A phase 1 safety and bioimaging trial of antibody DS-8895a against EphA2 in patients with advanced or metastatic EphA2 positive cancers

Hui K. Gan, Sagun Parakh, F. T. Lee, Niall C. Tebbutt, Malaka Ameratunga, Sze Ting Lee, Graeme J. O’Keefe, Sylvia J. Gong, Christine Vanrenen, Jaren Caine, Mara Giovannetti, Carmel Murone, Fiona E. Scott, Nancy Guo, Ingrid J.G. Burvenich, Cameron Paine, Mary J. Macri, Masakatsu Kotsuma, Giorgio Senaldi, Ralph VenhausAndrew M. Scott

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10 Citations (Scopus)

Abstract

Ephrin type-A 2 (EphA2) is a transmembrane receptor expressed in epithelial cancers. We report on a phase I dose escalation and biodistribution study of DS-8895a, an anti-EphA2 antibody, in patients with advanced EphA2 positive cancers. DS-8895a was administered at 1, 3, 10 or 20 mg/kg every 2 weeks to determine safety, pharmacokinetics and anti-tumor efficacy. All patients underwent 89Zr trace-labelled infusion of DS-8895a (89Zr-DS-8995a) positron emission tomography imaging to determine the biodistribution of DS-8895a, and correlate findings with EphA2 expression, receptor saturation and response. Nine patients were enrolled on study. Of patients enrolled, seven patients received at least one infusion of DS-8895a: four patients received 1 mg/kg dose (Cohort 1) and three patients received 3 mg/kg dose (Cohort 2). Median age was 67.0 years (range 52—81), majority male (71%), and median number of prior systemic therapies was three (range 0—8). The primary cancer diagnosis was colorectal cancer (two patients) and one patient each had gastric, head and neck, high-grade serous adenocarcinoma, lung, and pancreatic cancers. No dose-limiting toxicities or treatment-related adverse events reported. The best response for the patients in Cohort 1 was stable disease and in Cohort 2 was progressive disease. 89Zr-DS-8895a demonstrated no normal tissue uptake and specific low-grade uptake in most tumours. DS-8895a had limited therapeutic efficacy at doses evaluated and 89Zr-DS-8895a demonstrated low tumour uptake. The biodistribution data from this study were key in halting further development of DS-8895a, highlighting the importance of biodistribution studies in drug development. (Trial registration: ClinicalTrials.gov Identifier NCT02252211).

Original languageEnglish
Pages (from-to)747-755
Number of pages9
JournalInvestigational New Drugs
Volume40
Issue number4
DOIs
Publication statusPublished - Aug 2022
Externally publishedYes

Keywords

  • Zr-DS-8895a
  • DS-8895a
  • EphA2
  • Imaging

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