Phase Ib study of anti-CSF-1R antibody emactuzumab in combination with CD40 agonist selicrelumab in advanced solid tumor patients

Jean-Pascal Machiels, Carlos Gomez-Roca, Jean-Marie Michot, Dmitriy Zamarin, Tara Mitchell, Gaetan Catala, Lauriane Eberst, Wolfgang Jacob, Anna-Maria Jegg, Michael A Cannarile, Carl Watson, Galina Babitzki, Konstanty Korski, Irina Klaman, Priscila Teixeira, Sabine Hoves, Carola Ries, Georgina Meneses-Lorente, Francesca Michielin, Randolph Christen, Dominik Rüttinger, Martin Weisser, Jean-Pierre Delord, Philippe Cassier, Jean-Pascal Machiels, Carlos Gomez-Roca, Jean-Marie Michot, Dmitriy Zamarin, Tara Mitchell, Gaetan Catala, Lauriane Eberst, Wolfgang Jacob, Anna-Maria Jegg, Michael A Cannarile, Carl Watson, Galina Babitzki, Konstanty Korski, Irina Klaman, Priscila Teixeira, Sabine Hoves, Carola Ries, Georgina Meneses-Lorente, Francesca Michielin, Randolph Christen, Dominik Rüttinger, Martin Weisser, Jean-Pierre Delord, Philippe Cassier

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 CD14Dim CD16bright 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.

Trialregistration number: NCT02760797.

Keywords: clinical trials as topic; myeloid-derived suppressor cells; translational medical research; tumor biomarkers; tumor microenvironment.

Conflict of interest statement

Competing interests: Jean-Pascal Machiels: Advisory board consulting for Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boerhinger, BMS, Novartis, Janssen, Incyte, Cue Biopharma and ALX Oncology; travel expenses from Amgen, BMS, Pfizer, MSD; data safety monitoring board support for Debio, Nanobiotix and PsiOxus. Carlos Gomez-Roca: Consultancy for AstraZeneca and BMS; travel grant from Boehringer Ingelheim, BMS, Pierre Fabre, Roche and Sanofi Aventis; honoraria from BMS, Pierre Fabre and Roche; Jean-Marie Michot: Consultancy from Celgene, Bristol Myers Squibb, AstraZeneca and Janssen; travel grant and non-financial support from AstraZeneca, Roche, Novartis, Gilead, Celgene and Bristol Myers Squibb; Dmitriy Zamarin: Consultancy fees from Merck, Synlogic Therapeutics, Biomed Valley Discoveries, Trieza Therapeutics, Tesaro, and Agenus; Tara Mitchell: Advisory board consulting for Merck, BMS and Array; Gaetan Catala: Travel grants from Roche, Pharmamar, MSD and AstraZeneca; advisory role for MSD. Lauriane Eberst: None. Wolfgang Jacob: Sponsor employee and sponsor stock ownership. Anna-Maria Jegg: Former sponsor employee and has patent issued in the use of emactuzumab. Michael A Cannarile: Sponsor employee and sponsor stock ownership. Carl Watson: Sponsor consultant. Galina Babitzki: Sponsor employee. Konstanty Korski: Sponsor employee. Irina Klaman: Sponsor employee. Priscila C Teixeira: Sponsor employee. Sabine Hoves: Sponsor employee, sponsor stock ownership and has patent issued in the use of emactuzumab. Carola Ries: Former sponsor employee and has patent issued in the use of emactuzumab. Georgina Meneses-Lorente: Sponsor employee. Francesca Michielin: Sponsor employee. Randolph Christen: Sponsor employee and sponsor stock ownership. Dominik Rüttinger: Sponsor employee, sponsor stock ownership and has patent issued in the use of emactuzumab. Martin Weisser: Sponsor employee and sponsor stock ownership. Jean-Pierre Delord: Consulting or advisory role for Novartis, Roche/Genentech, Bristol Myers Squibb, MSD Oncology; research funding from Genentech, Bristol Myers Squibb, MSD Oncology. Philippe Cassier: Honoraria from Novartis, Roche/Genentech, Blueprint Medicines, Amgen and AstraZeneca; research funding from Novartis, Roche/Genentech, Eli Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Taiho Pharmaceuticals, Toray Industries, Transgene, Loxo, GlaxoSmithKline, Innatre Pharma and Janssen; travel grants from Roche, Amgen, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme and Netris Pharma.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Flow diagram of patient enrolment and emactuzumab/selicrelumab dose cohorts a One patient was planned to be dosed in the 1000 mg emactuzumab/12 mg selicrelumab cohort but died in the screening phase due to a biopsy-related hemorrhage.
Figure 2
Figure 2
Spider plot indicating the percentage change from baseline in sum of target lesion diameters per patient.
Figure 3
Figure 3
Percent change of peripheral B cells from baseline (a) per dose cohort and (b) for individual patients per dose cohort and percent change of peripheral proliferating CD3+CD8+Ki67+ T cells from baseline; (c) per dose cohort and (d) for individual patients per dose cohort.
Figure 4
Figure 4
Percent change of peripheral CD14dim CD16high monocytes from baseline per dose cohort.
Figure 5
Figure 5
Change from baseline of (a) CD163+ and CSF-1R+ TAMs in paired biopsies and (b) CD8+ T cells, Ki67+CD8+ TILs and FoxP3+ Tregs in paired biopsies. Doses (emactuzumab/selicrelumab) and tumor types are indicated. Please note: No data for T-cell analysis in situ for the 1000 mg emactuzumab plus 10 mg selicrelumab cohort were obtained due to insufficiently evaluable biopsy material. CRC, colorectal cancer; CSF-1R, anti-colony stimulating factor 1 receptor; TAM, tumor-associated macrophage; TNBC, triple-negative breast cancer.

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