title: First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors.
abstract: Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic target. We report results from a first-in-human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies.Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6-35) weeks. No apparent dose- or dose schedule-dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using 89Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens.
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: C Willemien
authors: CW
authors: Menke-van der Houven van Oordt
authors: Clinical Research Unit, Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France.
authors: Carlos
authors: C
authors: Gomez-Roca
authors: Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Carla
authors: C
authors: van Herpen
authors: Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA.
authors: Andrew L
authors: AL
authors: Coveler
authors: Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Devalingam
authors: D
authors: Mahalingam
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Henk M W
authors: HM
authors: Verheul
authors: Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Winette T A
authors: WT
authors: van der Graaf
authors: Product Development, Safety Risk Management, Roche, Basel, Switzerland.
authors: Randolph
authors: R
authors: Christen
authors: Pharma Research & Early Development, Roche Innovation Center, Penzberg, Germany.
authors: Dominik
authors: D
authors: Rüttinger
authors: Pharma Research & Early Development, Roche Innovation Center, Penzberg, Germany.
authors: Stefan
authors: S
authors: Weigand
authors: Pharma Research & Early Development, Roche Innovation Center, Penzberg, Germany.
authors: Michael A
authors: MA
authors: Cannarile
authors: Pharma Research & Early Development, Roche Innovation Center, Penzberg, Germany.
authors: Florian
authors: F
authors: Heil
authors: Pharma Research & Early Development, Roche Innovation Centre, Welwyn, UK.
authors: Michael
authors: M
authors: Brewster
authors: Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors: Antje-Christine
authors: AC
authors: Walz
authors: Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors: Tapan K
authors: TK
authors: Nayak
authors: Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors: Ernesto
authors: E
authors: Guarin
authors: Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors: Valerie
authors: V
authors: Meresse
authors: Department of Medical Oncology, Institut Curie, Saint-Cloud & Paris, France.|Versailles-Saint-Quentin-en-Yvelines University, Versailles, France.
authors: Christophe
authors: C
authors: Le Tourneau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010865:Pilot Projects; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015040:Zirconium / Q000493:pharmacokinetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C576196:RG7356; D019275:Radiopharmaceuticals; D015040:Zirconium
keywords: RG7356; advanced CD44-expressing solid malignancies; advanced solid tumors; anti-CD44 humanized antibody; phase I trial