title: Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study.
abstract: OBJECTIVE
  The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment.
  
  
  METHODS
  Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays.
  
  
  RESULTS
  66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected.
  
  
  CONCLUSIONS
  The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose.
  
  
  BACKGROUND
  NCT01149343, Results.
authors.affiliation: Skin Cancer Center Hannover , Hannover Medical School , Hannover , Germany.
authors.forename: R
authors.initials: R
authors.lastname: Gutzmer
authors.affiliation: Unit of Immunotherapy of Human Tumors , Fondazione RCCS Istituto Nazionale dei Tumori , Milan , Italy.
authors.forename: L
authors.initials: L
authors.lastname: Rivoltini
authors.affiliation: Petrov Research Institute of Oncology , St. Petersburg , Russia.
authors.forename: E
authors.initials: E
authors.lastname: Levchenko
authors.affiliation: Istituto Europeo Di Oncologia , Milano , Italy.
authors.forename: A
authors.initials: A
authors.lastname: Testori
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Utikal
authors.affiliation: Melanoma, Cancer Immunotherapy and Innovative Therapies Unit , Istituto Nazionale Tumori Fondazione Pascale , Naples , Italy.
authors.forename: P A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Cancer Research Center , Moscow , Russia.
authors.forename: L
authors.initials: L
authors.lastname: Demidov
authors.affiliation: Aix Marseille University Hôpital de la Timone, Service de Dermatologie , Marseille , France.
authors.forename: J J
authors.initials: JJ
authors.lastname: Grob
authors.affiliation: Immunotherapy Unit , Romagna Cancer Institute IRST- IRCCS , Meldola , Italy.
authors.forename: R
authors.initials: R
authors.lastname: Ridolfi
authors.affiliation: Department of Dermatology , University Hospital Essen , Essen , Germany.
authors.forename: D
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Istituto Nazionale per la Ricerca sul Cancro Oncologia Medica , Genova , Italy.
authors.forename: P
authors.initials: P
authors.lastname: Queirolo
authors.affiliation: Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS , Rozzano , Italy.
authors.forename: A
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Department of Dermatology , University of Mainz , Mainz , Germany.
authors.forename: C
authors.initials: C
authors.lastname: Loquai
authors.affiliation: Dermatology Clinic , Hôpital Hôtel-Dieu, CHU Nantes , Nantes , France.
authors.forename: B
authors.initials: B
authors.lastname: Dreno
authors.affiliation: Department of Dermatology , Skin Cancer Center, Schleswig-Holstein University Hospital , Kiel , Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hauschild
authors.affiliation: Department of Dermatology , Paracelsus Medical University, Klinikum Nuremberg , Nuremberg , Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schultz
authors.affiliation: Département d'Oncologie Médicale , Centre Eugène Marquis , Rennes , France.
authors.forename: T P
authors.initials: TP
authors.lastname: Lesimple
authors.affiliation: GSK Vaccines , Rixensart , Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Vanhoutte
authors.affiliation: GSK Vaccines , Rixensart , Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Salaun
authors.affiliation: GSK Vaccines , Rixensart , Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Gillet
authors.affiliation: GSK Vaccines , Rixensart , Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Jarnjak
authors.affiliation: GSK Vaccines, Rixensart, Belgium; Celyad, Mont-Saint-Guibert, Rixensart, Belgium.
authors.forename: P M
authors.initials: PM
authors.lastname: De Sousa Alves
authors.affiliation: GSK Vaccines , Rixensart , Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Louahed
authors.affiliation: GSK Vaccines, Rixensart, Belgium; Vianova-Biosciences, Lasne, Belgium.
authors.forename: V G
authors.initials: VG
authors.lastname: Brichard
authors.affiliation: GSK Vaccines, Rixensart, Belgium; Celyad, Mont-Saint-Guibert, Rixensart, Belgium.
authors.forename: F F
authors.initials: FF
authors.lastname: Lehmann
keywords: PRAME antigen; cancer immunotherapy; immunogenicity; metastatic melanoma; safety