2451 - Phase Ib dose-escalation/expansion study of BI 836880, a VEGF/Ang2-blocking nanobody®, in combination with BI 754091, an anti-PD-1 antibody, in patients with advanced solid tumours

Background

Preclinical evidence shows that vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) promote an immunosuppressive state in the tumour microenvironment, and that the combination of anti-VEGF/Ang2 with anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell mediated tumour cell killing. BI 836880, a humanised bispecific nanobody that targets VEGF and Ang2, and BI 754091, an anti-PD-1 antibody, have shown safety and preliminary antitumour activity as monotherapies in phase I studies (RP2D, 720 mg iv q3w for BI 836880 and 240 mg iv q3w for BI 754091). The safety and efficacy of BI 836880 + BI 754091 are being assessed in this phase Ib trial in patients (pts) with advanced solid tumours.

Trial design

This open-label, dose-escalation/cohort-expansion trial is being conducted in two parts: Part 1, dose escalation of BI 836880 with BI 754091 in pts with advanced/metastatic, PD-L1 positive, nonsquamous NSCLC; Part 2, exploratory expansion cohorts (A–F) in 6 pt populations (A: metastatic [m] NSCLC after checkpoint inhibitor [CPI] monotherapy; B: mNSCLC after chemotherapy [CTX] + CPI; C: mSCLC after CTX with/without CPI; D: immunotherapy-resistant m-melanoma; E: recurrent glioblastoma after 1^st line CTX; F: hepatocellular carcinoma after prior sorafenib or lenvatinib with/without subsequent CPI therapy). In Part 1, pts will receive BI 836880 (cohorts of 360, 500 and 720 mg iv q3w) + fixed-dose BI 754091 240 mg iv q3w, following a Bayesian logistic regression model with overdose control, with oversight from a safety monitoring committee. The primary endpoint in Part 1 is the MTD/RP2D, based on DLTs in Cycle 1. In Part 2, pts will receive BI 836880 at the RP2D + BI 754091 240 mg iv q3w. The primary endpoint in Part 2 is objective response; secondary endpoints are disease control, duration of response, PFS and tumour shrinkage. Safety, PK and exploratory biomarkers will be assessed. ∼220 pts will enroll globally: 20–25 pts in Part 1 and ∼200 in Part 2 (40 in Cohorts A/B; 30 in Cohorts C–F). As of May 2019, 6 pts have been treated in Part 1. Part 2 will begin once the RP2D is established in Part 1. Updates will be presented.

Clinical trial identification

NCT03468426.

Editorial acknowledgement

Fiona Scott, PhD, of GeoMed, an Ashfield company, part of UDG Healthcare plc; supported financially by Boehringer Ingelheim.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim GmbH & Co, Ingelheim, Germany.

Disclosure

N. Girard: Advisory / Consultancy, Research grant / Funding (self), Corporate sponsored research, Advisory council or committee, Consulting fee, Grants or funds: BMS; Advisory / Consultancy, Research grant / Funding (self), Corporate sponsored research, Advisory council or committee, Consulting fee, Grants or funds: Boehringer; Advisory / Consultancy, Research grant / Funding (self), Corporate sponsored research, Advisory council or committee, Consulting fee: MSD; Advisory / Consultancy, Research grant / Funding (self), Corporate sponsored research, Advisory council or committee, Consulting fee, Grants or funds: Roche; Advisory / Consultancy, Research grant / Funding (self), Corporate sponsored research, Advisory council or committee, Consulting fee, Grants or funds: AstraZeneca. B. Hackanson: Honoraria (self), Advisory / Consultancy: Boehringer; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Roche. M. Wermke: Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self): Novartis; Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Glenmark; Honoraria (self): Kite; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Gemoab. F. Barlesi: Honoraria (self), Honoraria (institution): AstraZeneca; Honoraria (self), Honoraria (institution): Bristol-Myers Squibb; Honoraria (self), Honoraria (institution): Boehringer–Ingelheim; Honoraria (self), Honoraria (institution): Eli Lilly Oncology; Honoraria (self), Honoraria (institution): F. Hoffmann–La Roche Ltd; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Merck; Honoraria (self), Honoraria (institution): MSD; Honoraria (self), Honoraria (institution): Pierre Fabre; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self), Honoraria (institution): Takeda; Honoraria (institution): AbbVie; Honoraria (institution): ACEA; Honoraria (institution): Amgen; Honoraria (institution): Bayer; Honoraria (institution): Eisai; Honoraria (institution): Genentech; Honoraria (institution): Ipsen; Honoraria (institution): Ignyta; Honoraria (institution): Innate Pharma; Honoraria (institution): Loxo; Honoraria (institution): MedImmune; Honoraria (institution): Sanofi-Aventis. H.T. Landsteiner: Full / Part-time employment: Boehringer Ingelheim . G. Jayadeva: Full / Part-time employment: Boehringer Ingelheim. J. Alt: Advisory / Consultancy, Consulting fee: Boehringer Ingelheim.