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|Authors||Christophe Le Tourneau, Rainer Claus, Francesco Ricci, Bjorn Hackanson, Christoph Rummelt, Oliver Fietz, Thomas Arnhold, Dooti Roy, Zohra Oum'Hamed, Ralph M Fritsch|
|Title||First-in-human phase I trial of BI 836880, a vascular endothelial growth factor (VEGF)/angiopoietin-2 (Ang-2)-blocking nanobody, given every 3 weeks (q3w) in patients (pts) with advanced/metastatic solid tumors.|
|Abstract Text||Background: VEGF and Ang-2 inhibitors have demonstrated clinical activity in various tumor types. Given the overlap of the VEGF/VEGFR2 and Ang-2/Tie-2 signaling pathways there is a rationale for dual inhibition. BI 836880 is a humanized bispecific nanobody (engineered antibody fragment of variable antibody domains) that inhibits VEGF and Ang2 and has demonstrated preclinical activity in cancer models. Methods: Pts with solid tumors refractory after standard therapies/for whom no established treatment options were available received BI 836880 q3w (IV; starting dose 40 mg). Dose escalation followed a Bayesian logistic regression model with overdose control. The maximum-tolerated dose (MTD; primary endpoint) was evaluated based on dose-limiting toxicities (DLTs) in the first 21-day cycle. Treatment-related AEs (TRAEs) leading to dose reduction/discontinuation, exposure/disposition kinetic measures (both secondary endpoints) and best overall response were also assessed. Results: 29 pts were treated: median age 57 yrs (range 28–79); 62% female. The MTD was determined as BI 836880 720 mg q3w (Table). All pts had at least 1 AE, most commonly (all grade/grade ≥3): hypertension 86%/34%, asthenia 48%/10%, nausea 45%/3% and vomiting 38%/3%. 23 (79%) pts had TRAEs; none led to dose reduction. One patient had a TRAE leading to discontinuation (pulmonary embolism DLT at 1000 mg). Two (7%) pts (nasopharyngeal [n = 1] and breast [n = 1] carcinoma) had a partial response and 9 (31%) pts had stable disease. PK/PD analysis of 14 evaluable pts showed dose-proportional plasma kinetics of BI 836880, complete peripheral target inhibition at doses ≥360 mg q3w and predicted required trough values at doses ≥720 mg q3w. Clinical trial information: NCT02674152. Conclusions: The MTD/recommended phase 2 dose of BI 836880 was determined as 720 mg q3w based on safety and PK/PD analyses. Early signs of antitumor activity were observed.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||BI 836880||Phase I||Actionable||In a Phase I trial, BI 836880 treatment was well tolerated, and resulted in partial response in 7% (2/29) and stable disease in 31% (9/29) of patients with advanced solid tumors (J Clin Onc 2018 36:15_suppl, 12024; NCT02674152).||detail...|
|Unknown unknown||breast carcinoma||not applicable||BI 836880||Case Reports/Case Series||Actionable||In a Phase I trial, BI 836880 treatment was well tolerated in patients with advanced solid tumors, and resulted in 2 partial responses (n=29), including a partial response in a patient with breast carcinoma (J Clin Onc 2018 36:15_suppl, 12024; NCT02674152).||detail...|
|Unknown unknown||nasopharynx carcinoma||not applicable||BI 836880||Case Reports/Case Series||Actionable||In a Phase I trial, BI 836880 treatment was well tolerated in patients with advanced solid tumors, and resulted in 2 partial responses (n=29), including a partial response in a patient with nasopharyngeal carcinoma (J Clin Onc 2018 36:15_suppl, 12024; NCT02674152).||detail...|