title: Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies.
abstract: OBJECTIVE
  We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds.
  
  
  METHODS
  We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013.
  
  
  RESULTS
  A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion.
  
  
  CONCLUSIONS
  This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy. diego.tosi@icm.unicancer.fr.
authors.forename: Diego
authors.initials: D
authors.lastname: Tosi
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Yassine
authors.initials: Y
authors.lastname: Laghzali
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Marie
authors.initials: M
authors.lastname: Vinches
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Marie
authors.initials: M
authors.lastname: Alexandre
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Krisztian
authors.initials: K
authors.lastname: Homicsko
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Fasolo
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Del Conte
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Durigova
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Hayaoui
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gourgou
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.affiliation: Diego Tosi, Yassine Laghzali, Marie Vinches, Marie Alexandre, Nadia Hayaoui, Sophie Gourgou, and Caroline Mollevi, Institut Régional du Cancer de Montpellier-Val d'Aurelle, Montpellier, France; Krisztian Homicsko, Centre Hospitalier Universitaire Vaudois, Lausanne; Anna Durigova, Geneva University Hospitals, Geneva, Switzerland; and Angelica Fasolo, Gianluca Del Conte, and Luca Gianni, San Raffaele-Scientific Institute, Milan, Italy.
authors.forename: Caroline
authors.initials: C
authors.lastname: Mollevi
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D012107:Research Design
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents