A phase 1 study of a CDH6-Targeting antibody-drug conjugate in patients with advanced solid tumors with evaluation of inflammatory and neurological adverse events

Patrick Schöffski, Nicole Concin, Cristina Suarez, Vivek Subbiah, Yuichi Ando, Shiling Ruan, Joel P. Wagner, Keith Mansfield, Xu Zhu, Shizuka Origuchi, Sarah Didominick, Carl U. Bialucha, Jason E. Faris, Ben Tran

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Purpose: This first-in-human study (NCT02947152) evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of HKT288, a first-in-class CDH6-targeting antibody-drug conjugate (ADC). Experimental Design: HKT288 was administered intravenously (IV) every 3 weeks until patients experienced unacceptable toxicity or progressive disease (PD). The starting dose of 0.3 mg/kg was determined based on the highest nonseverely toxic dose in monkeys, which was 2 mg/kg IV weekly. Based on preclinical toxicology, skin, eyes, bone marrow, and liver were expected targets of toxicity. Results: Nine patients were enrolled: 5 with renal cell carcinoma and 4 with epithelial ovarian cancer. The best overall response on the 0.3 mg/kg cohort in patients with measurable disease was RECIST v1.1 stable disease in 3 patients and PD in 2 patients. The most frequent adverse events (AEs) regardless of causality were pyrexia (44.4%), constipation (44.4%), fatigue (33.3%), and vomiting (33.3%). Three suspected-related neurologic AEs (Grade 2) were reported on the 0.75 mg/kg cohort: seizure in 1 patient and another patient with aphasia and encephalopathy. Further studies were unable to identify the underlying mechanism of the neurologic AEs, and the study was terminated early. Conclusions: Preclinical toxicology did not predict the neurotoxicity observed with HKT288, and a comprehensive assessment performed post hoc did not identify the mechanism of toxicity. The development of further CDH6-targeting ADCs should be pursued with caution.

Original languageEnglish (US)
Pages (from-to)547-556
Number of pages10
JournalOncology research and treatment
Volume44
Issue number10
DOIs
StatePublished - Oct 1 2021

Keywords

  • Advanced solid tumors
  • Cadherin-6
  • HKT288
  • Neurological toxicity
  • Phase 1

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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