Phase I clinical study of RG7356, an anti-CD44 humanized antibody, in patients with acute myeloid leukemia

Abstract

// Norbert Vey 1, 2 , Jacques Delaunay 3 , Giovanni Martinelli 4 , Walter Fiedler 5 , Emmanuel Raffoux 6 , Thomas Prebet 1 , Carlos Gomez-Roca 7, 8 , Cristina Papayannidis 4 , Maxim Kebenko 5 , Peter Paschka 9 , Randolph Christen 10 , Ernesto Guarin 11 , Ann-Marie Bröske 12 , Monika Baehner 12 , Michael Brewster 13 , Antje-Christine Walz 11 , Francesca Michielin 11 , Valeria Runza 12 , Valerie Meresse 11 , Christian Recher 7, 14 1 Institut Paoli-Calmettes, Marseille, France 2 Aix Marseille Université, Marseille, France 3 Service d'Hématologie Clinique, Hôpital Hôtel-Dieu, Nantes, France 4 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy 5 Department of Medicine II, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 6 Hôpital Saint Louis, AP-HP, EA3518 Université Paris VII, Paris, France 7 Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France 8 Institut Claudius Regaud, Clinical Research Unit, Toulouse, France 9 Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany 10 Product Development, Safety Risk Management, Roche, Basel, Switzerland 11 Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland 12 Pharma Research & Early Development, Roche Innovation Center Penzberg, Penzberg, Germany 13 Pharma Research & Early Development, Roche Innovation Centre, Welwyn, UK 14 CHU de Toulouse, Université Toulouse III, Toulouse, France Correspondence to: Norbert Vey, email: veyn@ipc.unicancer.fr Keywords: RG7356, relapsed/refractory acute myeloid leukemia, anti-CD44 humanized antibody, phase I trial, cell adhesion Received: January 20, 2016      Accepted: March 28, 2016      Published: April 11, 2016 ABSTRACT RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, inhibits cell adhesion and has been associated with macrophage activation in preclinical models. We report results of a phase I dose-escalation study of RG7356 in relapsed/refractory acute myeloid leukemia (AML). Eligible patients with refractory AML, relapsed AML after induction chemotherapy, or previously untreated AML not eligible for intensive chemotherapy were enrolled and received intravenous RG7356 at dosages ≤ 2400 mg every other week or ≤ 1200 mg weekly or twice weekly; dose escalation started at 300 mg. Forty-four patients (median age, 69 years) were enrolled. One dose-limiting toxicity occurred (grade 3 hemolysis exacerbation) after one 1200 mg dose (twice-weekly cohort). The majority of adverse events were mild/moderate. Infusion-related reactions occurred in 64% of patients mainly during cycle 1. Two patients experienced grade 3 drug-induced aseptic meningitis. Pharmacokinetics increased supraproportionally, suggesting a target-mediated drug disposition (TMDD) at ≥ 1200 mg. Two patients achieved complete response with incomplete platelet recovery or partial response, respectively. One patient had stable disease with hematologic improvement. RG7356 was generally safe and well tolerated. Maximum tolerated dose was not reached, but saturation of TMDD was achieved. The recommended dose for future AML evaluations is 2400 mg every other week.