Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients Journal Article
| Authors: | Machiels, J. P.; Gomez-Roca, C.; Michot, J. M.; Zamarin, D.; Mitchell, T.; Catala, G.; Eberst, L.; Jacob, W.; Jegg, A. M.; Cannarile, M. A.; Watson, C.; Babitzki, G.; Korski, K.; Klaman, I.; Teixeira, P.; Hoves, S.; Ries, C.; Meneses-Lorente, G.; Michielin, F.; Christen, R.; Rüttinger, D.; Weisser, M.; Delord, J. P.; Cassier, P. |
| Article Title: | Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients |
| Abstract: | Background This phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors. Methods Both emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments. Results Three dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67 +-activated CD8 + T cells accompanied by a decrease of B cells and the reduction of CD14 Dim CD16 bright monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients. Conclusion Emactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses. © 2020 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. |
| Keywords: | immunohistochemistry; adult; human tissue; aged; drug tolerability; placebo; drug safety; clinical trials as topic; cancer patient; flow cytometry; cd8 antigen; ki 67 antigen; cd8+ t lymphocyte; t lymphocyte; tumor associated leukocyte; interleukin 2; cancer immunotherapy; progression free survival; pharmacodynamics; skin biopsy; melanocyte; creatinine; enzyme linked immunosorbent assay; monoclonal antibody; drug dose escalation; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; bilirubin; cd16 antigen; regulatory t lymphocyte; blood analysis; immunogenicity; vaccination; patient safety; tumor immunity; creatine kinase; maximum tolerated dose; phase 1 clinical trial; monocyte; enzyme linked immunospot assay; gamma glutamyltransferase; t lymphocyte activation; cd14 antigen; fibrinogen; creatine kinase blood level; tumor microenvironment; blood donor; tumor biomarkers; cd40 ligand monoclonal antibody; translational medical research; limit of quantitation; human; male; female; priority journal; article; myeloid-derived suppressor cells; solid malignant neoplasm; emactuzumab; selicrelumab |
| Journal Title: | Journal for ImmunoTherapy of Cancer |
| Volume: | 8 |
| Issue: | 2 |
| ISSN: | 2051-1426 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2020-07-01 |
| Start Page: | e001153 |
| Language: | English |
| DOI: | 10.1136/jitc-2020-001153 |
| PUBMED: | 33097612 |
| PROVIDER: | scopus |
| PMCID: | PMC7590375 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2020 -- Source: Scopus |
