Phase 1/2a trial of intravenous BAL101553, a novel controller of the spindle assembly checkpoint, in advanced solid tumours

Rebecca Kristeleit,L Rhoda Molife,Uzma Asghar,Jeffry Evans,Nicholas F Brown,Heidi A Lane,Felix Bachmann,Mihaela Rata,Sarah Slater,Stephanie Anderson,R Rulach ,Patrice Larger ,Noor Md Haris ,Alastair Greystoke,Marc Engelhardt,Alexandar Tzankov,Martin Förster ,Nina Tunariu,Thomas Kaindl,Ruth Plummer,Anne Schmitt‐Hoffmann ,Alison L Hannah ,Heather Shaw,Nikolaos Diamantis,Juanita Lopez

doi:10.1038/s41416-020-1010-8

Abstract

BackgroundBAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents.MethodsThis two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D).ResultsSeventy-three patients received BAL101553 at doses of 15–80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2–3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population.ConclusionsThe RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent’s vascular-disrupting properties.Clinical trial registrationEudraCT: 2010-024237-23.

Highlights

BAL101553, the lysine prodrug of BAL27862, exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents
The first patient, first visit was on 12 July 2011 and the last patient, last visit was on 6 April 2016
Thirty-four (46%) patients had previously been treated with Microtubule-targeting agents (MTAs), of which 24 had discontinued treatment due to documented disease progression

Summary

Introduction

BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. METHODS: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). Despite a high initial sensitivity of many malignancies to MTAs, resistance invariably arises through several mechanisms that are postulated to include drug efflux pump (P-glycoprotein) overexpression, aberrant expression of tubulin isotypes and BRCA1, and deregulated cell survival pathways.[3,5,6,7] There is an urgent clinical need for novel treatment options for patients with advanced solid tumours, who are refractory to conventional MTAs

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