title: Phase I clinical study of RG7356, an anti-CD44 humanized antibody, in patients with acute myeloid leukemia.
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.
authors.affiliation: Institut Paoli-Calmettes, Marseille, France.|Aix Marseille Université, Marseille, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.affiliation: Service d'Hématologie Clinique, Hôpital Hôtel-Dieu, Nantes, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Delaunay
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.affiliation: Department of Medicine II, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.affiliation: Hôpital Saint Louis, AP-HP, EA3518 Université Paris VII, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.affiliation: Institut Paoli-Calmettes, Marseille, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prebet
authors.affiliation: Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.|Institut Claudius Regaud, Clinical Research Unit, Toulouse, France.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gomez-Roca
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Papayannidis
authors.affiliation: Department of Medicine II, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Maxim
authors.initials: M
authors.lastname: Kebenko
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.affiliation: Product Development, Safety Risk Management, Roche, Basel, Switzerland.
authors.forename: Randolph
authors.initials: R
authors.lastname: Christen
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guarin
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Bröske
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Baehner
authors.affiliation: Pharma Research & Early Development, Roche Innovation Centre, Welwyn, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Brewster
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Antje-Christine
authors.initials: AC
authors.lastname: Walz
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Michielin
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
authors.forename: Valeria
authors.initials: V
authors.lastname: Runza
authors.affiliation: Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Meresse
authors.affiliation: Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.|CHU de Toulouse, Université Toulouse III, Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Recher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C576196:RG7356
keywords: RG7356; anti-CD44 humanized antibody; cell adhesion; phase I trial; relapsed/refractory acute myeloid leukemia