title: Predictive factors of renal toxicities related to anti-VEGFR multikinase inhibitors in phase 1 trials.
abstract: Purpose Renal toxicities are common with angiogenesis multikinase inhibitors (AMKI), and can be limiting in phase I trials. Factors associated with such toxicities are poorly known. The aims of this exploratory study were to describe renovascular toxicities associated with AMKI, impact on drug development and to identify baseline parameters associated with the occurrence of renal toxicities in phase I trials. Methods Consecutive patients treated with AMKI in Gustave Roussy phase I unit between October 2005 and August 2013 were included. We retrospectively collected baseline characteristics and renovascular side effects. Associations were assessed in univariate and multivariate analyses. Results Overall, 168 patients were included: male 53.0 %, mean age 55.5 years old, history of hypertension 26.8 %, diabetes 6.0 %, atherosclerosis 13.6 %, stage 3 Chronic Kidney Disease (CKD, NKF-KDOQI) 17.2 %. Incidences of reno-vascular side effects were: hypertension 47.6 %, proteinuria 19.0 %, renal failure 11.9 % and thrombotic microangiopathy 10.1 %. Eighty percent of dose limiting toxicities (DLTs) were related to a renal toxicity. Multivariate analysis showed that onset of renal failure was associated with history of hypertension (p = 0.0003) and stage 3 CKD (p = 0.032). Conclusions A majority of the DLTs associated with AMKI in phase 1 trials are renal toxicities. Baseline hypertension and stage 3 CKD (NKF-KDOQI) might help to better identify patients at risk of AMKI-related renal toxicities.
authors: Department of Drug Development (DITEP), Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94805, Villejuif, France.
authors: Emilie
authors: E
authors: Boissier
authors: Department of Drug Development (DITEP), Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94805, Villejuif, France.
authors: Olivier
authors: O
authors: Mir
authors: Department of Drug Development (DITEP), Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94805, Villejuif, France.
authors: Antoine
authors: A
authors: Hollebecque
authors: Department of Nephrology, Park Monceau International Clinic, 21 Rue de Chazelles, 75017, Paris, France.
authors: Hassan
authors: H
authors: Izzedine
authors: Department of Cardiology, Saint Antoine Teaching Hospital, 184 Rue du Faubourg Saint-Antoine, Assistance Publique - Hôpitaux de Paris, 75012, Paris, France.
authors: Stéphane
authors: S
authors: Ederhy
authors: Department of Drug Development (DITEP), Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94805, Villejuif, France.
authors: Anas
authors: A
authors: Gazzah
authors: Department of Drug Development (DITEP), Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94805, Villejuif, France.
authors: Rastislav
authors: R
authors: Bahleda
authors: Department of Drug Development (DITEP), Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94805, Villejuif, France.
authors: Christophe
authors: C
authors: Massard
authors: Clinical Pharmacology, Henri Mondor Teaching Hospital, 51 avenue du Maréchal de Lattre de Tassigny, Assistance Publique - Hôpitaux de Paris, 94000, Créteil, France.
authors: Isabelle
authors: I
authors: Macquin-Mavier
authors: Faculty of Medicine, University of Paris-Est, 61 Avenue du Général de Gaulle, 94000, Créteil, France.|Department of Medical Oncology, Henri Mondor Teaching Hospital, Assistance Publique - Hôpitaux de Paris, 51 avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France.
authors: Christophe
authors: C
authors: Tournigand
authors: Department of Medical Oncology, Pitié Salpêtrière Teaching Hospital, 47-83 Boulevard de l'Hôpital, Assistance Publique-Hôpitaux de Paris, 75013, Paris, France.|Faculty of Medicine, Université Pierre et Marie Curie, 91-105 Boulevard de l'Hôpital, 75013, Paris, France.
authors: Jean-Philippe
authors: JP
authors: Spano
authors: Department of Drug Development (DITEP), Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94805, Villejuif, France.|Faculty of Medicine, Paris Sud University, 63 Rue Gabriel Péri, 94270, Le Kremlin-Bicêtre, France.
authors: Jean-Charles
authors: JC
authors: Soria
authors: Clinical Pharmacology, Henri Mondor Teaching Hospital, 51 avenue du Maréchal de Lattre de Tassigny, Assistance Publique - Hôpitaux de Paris, 94000, Créteil, France. benoit.rousseau@aphp.fr.|Faculty of Medicine, University of Paris-Est, 61 Avenue du Général de Gaulle, 94000, Créteil, France. benoit.rousseau@aphp.fr.|Department of Medical Oncology, Henri Mondor Teaching Hospital, Assistance Publique - Hôpitaux de Paris, 51 avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. benoit.rousseau@aphp.fr.|INSERM U955 Team 18, 8 rue du Général Sarrail, 94010, Créteil Cedex, France. benoit.rousseau@aphp.fr.|Oncologie médicale, CHU Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. benoit.rousseau@aphp.fr.
authors: Benoît
authors: 0000-0002-1594-4827
authors: B
authors: Rousseau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Antiangiogenic agents; Cancer; Drug safety; Renal failure