Babar Bashir, MD from Jefferson Health discussed an ASCO 2020 abstract entitled BT5528-100 phase I/II study of the safety, pharmacokinetics, and preliminary clinical activity of BT5528 in patients with advanced malignancies associated with EphA2 expression.
Context:
BT5528 is a Bicycle Toxin Conjugate (BTC), consisting of a tumor antigen EphA2 targeting bicyclic peptide, connected to a cytotoxin (monomethyl auristatin E [MMAE]) through a cleavable tumor microenvironment linker. Bicycles, developed by Bicycle Therapeutics, are a novel class of chemically synthesized restricted peptides. EphA2 is reported to be overexpressed in a number of solid tumors, leading to oncogenesis, angiogenesis associated with tumours, and metastasis. The signaling of intracellular EphA2 converges on pathways integral to cell development, proliferation , migration and invasion. Increased expression of EphA2 has been identified as a mechanism of resistance to the therapy based on EGFR Tyrosine Kinase Inhibitor. BT5528 action mechanism is based on tumor penetration, target binding, and MMAE toxin payload release. BTCs provide advantages over antibody-toxin conjugates that display rapid dense tumor penetration and reduced sensitivity to extra tumors. BT5528 had a favorable preclinical profile promoting the initiation of a first-in-human study to examine the safety and effectiveness of BT5528 in indications of EphA2 expression including non-small cell lung cancer ( NSCLC), ovarian cancer, triple-negative breast cancer (TNBC), stomach / upper gastrointestinal (GI), pancreatic and urothelial cancers.
Approaches:
The Ph I / II research BT5528-100 (NCT04180371) tests the protection and tolerability of BT5528 alone and in combination with Q4W nivolumab on a weekly basis. For BT5528 with and without nivolumab, each dose escalation uses a 3 + 3 design that converts to a Bayesian design to assess MTD or Crazy and RP2D. Qualified patients must have advanced solid tumors associated with the expression EphA2 that have recurred after the traditional therapeutic options have been exhausted. Patients must have tumor tissue available and an appropriate hematological and organ function, except uncontrolled brain metastases, thromboembolic events, bleeding disorders, uncontrolled hypertension, CYP3A4 inhibitors / inducers, or autoimmune disease for the nivolumab cohorts. Biomarker tests including tumor expression EphA2, ADA, and candidate response biomarkers for BT5528 alone and nivolumab combination will be collected for on-study tumor and blood samples. Pharmacokinetic data for BT5528 and MMAE will be published in C1D1 and D15. The expansion process will enroll particular types of tumors to determine BT5528 ‘s clinical activity. Continuous enrollment. Data on clinical trials: NCT04180371.