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

Sarina A. Piha-Paul, Analía Azaro, Hendrik Tobias Arkenau, Do Youn Oh, Matthew D. Galsky, Sumanta Kumar Pal, Kensuke Hamada, Yaohua He, Ikuo Yamamiya, Karim A. Benhadji, Antoine Hollebecque

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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://clinicaltrials.gov/ct2/show/NCT03410927; registered on January 25, 2018.

Original languageEnglish (US)
Pages (from-to)1324-1334
Number of pages11
JournalInvestigational New Drugs
Volume39
Issue number5
DOIs
StatePublished - Oct 2021

Keywords

  • Erb-B2 receptor tyrosine kinase 3
  • Human epidermal growth factor receptor 2
  • Neoplasms
  • Phase I study
  • TAS0728

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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