD was not determined. ClinicalTrials.gov registration number: https://ichgcp.net/clinical-trials-registry/NCT03410927 ; registered on January 25, 2018.

Keywords: Erb-B2 receptor tyrosine kinase 3; Human epidermal growth factor receptor 2; Neoplasms; Phase I study; TAS0728.

Conflict of interest statement

SAP-P reports clinical trial research support from AbbVie, ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Chugai Pharmaceutical, Curis, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma, Incyte, Jacobio Pharmaceuticals, MedImmune, Medivation, Merck Sharp and Dohme, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, and TransThera Biosciences, and grant support from the National Cancer Institute/National Institute of Health (NCI/NIH): P30CA016672 - Core Grant (CCSG Shared Resources) outside the submitted work. AA is an employee of AstraZeneca. D-YO reports grants from Array, AstraZeneca, BeiGene, Eli Lilly, MSD, Novartis, and Servier outside the submitted work. MDG reports grants and personal fees from AstraZeneca, Bristol Myers Squibb, Dendreon, Genentech/Roche, Merck Sharp and Dohme, and Novartis; and personal fees from Alleron Therapeutics, Astellas Pharma, Basilea, BioMotiv, Dracen Pharmaceuticals, Dragonfly Therapeutics, EMD Serono, GlaxoSmithKline, Incyte, Janssen Oncology, Inovio Pharmaceuticals, NuMab Therapeutics, Pfizer, Seattle Genetics, and Urogen Pharma outside the submitted work. SKP reports personal fees from Astellas, Genentech, Aveo, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Novartis, Pfizer, and Roche outside the submitted work. AH reports grants and personal fees from AstraZeneca, Amgen and Incyte; and personal fees from Eisai, Servier, QED Therapeutics, Eli Lilly, Spectrum Therapeutics, and Roche outside the submitted work. KH, YH, IY and KAB are employees of Taiho. KAB is a former employee of Eli Lilly and is a stockholder of Eli Lilly. No conflicts of interest were reported by HTA.

© 2021. The Author(s).

Figures

Fig. 1

Duration of exposure (all treated population)*

Fig. 2

Waterfall plot of best change from baseline in the size of target lesions for patients with tumor response data*