Abstract 382P
Background
Lisavanbulin (BAL101553, prodrug of BAL27862) promotes tumour cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic small molecule shown in rodents to penetrate the brain. In preclinical models BAL27862 inhibits microtubule plus EB1-dependent migration and invasion of GBM stem-like cells, with a profound EB1-associated survival advantage.
Methods
Patients with histologically-confirmed recurrent GBM or high-grade glioma received QD oral lisavanbulin in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). Adverse events were assessed by CTCAE v4.03 grade (G) and tumour response by RANO every 8 weeks. EB1 immunohistochemistry was undertaken in available tissue samples and whole-genome sequencing, methylation and transcriptome analysis was performed in a subset of patients. EB1 expression was also explored in separate retrospective tissue microarray (TMA) studies using three independent GBM cohorts.
Results
28 patients (16M/12F; median age 50 y, min-max 25-71 y) number of prior regimens = 2 (1-5), received lisavanbulin at 8, 15, 20, 25, 30 or 35 mg/d. At 35 mg/d, DLTs of G3 hallucinations, G3 confusion and G2 gait disturbance were observed. The MTD was 30 mg/d with no DLT in 6 evaluable patients. One patient with an IDH-mutated, C-MYC amplified GBM with high EB1 expression had a partial response at 25 mg/d (88% area reduction per RANO) and continues on study >24 months. At doses of 25-30mg/d another 2 GBM patients had stable disease; and one patient had a radiological mixed response after 2 cycles, discontinuing the trial but remaining alive >24 months, resulting in an overall clinical benefit rate at 6 months of 44% (4/9 GBM patients). TMA data showed a prevalence of high EB1 expression in 2-5% of GBM.
Conclusions
Oral lisavanbulin is well tolerated up to 30 mg/d in patients with GBM, and shows indications of clinical activity. Tissue analysis of an exceptional responder supports preclinical data of EB1-positivity as a potential biomarker of response. A phase 2a biomarker-driven study in GBM is expected to commence recruitment in 2020.
Clinical trial identification
NCT02490800.
Editorial acknowledgement
Legal entity responsible for the study
Basilea Pharmaceutica International Ltd.
Funding
Basilea Pharmaceutica International Ltd.
Disclosure
A. Tzankov: Research grant/Funding (institution): Basilea Pharmaceutica International Ltd. R. Plummer: Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self), Part funding of CASE PhD studentship: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Advisory/Consultancy: Sanofi Aventis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Bayer; Honoraria (self), Advisory/Consultancy: Pierre Faber; Honoraria (self), Advisory/Consultancy: Genmab; Honoraria (self), Advisory/Consultancy: Octimet; Honoraria (self), Advisory/Consultancy: Clovis Oncology; Honoraria (self), Advisory/Consultancy: Karus Therapeutics; Honoraria (self), Advisory/Consultancy: Biosceptre; Honoraria (self), Advisory/Consultancy: Ellipses; Honoraria (self), Advisory/Consultancy: CV6 Therapeutics; Honoraria (self), Advisory/Consultancy: Cybrexa; Honoraria (self), Speaker Bureau/Expert testimony: Tesaro; Honoraria (self), Speaker Bureau/Expert testimony: Expert Medical Events; Research grant/Funding (institution), Clinical trial costs from multiple trial sponsors to cover costs of clinical investigatons: Sponsors; Non-remunerated activity/ies, Principal Investigator on multiple trials with multiple sponsors (>30 over last 2 years): Sponsors; Research grant/Funding (institution), Clinical trial costs to cover costs of clinical investigatons: Basilea Pharmaceutica International Ltd.; Licensing/Royalties, Discretionary payment from Newcastle Uni in recognition of royalty payments they receive from Clovis Oncology: Newcastle University. I. Vivanco: Research grant/Funding (institution): Basilea Pharmaceutica International Ltd.; Research grant/Funding (institution): Genmab; Advisory/Consultancy: AbbVie. P.J. Mulholland: Travel/Accommodation/Expenses: GSK; Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution), Clinical trial costs: AstraZeneca; Research grant/Funding (institution), Travel/Accommodation/Expenses, Clinical trial costs: BMS. S. Anderson, F. Bachmann, M. Engelhardt, T. Kaindl, H. Lane, K. Litherland, C. Pognan: Shareholder/Stockholder/Stock options, Full/Part-time employment: Basilea Pharmaceutica International Ltd. S. Berezowska: Research grant/Funding (institution): Basilea Pharmaceutica International Ltd. J. Evans: Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Basilea Pharmaceutica International Ltd.; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, Support for costs of clinical trials payable to the institution: Bayer; Research grant/Funding (institution), Support for costs of clinical trials payable to the institution from multiple sponsors: Sponsors; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, Support for costs of clinical trials payable to the institution: BMS; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Clovis; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Eisai; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Genentech; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Glaxo Smith Kline; Honoraria (institution), Advisory/Consultancy: Immunova; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Otsuka; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Roche; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, Support for costs of clinical trials payable to the institution: MSD; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses, Support for costs of clinical trials payable to the institution: Celgene; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Nucana; Honoraria (institution), Advisory/Consultancy: Karus Therapeutics; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Medivir. R. Kristeleit: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Basilea Pharmaceutica International Ltd. J.S. Lopez: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Support for costs of clinical trials payable to the institution: Basilea Pharmaceutica International Ltd.; Honoraria (self), Research grant/Funding (institution): Genmab; Honoraria (self), Research grant/Funding (institution): Roche-Genentech; Honoraria (self): Eisai. All other authors have declared no conflicts of interest.