Phase I dose-escalation study of F50067, a humanized anti-CXCR4 monoclonal antibody alone and in combination with lenalidomide and low-dose dexamethasone, in relapsed or refractory multiple myeloma
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Guillemette Fouquet1,*, Stéphanie Guidez2,11,*, Valentine Richez2, Anne-Marie Stoppa3, Christophe Le Tourneau4, Margaret Macro5, Cécile Gruchet2, Arthur Bobin2, Niels Moya2, Thomas Syshenko2, Florence Sabirou2, Anthony Levy2, Paul Franques2, Hélène Gardeney2, Lionel Karlin6, Lotfi Benboubker7, Monia Ouali10, Jean-Claude Vedovato10, Pierre Ferre10, Mariya Pavlyuk10, Michel Attal8, Thierry Facon9 and Xavier Leleu2,11
1Institut Imagine, Unité Inserm U1163, Centre National de la Recherche Scientifique CNRS ERL8254, Paris, France
2Hôpital La Milétrie, Centre Hospitalier Universitaire, Poitiers, France
3Institut Paoli Calmettes, Marseille, France
4Institut Curie, Paris, France
5Centre Hospitalier Universitaire, Caen, France
6Centre Hospitalier Lyon Sud, Lyon, France
7Centre Hospitalier Universitaire Tours, Tours, France
8Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
9Service des Maladies du Sang, Centre Hospitalier Régional Universitaire, Lille, France
10Institut de Recherche Pierre Fabre, Toulouse, France
11Inserm Centre d’Investigation Clinique U1402, Centre Hospitalier Universitaire, Poitiers, France
Xavier Leleu, email: [email protected]
Keywords: multiple myeloma; CXCR4; monoclonal antibody; immunotherapy; homing of tumor cells
Received: January 08, 2018 Accepted: March 29, 2018 Published: May 08, 2018
Purpose: Multiple myeloma (MM) remains an incurable disease as tumor cells ultimately resist to all available drugs. Homing of tumor cells to the bone marrow microenvironment, involving especially the CXCR4/SDF-1 axis, allows them to survive, proliferate and resist to therapy. F50067, a humanized anti-CXCR4 IgG1 antibody, has promising preclinical activity in MM.
We present a phase I multicenter escalation study in relapsed/refractory MM (RRMM) to determine the maximum tolerated dose (MTD) for F50067 alone and in combination with lenalidomide and low dose dexamethasone (Len-Dex).
Experimental design: 14 end-stage RRMM patients received F50067 single agent (n = 10) or in combination with Len-Dex (n = 4).
Results: One dose-limiting toxicity was observed, a grade 4 neutropenia lasting more than 7 days in combination arm. MTD could not be established. Thrombocytopenia was observed in 100% and neutropenia in 92.9% of patients with no cases of febrile neutropenia and no severe bleeding or hematoma. Non-hematological adverse events were of mild to moderate severity.
Nine patients (6 in single arm and 3 in combination arm) were evaluable for response, with 66.7% overall response rate (≥PR) in combination arm, and 33.3% of disease control (≥SD) in single agent arm. At the time of study termination, 55.6% had progressed.
Conclusion: This study suggests that egression of tumor cells to the blood stream can represent a novel therapeutic strategy for MM. However, because of significant hematological toxicity, this study had to be discontinued. Further studies are needed to validate the feasibility of this approach in clinical practice.
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