Abstract LB_A17: Trial in progress: First-in-human phase I dose-escalation study of a novel Bicycle toxin conjugate (BT5528) targeting EphA2 in patients with advanced solid tumors
Authors: Fontana Elisa , Bashir Babar , Wang Judy S. , Aljumaily Raid , Machiels Jean-Pascal , Vieito Maria , Falchook Gerald , Carter Louise , de Spéville Bernard Doger , Greystoke Alastair , Kim Sang Wun , Kotecki Nuria , Spira Alexander I. , Candilejo Irene Moreno , Basu Bristi , Prenen Hans , Bessudo Alberto , Nagasaka Misako , Ahnert Jordi Rodón , Park Joo-Hwan , Teo Min-Yuen , Rotow Julia , Liu Jie , De Rienzo Assunta , Li Mengyao , Domingo Adriana , Orr Hanna , Bennett Gavin , Sharma Rajiv , McKean Meredith 
Published: December 2023

Abstract
Background: Bicycles are a novel class of synthetic molecules formed by short linear peptides constrained in a stabilized bi-cyclic structure that can be conjugated to other molecules. BT5528 is a Bicycle Toxin Conjugate, comprising a bicyclic peptide targeting EphA2 linked to a cytotoxin (monomethyl auristatin E [MMAE]). EphA2 is expressed at low levels in normal tissues but overexpressed in many solid tumors; EphA2 expression correlates with malignant progression and poor patient outcome. BT5528 is ~40X smaller than antibody-drug conjugates (ADCs) and has the potential to penetrate solid tumors. Within the tumor, release of MMAE disrupts intracellular microtubule dynamics leading to inhibited proliferation and tumor cell death with bystander killing effect. The pharmacokinetic (PK) profile of BT5528 is distinct from ADCs with lack of Fc-mediated non-specific uptake, fast distribution, and renal elimination, leading to lower vascular exposure and potentially reduced toxicity in non-target tissues. The preclinical profile supported the initiation of a first-in-human study to investigate BT5528 safety and efficacy in advanced solid tumors with EphA2 expression (NCT04180371).
Methods: This phase 1/2 multicenter, open-label trial evaluates BT5528 as monotherapy and in combination with nivolumab (nivo) in up to 288 patients. Phase 1 employs a 3+3 dose-escalation design for the first two dose levels followed by a Bayesian logistic regression model. Phase 2 expansion will test the selected dose(s) of BT5528 in six tumor-specific cohorts with high EphA2 expression (NSCLC, ovarian, TNBC, gastric/upper GI, head and neck, and urothelial cancer). BT5528 will be administered intravenously (IV) in ascending doses either weekly or every other week as monotherapy in Part A-1 and in combination with nivo in Part A-2 (480 mg of IV nivo every 4 weeks or 240 mg every 2 weeks), and as per the recommended phase 2 dose(s) (RP2D) in Part B. Part A patients must have a metastatic solid tumor type known to have high EphA2 tumor expression and Part B patients must have one of the specified tumor types; all patients must have failed or be ineligible for appropriate treatment options with evidence of radiographic progression on the most recent line of therapy. Additional eligibility criteria include ≥18 years of age, ECOG performance status of 0 or 1, and adequate organ function. Primary objectives for Part A are safety and tolerability and to define the maximum tolerated dose (if observed) and RP2D(s) as monotherapy and in combination with nivo. The primary objective for Part B is to assess clinical activity of BT5528 monotherapy. Secondary objectives include preliminary efficacy (Part A), safety and tolerability (Part B), correlation of EphA2 expression with efficacy (Part B), PK parameters of BT5528 and MMAE, and incidence of anti-drug antibodies. Tumor and blood samples will be collected for biomarker evaluations including tumor EphA2 expression, ADAs, and candidate response biomarkers for BT5528 alone and in combination with nivo. This study is actively recruiting.
Citation Format: Elisa Fontana, Babar Bashir, Judy S. Wang, Raid Aljumaily, Jean-Pascal Machiels, Maria Vieito, Gerald Falchook, Louise Carter, Bernard Doger de Spéville, Alastair Greystoke, Sang Wun Kim, Nuria Kotecki, Alexander I. Spira, Irene Moreno Candilejo, Bristi Basu, Hans Prenen, Alberto Bessudo, Misako Nagasaka, Jordi Rodón Ahnert, Joo-Hwan Park, Min-Yuen Teo, Julia Rotow, Jie Liu, Assunta De Rienzo, Mengyao Li, Adriana Domingo, Hanna Orr, Gavin Bennett, Rajiv Sharma, Meredith McKean. Trial in progress: First-in-human phase I dose-escalation study of a novel Bicycle toxin conjugate (BT5528) targeting EphA2 in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A17.