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. GilletS. Jarnjak, P. M. De Sousa Alves, J. Louahed, V. G. Brichard, F. F. Lehmann

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Article numbere000068
JournalESMO Open
Volume1
Issue number4
DOIs
Publication statusPublished - Jul 1 2016

Fingerprint

Melanoma
Safety
Neoplasms
Cellular Immunity
Immunization
T-Lymphocytes
Immunologic Adjuvants
Chills
Intramuscular Injections
Brain Edema
Neoplasm Antigens
Humoral Immunity
Proteinuria
Recombinant Proteins
Fatigue
Headache
Anti-Idiotypic Antibodies
Fever
Enzyme-Linked Immunosorbent Assay
Research Personnel

Keywords

  • cancer immunotherapy
  • immunogenicity
  • metastatic melanoma
  • PRAME antigen
  • safety

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma : Results of a phase i dose escalation study. / Gutzmer, R.; Rivoltini, L.; Levchenko, E.; Testori, A.; Utikal, J.; Ascierto, P. A.; Demidov, L.; Grob, J. J.; Ridolfi, R.; Schadendorf, D.; Queirolo, P.; Santoro, A.; Loquai, C.; Dreno, B.; Hauschild, A.; Schultz, E.; Lesimple, T. P.; Vanhoutte, N.; Salaun, B.; Gillet, M.; Jarnjak, S.; De Sousa Alves, P. M.; Louahed, J.; Brichard, V. G.; Lehmann, F. F.

In: ESMO Open, Vol. 1, No. 4, e000068, 01.07.2016.

Research output: Contribution to journalArticle

Gutzmer, R, Rivoltini, L, Levchenko, E, Testori, A, Utikal, J, Ascierto, PA, Demidov, L, Grob, JJ, Ridolfi, R, Schadendorf, D, Queirolo, P, Santoro, A, Loquai, C, Dreno, B, Hauschild, A, Schultz, E, Lesimple, TP, Vanhoutte, N, Salaun, B, Gillet, M, Jarnjak, S, De Sousa Alves, PM, Louahed, J, Brichard, VG & Lehmann, FF 2016, 'Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: Results of a phase i dose escalation study', ESMO Open, vol. 1, no. 4, e000068. https://doi.org/10.1136/esmoopen-2016-000068
Gutzmer, R. ; Rivoltini, L. ; Levchenko, E. ; Testori, A. ; Utikal, J. ; Ascierto, P. A. ; Demidov, L. ; Grob, J. J. ; Ridolfi, R. ; Schadendorf, D. ; Queirolo, P. ; Santoro, A. ; Loquai, C. ; Dreno, B. ; Hauschild, A. ; Schultz, E. ; Lesimple, T. P. ; Vanhoutte, N. ; Salaun, B. ; Gillet, M. ; Jarnjak, S. ; De Sousa Alves, P. M. ; Louahed, J. ; Brichard, V. G. ; Lehmann, F. F. / Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma : Results of a phase i dose escalation study. In: ESMO Open. 2016 ; Vol. 1, No. 4.
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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.",
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author = "R. Gutzmer and L. Rivoltini and E. Levchenko and A. Testori and J. Utikal and Ascierto, {P. A.} and L. Demidov and Grob, {J. J.} and R. Ridolfi and D. Schadendorf and P. Queirolo and A. Santoro and C. Loquai and B. Dreno and A. Hauschild and E. Schultz and Lesimple, {T. P.} and N. Vanhoutte and B. Salaun and M. Gillet and S. Jarnjak and {De Sousa Alves}, {P. M.} and J. Louahed and Brichard, {V. G.} and Lehmann, {F. F.}",
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T1 - Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma

T2 - Results of a phase i dose escalation study

AU - Gutzmer, R.

AU - Rivoltini, L.

AU - Levchenko, E.

AU - Testori, A.

AU - Utikal, J.

AU - Ascierto, P. A.

AU - Demidov, L.

AU - Grob, J. J.

AU - Ridolfi, R.

AU - Schadendorf, D.

AU - Queirolo, P.

AU - Santoro, A.

AU - Loquai, C.

AU - Dreno, B.

AU - Hauschild, A.

AU - Schultz, E.

AU - Lesimple, T. P.

AU - Vanhoutte, N.

AU - Salaun, B.

AU - Gillet, M.

AU - Jarnjak, S.

AU - De Sousa Alves, P. M.

AU - Louahed, J.

AU - Brichard, V. G.

AU - Lehmann, F. F.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

KW - cancer immunotherapy

KW - immunogenicity

KW - metastatic melanoma

KW - PRAME antigen

KW - safety

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