Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study

R Gutzmer, L Rivoltini, E Levchenko, A Testori, J Utikal, P A Ascierto, L Demidov, J J Grob, R Ridolfi, D Schadendorf, P Queirolo, A Santoro, C Loquai, B Dreno, A Hauschild, E Schultz, T P Lesimple, N Vanhoutte, B Salaun, M Gillet, S Jarnjak, P M De Sousa Alves, J Louahed, V G Brichard, F F Lehmann, R Gutzmer, L Rivoltini, E Levchenko, A Testori, J Utikal, P A Ascierto, L Demidov, J J Grob, R Ridolfi, D Schadendorf, P Queirolo, A Santoro, C Loquai, B Dreno, A Hauschild, E Schultz, T P Lesimple, N Vanhoutte, B Salaun, M Gillet, S Jarnjak, P M De Sousa Alves, J Louahed, V G Brichard, F F Lehmann

Abstract

Purpose: 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.

Patients and 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.

Trial registration number: NCT01149343, Results.

Keywords: PRAME antigen; cancer immunotherapy; immunogenicity; metastatic melanoma; safety.

Conflict of interest statement

Employment: MG (GSK group of companies); NV (GSK group of companies); BS (GSK group of companies); SJ (GSK group of companies); PMDeSA (GSK group of companies); FFL (GSK group of companies); JL (GSK group of companies); VGB (GSK group of companies). Stock Ownership: SJ (GSK group of companies), FFL (GSK group of companies); JL (GSK group of companies); VGB (GSK group of companies); PMDeSA (GSK group of companies). Honoraria: BD (Roche, GSK, BMS), DS (GSK, Roche, BMS, Amgen, Novartis, Merck/MSD), JJG (GSK, BMS, Roche, Amgen, MSD, Novartis, Meda), AT (BMS, GSK, Amgen, Roche), AH (Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, Roche Pharma), RG (GSK, Roche, BMS, MSD, Novartis, Pfizer, Janssen, Amgen, Merck Serono, Boehringer, Almirall Hermal), JU (Roche, GSK, BMS), PA (BMS, Roche/Genentech, GSK, Ventana), RR (BMS, GSK), ES (Novartis, BMS, DermaPharm), TL (GSK, BMS, Merck, Roche). Consultant or Advisory Role: BD (Roche, BMS, GSK), DS (GSK, Roche, BMS, Amgen, Novartis, Merck/MSD), JJG (GSK, BMS, Roche, Amgen, MSD, Novartis, Meda), AT (BMS, GSK, Amgen, Roche), AH (Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, Roche Pharma), RG (GSK, BMS, Roche, Novartis, Almirall Hermal, MSD, Amgen), JU (Roche, GSK), PA (BMS, Roche/Genentech, MSD, GSK, Ventana, Novartis, Amgen), PQ (GSK, Roche, Bristol, MSD), CL (Roche, BMS, MSD), ES (BMS). Speakers’ Bureau: DS (GSK; Roche, BMS, Amgen, Novartis, Merck/MSD), JJG (GSK), RG (GSK), JU (Roche), CL (Roche, BMS, MSD, Leo), TL (GSK, Merck, Roche), LD (GSK, BMS, Roche, MSD). Research funding: BD (Roche, GSK), DS (Merck), JJG (Roche), AH (trial grants from Amgen, BMS, Celgene, Eisai, GSK, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, Roche Pharma), RG (Roche, Novartis, Pfizer, Johnson & Johnson), PA (BMS, Roche/Genentech, Ventana). Patents, royalties, other intellectual property: ES (Royalties from Ludwig Institute for Cancer Research for contribution to a patent on human tumor antigen). Travel, accommodations, expenses: BD (Roche, BMS), DS (GSK, Roche, BMS, Amgen, Novartis, Merck/MSD), AT (Oncovision), RG (Roche, BMS), JU (Roche, GSK), PQ (Roche, GSK, MSD), CL (Roche, BMS, Leo), TL (Roche). EL, LR, AS declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Seropositivity rates and geometric mean antibody concentrations (GMCs) for anti-PRAME IgG antibodies (ATP cohort for immunogenicity). Footnote: N=number of patients with available results, n/%=number/percentage of patients with concentrations above the cut-off, vertical lines indicate 95% CIs, dotted line shows assay cut-off (12 E.U/mL), Pre=prior to dose 1, Post II=2 weeks after the second dose, Post IV=2 weeks after the fourth dose. ATP, according-to-protocol; PRAME, PReferentially expressed Antigen of Melanoma.
Figure 2
Figure 2
PRAME-specific CD4+ T-cell (TNF-α+/IFN-γ+) immunogenicity scores and cellular response prior to treatment and postdose 4 (ATP cohort for immunogenicity). Footnote: N=number of patients with available results, n/%=number/percentage of patients with immunogenicity score/response, vertical lines indicate 95% CIs, dotted line shows cut-off (2.68), Pre=prior to dose 1, Post IV=2 weeks after the fourth dose. See online supplementary data for details of the derivation of cut-offs and methods. ATP, according-to-protocol; IFN-γ, interferon-γ; TNF-α, tumour necrosis factor α; PRAME, PReferentially expressed Antigen of Melanoma.

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