A Cancer Research UK phase I/IIa trial of BT1718 (a first in class Bicycle Toxin Conjugate) given intravenously in patients with advanced solid tumours
Session type: Poster / e-Poster / Silent Theatre session
Membrane type I matrix metalloproteinase (MT1-MMP) is a member of the matrix metalloproteinase (MMP) family involved in tissue remodelling through proteolysis of extracellular matrix components. Overexpression of MT1-MMP is seen in multiple tumour types including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC) and sarcoma. BT1718 is a novel first in class bicyclic targeting peptide that binds MT1-MMP and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicyclic peptides have a low molecular weight in comparison to other conjugated toxin approaches, enabling rapid penetration and a short systemic half-life, potentially reducing toxicity.
This is an open label first in human phase I/IIa study. The primary objective is to propose a recommended phase 2 dose (RP2D) and schedule of BT1718. Secondary objectives include pharmacokinetic (PK) parameters and preliminary clinical responses in biomarker pre-defined cohorts of patients. Tertiary objectives include correlative studies related to predictive biomarkers of response.
Dose escalation (phase I)
Stage 1: Exploring an initial twice-a-week schedule. There will be single patient cohorts until either Grade 2 drug related toxicity or dose exceeding 6 mg/m2 twice a week. A 3+3 design will then be followed until the RP2D.
Stage 2: Exploring a once-weekly schedule, using a 3+3 design until the RP2D for this schedule has also been established.
Dose expansion (phase IIa)
Part A: 14 patients with MT1-MMP expressing NSCLC or TNBC, treated with BT1718 at the twice-a-week RP2D. At least 6 will have pre- and post-treatment biopsies.
Part B: 14 patients with MT1-MMP expressing NSCLC or TNBC, treated with BT1718 at the once-weekly RP2D. At least 6 will have pre- and post-treatment biopsies.
Part C/D: following parts A & B, a decision will be made to explore the selected schedule in tumour-specific cohort(s) of around 15 patients, with refined MT1-MMP biomarker selection.