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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://clinicaltrials.gov/ct2/show/NCT02674152 and NCT02689505; https://clinicaltrials.gov/ct2/show/NCT02689505., Competing Interests: 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.)

Evasion of apoptosis is fundamental to the pathogenesis of cancer. Members of the B-cell Lymphoma 2 (BCL-2) protein family are key pro- and anti-apoptotic regulators, and in healthy cells are held in a fine, delicate balance - perturbations of which may tip a cell irreversibly towards cellular death or, conversely, allow a cell to permanently escape apoptosis and immortalize itself as a malignant clone. The restoration of this balance or, indeed, adjustment in favor of apoptosis via manipulation of the BCL-2 family, is a promising area in the realm of molecular therapeutics, and one in which breathtaking advances are currently being made. The purpose of this review is to outline the role of the BCL-2 family in apoptosis, to contrast its optimal functioning with those disruptions seen in malignancy, and to provide an overview of the medications both presently available and currently under development which selectively target members of this family., (Copyright © 2019 Elsevier Inc. All rights reserved.)