Comprehensive biomarker and modeling approach to support dose finding for BI 836880, a VEGF/Ang-2 inhibitor

Abstract

Background: BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880.

Methods: Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied.

Results: DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level.

Conclusions: The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule.

Trial registration: NCT02674152 and NCT02689505.

Keywords: Ang-2; BI 836880; Biomarkers; Pharmacodynamics; Pharmacokinetics; VEGF.

Fig. 1

Mean free VEGF-A (A), total VEGF-A (B), free Ang-2 (C), total Ang-2 (D) plasma levels over time in patients treated with increasing doses of BI 836880. For A, C, D, the number of patients per dose level at baseline were as follows: 40 mg, n = 3; 120 mg, n = 2; 360 mg, n = 2; 720 mg, n = 17; 1000 mg, n = 5. However, on-treatment numbers may decrease as patients dropped out of the study. B Due to the complexity of the assay, only 2 patients per dose level were analyzed. C The inset shows the same data on a different scale in order to improve readability. Standard deviations are not included, since for some dose levels and graphs only 2 patients have been included, and numbers of observations may vary between timepoints even at the same dose level. Ang-2: angiopoietin-2; VEGF-A: vascular endothelial growth factor

Fig. 2

Levels of sVEGFR3 (A), sTie2 (B) and PlGF (C) at baseline and On-treatment (cycle 2, day 1 for sVEGFR3 and sTie2 and at cycle 1, day 3 for PlGF), per dose level. The number of patients per dose level are indicated above each boxplot. PlGF: placenta growth factor; sTie2: soluble Tie2; sVEGFR3: soluble vascular endothelial growth factor receptor 3

Fig. 3

Change of tumor blood flow and/or permeability as determined by DCE-MRI in patients treated with BI 836880 in study 1336.1. Ktrans was determined via a model that describes the volume transfer coefficient of the gadolinium-based contrast agent between the blood plasma and the extracellular extravascular leakage space. A The percent change of Ktrans from baseline to week 2, 6, and/or 12 after treatment onset. B An example of a DCE-MRI scan from baseline (left) and the first follow up scan 2 weeks after treatment with BI 836880 (right) from a patient of the 1000 mg cohort with a not otherwise defined neoplasm, for whom an 80% reduction in Ktrans was calculated. Ca: carcinoma; DCE-MRI: dynamic contrast-enhanced-magnetic resonance imaging; ER + : estrogen receptor positive; Her2: human epidermal growth factor receptor 2 negative; Ktrans: transfer constants