Two phase I studies of BI 836880, a vascular endothelial growth factor/angiopoietin-2 inhibitor, administered once every 3 weeks or once weekly in patients with advanced solid tumors

C Le Tourneau, H Becker, R Claus, E Elez, F Ricci, R Fritsch, Y Silber, A Hennequin, J Tabernero, G Jayadeva, D Luedtke, M He, N Isambert, C Le Tourneau, H Becker, R Claus, E Elez, F Ricci, R Fritsch, Y Silber, A Hennequin, J Tabernero, G Jayadeva, D Luedtke, M He, N Isambert

Abstract

Background: BI 836880 is a humanized bispecific nanobody® that inhibits vascular endothelial growth factor and angiopoietin-2. Here, we report results from two phase I, nonrandomized, dose-escalation studies (NCT02674152 and NCT02689505; funded by Boehringer Ingelheim) evaluating BI 836880 in patients with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy, or for which standard therapy was ineffective.

Patients and methods: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function received escalating intravenous doses of BI 836880 once every 3 weeks (Q3W; Study 1336.1) or once weekly (QW; Study 1336.6). Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose of BI 836880, based on dose-limiting toxicities (DLTs) during the first cycle.

Results: Patients received one of five dosages of 40-1000 mg Q3W (29 patients) or 40-240 mg QW (24 patients). One DLT occurred with Q3W treatment [Grade (G) 3 pulmonary embolism (1000 mg)]. Five DLTs occurred in four patients treated QW [G2 proteinuria (120 mg); G3 hypertension (180 mg); G3 proteinuria and G3 hypertension (240 mg); and G4 respiratory distress (240 mg)]. All patients experienced adverse events, most commonly hypertension with Q3W treatment (89.7%; G3 41.4%), and asthenia with QW treatment (62.5%). Two patients treated Q3W (both 1000 mg) and three patients treated QW (120 mg, 2 patients; 180 mg, 1 patient) experienced partial response.

Conclusions: The MTD of BI 836880 was 720 mg Q3W and 180 mg QW. BI 836880 was generally manageable and demonstrated preliminary efficacy.

Clinical trial registration: ClinicalTrials.govNCT02674152; https://ichgcp.net/clinical-trials-registry/NCT02674152 and NCT02689505; https://ichgcp.net/clinical-trials-registry/NCT02689505.

Keywords: Vascular endothelial growth factor; advanced solid tumors; angiopoietin-2; nanobody; phase I.

Conflict of interest statement

Disclosure CLT reports consulting fees from Merck Sharp & Dohme, Bristol Myers Squibb, Merck Serono, Nanobiotix, Seattle Genetics, GlaxoSmithKline, Roche, Rakuten, and Celgene. HB reports receiving honoraria from Bristol Myers Squibb, Roche, Novartis, Servier, Pierre Fabre, and Merck Sharp & Dohme. EE reports being part of an advisory council or committee for Hoffman La Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, and Sanofi; receiving honoraria from Array Biopharma, Merck Sharp & Dohme, AbbVie, Amgen, GlaxoSmithKline, AstraZeneca, Merck Sharp & Dohme Corp., Bristol Myers Squibb, Novartis, Boehringer Ingelheim, and Hoffman La Roche; receiving consulting fees from Hoffman La Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, and Sanofi; receiving grants or funds from Roche, Amgen, Merck Serono, Sanofi/Aventis, Bristol Myers, Servier, and Array Biopharma. RF reports serving on safety monitoring committee of follow-up combination trial and receiving honoraria for this role from Boehringer Ingelheim. JT reports receiving honoraria for his educational collaboration with Imedex, Medscape Education, MJH Life Sciences, and PeerView Institute for Medical Education and Physicians Education Resource (PER); and receiving consulting fees for scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, NeoPhore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, and TheraMyc. GJ, DL, and MH report being employed with Boehringer Ingelheim. NI reports being part of an advisory council or committee for Eisai, Pfizer, and Daichi; receiving honoraria from Amgen, Transgene, and Ipsen. The remaining authors have declared no conflicts of interest. Data sharing To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete, and other criteria are met. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
gMean plasma concentration–time profiles after first infusion (Cycle 1) of BI 836880 administered Q3W. conc, concentration; gMean, geometric mean; Q3W, once every 3 weeks.
Figure 2
Figure 2
Mean binding-time profiles of (A) Ang-2 and (B) VEGF-A to BI 836880 after multiple Q3W infusions. Ang-2, angiopoietin-2; Q3W, once every 3 weeks; VEGF-A, vascular endothelial growth factor A.
Figure 3
Figure 3
Waterfall plots of best percentage decrease from baseline in sum of target lesion diameter of indicator lesions in patients treated (A) Q3W and (B) QW, and spider plots of target tumor response by dose level in patients treated (C) Q3W and (D) QW. Q3W, once every 3 weeks; QW, once weekly. Positive values represent tumor growth; negative values represent tumor shrinkage. One patient treated Q3W had an unconfirmed partial response (who only had one postbaseline tumor measurement). The asterisk indicates patients with best overall response of confirmed partial response.

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Source: PubMed

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