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Background: The phase I GATTO study (NCT03360734) explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab, a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin 1 (TA-MUC1) and an anti-epidermal growth factor receptor (anti-EGFR) antibody in refractory solid tumors., Patients and Methods: Initially the study enrolled primary phase (PP) patients with EGFR-positive metastatic solid tumors, for whom no standard treatment was available. Patients received gatipotuzumab administered at 1400 mg every 2 weeks, 6 weeks after the start of the glyco-optimized anti-EGFR antibody tomuzotuximab at 1200 mg every 2 weeks. As this regimen was proven safe, enrollment continued in an expansion phase (EP) of patients with refractory metastatic colorectal cancer, non-small-cell lung cancer, head and neck cancer and breast cancer. Tomuzotuximab and gatipotuzumab were given at the same doses and gatipotuzumab treatment started 1 week after the first dose of the anti-EGFR antibody. Additionally, investigators could use a commercial anti-EGFR antibody in place of tomuzotuximab., Results: A total of 52 patients were enrolled, 20 in the PP and 32 in the EP. The combined treatment was well tolerated and no dose-limiting toxicity was observed in the whole study, nor related serious adverse event or death. Preliminary activity of the combination was observed, with one and four RECIST partial responses in the PP and EP, all in colorectal cancer patients. The trial was accompanied by a comprehensive translational research program for identification of biomarkers, including soluble TA-MUC1 (sTA-MUC1) in serum. In the EP, patients with baseline sTA-MUC1 levels above the median appeared to have improved progression-free survival and overall survival., Conclusions: Combination of a TA-MUC1-targeting antibody and an EGFR-targeting antibody is safe and feasible. Interesting antitumor activity was observed in heavily pretreated patients. Future studies should test this combination together with chemotherapy and explore the potential of sTA-MUC1 as a companion biomarker for further development of the combination., Competing Interests: Disclosure OS: advisory board participation, invited speaker or conference honoraria from: Merck Sarono, Merck Sharp & Dohme (MSD), Ipsen, AstraZeneca, Roche, Immunocore, CureVac, Glenmark and Bristol-Myers Squibb (BMS). FW: consultancy or advisory role for AbbVie, Amgen, ARIAD, Celgene, Jazz Pharmaceuticals, Novartis, MorphoSys and Pfizer; research funding from Amgen; patents, royalties or other intellectual property from a patent on immunotherapy in acute myeloid leukemia (AML) obtained together with Amgen; and travel support from Amgen, Daiichi Sankyo, Jazz Pharmaceuticals and Servier. DCG: advisory boards and travel expenses for conferences: Novartis, BMS, Astellas, Pfizer, Jannsen. MI: ESMO Research Fellowship sponsored by Roche; honoraria for serving as a speaker bureau for MSD. HB: employment with Glycotope GmbH. IAF: employment with Glycotope GmbH. RF: bureau, research collaboration and research support—AstraZeneca, GSK, MSD, Clovis, Roche. LD: consultant/advisor: AstraZeneca, GSK, MSD, Pharmamar, Clovis, Merck Serono, Novartis, Amgen, Eisai; promotional speaker: GSK, Clovis, AstraZeneca, Genmab, MSD; investigator/researcher: GSK, Clovis, MSD, AstraZeneca, Immonogen, Genmab, Corcept, Roche, Eisai; support for travel: AstraZeneca, GSK, Roche. KU: advisory boards, speaker bureau, trial support, research collaboration and research support; Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Glycotope, Innate, Lilly, Medimmune, Merck Serono, MSD/Merck, Novartis, Pfizer, Roche/Genentech, Sirtex. KK: advisory board participation, invited speaker or conference honoraria from: Merck, Sanofi, MSD, Glycotope, Roche, Novartis and BMS. BH: employment and shares with Glycotope GmbH. ZA: employment with Glycotope GmbH. GE: research: Novartis/Roche/Thermo Fisher/AstraZeneca/Taiho/BeiGene; consultant/advisor: Roche/Genentech–F.Hoffmann/La Roche–Ellipses Pharma–Neomed Therapeutics 1 Inc.–Boehringer Ingelheim–Janssen Global Services–SeaGen–TFS–Alkermes–Thermo Fisher–BMS–MabDiscovery–Anaveon; speakers bureau: MSD/Roche/Thermo Fisher/Lilly; clinical trials PI or Co-PI (Institution): Affimed GmbH–Amgen SA–Anaveon AG–AstraZeneca AB–BioNTech GmbH–CatalYm GmbH–Cytomx–F. Hoffmann La Roche Ltd–F-Star Beta Limited–Genentech Inc.–Genmab B.V.–Hutchison Medipharma Limited–Icon–Imcheck Therapeutics–Immunocore Ltd–Janssen-Cilag SA–Medimmune LLC–Merck KGaA–Novartis Farmacéutica, S.A.–Peptomyc–Ribon Therapeutics–Roche Farma SA–Seattle Genetics Inc.–Symphogen A/S–Taiho Pharma USA Inc. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Inflammation with leukocyte activation is a hallmark of cancer-associated thrombosis (CAT), and elevated leukocytes predict venous thromboembolism in cancer outpatients. In a recent trial, rivaroxaban was more efficacious than dalteparin in preventing CAT recurrence., Objectives: In a proof-of-concept study, we aimed to provide a mechanistic basis for improved efficacy of rivaroxaban compared to low molecular weight heparin in CAT treatment., Methods: We studied the effects of rivaroxaban, dalteparin, and tinzaparin at peak and trough levels on tumor cell-induced procoagulant activity and platelet aggregation in the presence or absence of the cationic leukocyte-derived enzyme, myeloperoxidase (MPO). Furthermore, pro-inflammatory conditions were generated by stimulating whole blood with lipopolysaccharide (LPS) or phorbol-myristate-acetate (PMA), before measuring thrombin generation in plasma supernatants., Results: All three anticoagulants inhibited thrombin generation, fibrin clot formation, and platelet aggregation induced by the tissue factor-expressing prostate carcinoma cell line, 22Rv1. Pre-incubation with MPO partially attenuated the anticoagulant activity of dalteparin and tinzaparin, but not rivaroxaban, at trough levels. The effect of MPO did not involve the enzyme's catalytic properties, but required its structural integrity, as indicated by heat denaturation. In plasma obtained from LPS- or PMA-stimulated whole blood, elevated MPO antigen levels inversely correlated with the ability of tinzaparin to inhibit 22Rv1-induced thrombin generation., Conclusions: Myeloperoxidase release may partially attenuate the anticoagulant activity of trough levels of dalteparin and tinzaparin in the context of paraneoplastic leukocyte activation. However, this effect is likely not sufficient to explain the improved efficacy of rivaroxaban, and possibly other oral factor Xa inhibitors, in CAT treatment., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)