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


Year:

Session type:

Theme:

Udai Banerji1,Natalie Cook2,T.R. Jeffry Evans3,Irene Moreno Candilejo1,Patricia Roxburgh3,Claire Kelly2,Narmatha Sabaratnam1,Rashmi Passi1,Sawretse Leslie4,Sidath Katugampola4,Lisa Godfrey4,Neil Tremayne4,Gavin Halbert5,Gavin Bennett6,Maria Koehler6,Gillian Langford6,Marc Pittman4,Stefan Symeonides7
1Institute of Cancer Research & Royal Marsden NHS Foundation Trust,2University of Manchester & Christie NHS Foundation Trust,3University of Glasgow & Beatson West of Scotland Cancer Centre,4Cancer Research UK Centre for Drug Development,5Cancer Research UK Formulation Unit, University of Strathclyde,6Bicycle Therapeutics,7Cancer Research UK Centre for Drug Development & University of Edinburgh

Abstract

Background

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.

Method

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.