Phase I clinical study of RG7356, an anti-CD44 humanized antibody, in patients with acute myeloid leukemia
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Norbert Vey1,2, Jacques Delaunay3, Giovanni Martinelli4, Walter Fiedler5, Emmanuel Raffoux6, Thomas Prebet1, Carlos Gomez-Roca7,8, Cristina Papayannidis4, Maxim Kebenko5, Peter Paschka9, Randolph Christen10, Ernesto Guarin11, Ann-Marie Bröske12, Monika Baehner12, Michael Brewster13, Antje-Christine Walz11, Francesca Michielin11, Valeria Runza12, Valerie Meresse11, Christian Recher7,14
1Institut Paoli-Calmettes, Marseille, France
2Aix Marseille Université, Marseille, France
3Service d'Hématologie Clinique, Hôpital Hôtel-Dieu, Nantes, France
4Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
5Department of Medicine II, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
6Hôpital Saint Louis, AP-HP, EA3518 Université Paris VII, Paris, France
7Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
8Institut Claudius Regaud, Clinical Research Unit, Toulouse, France
9Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
10Product Development, Safety Risk Management, Roche, Basel, Switzerland
11Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland
12Pharma Research & Early Development, Roche Innovation Center Penzberg, Penzberg, Germany
13Pharma Research & Early Development, Roche Innovation Centre, Welwyn, UK
14CHU de Toulouse, Université Toulouse III, Toulouse, France
Norbert Vey, email: email@example.com
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
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.
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