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

2022-08

Gan, Hui K

Parakh, Sagun

Lee, Fook-Thean

Tebbutt, Niall C

Ameratunga, Malaka

Lee, Sze Ting

O'Keefe, Graeme J

Gong, Sylvia J

Vanrenen, Christine

Caine, Jaren

Giovannetti, Mara

Murone, Carmel

Scott, Fiona E

Guo, Nancy

Burvenich, Ingrid J G

Paine, Cameron

Macri, Mary J

Kotsuma, Masakatsu

Senaldi, Giorgio

Venhaus, Ralph

Scott, Andrew M

89Zr-DS-8895a

DS-8895a

EphA2

Imaging

Journal Article

http://orcid.org/0000-0001-7319-8546

https://orcid.org/0000-0003-3891-2489

https://orcid.org/0000-0001-6755-3951

https://orcid.org/0000-0003-2613-5168

https://orcid.org/0000-0002-7171-6781

https://orcid.org/0000-0001-8641-456X

https://orcid.org/0000-0002-8538-6170

https://orcid.org/0000-0003-2426-1638

https://orcid.org/0000-0001-8384-2403

https://orcid.org/0000-0002-6656-295X

10.1007/s10637-022-01237-3

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).

link

Investigational New Drugs 2022; 40(4): 747-755

Investigational new drugs