Activation of immune responses in patients with relapsed-metastatic head and neck cancer (CONFRONT phase I-II trial): Multimodality immunotherapy with avelumab, short-course radiotherapy, and cyclophosphamide

Marco C Merlano, Anna M Merlotti, Lisa Licitra, Nerina Denaro, Elena Fea, Danilo Galizia, Massimo Di Maio, Claudia Fruttero, Paola Curcio, Stefania Vecchio, Elvio G Russi, Renzo Corvò

Research output: Contribution to journalArticle

Abstract

Introduction and background: Second-line treatment of platinum-resistant relapsed/metastatic (R/M) head and neck cancer (HNC) is a currently unmet clinical need. Clinical trials showed improvement in overall survival and quality of life of R/M-HNC patients treated with anti-PD-1 regardless of the number of prior chemotherapy lines; however, the percentage of long-term survivors remains limited.This study aims to test the hypothesis that attacking the tumor microenvironment at multiple levels can increase immunogenicity of R/M-HNC without worsening the safety profile of immune checkpoint inhibitors.

Methods/design: In this open label, multi-center, single-arm, Phase Ib/II, R/M-HNC patients pretreated with at least one line of therapy containing platinum, fluorouracil, and cetuximab will receive a daily metronomic dose of 50 mg cyclophosphamide without a drug-free break, 10 mg/kg avelumab on day 1 and every other week until progression, and a single fraction of 8 Gy radiotherapy on day 8.

Discussion: The treatment protocol aims to reverse immune evasion of the tumor through a radiotherapy-induced self-vaccination effect, suppression of CD4+ CD25+ FoxP3+ regulatory T-cell function by metronomic cyclophosphamide, and effector T-cell reactivation owing to the inhibition of the PD-1-PD-L1 axis by avelumab.The immunologic interplay induced by the proposed combined treatment may theoretically improve the activity of avelumab without increasing its toxicity profile.Finally, an ancillary translational study will be extended to all the patients' population.

Trial registration: EudraCT n. 2017-000353-39.

Original languageEnglish
Pages (from-to)47-52
Number of pages6
JournalClinical and translational radiation oncology
Volume12
DOIs
Publication statusPublished - Aug 2018

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Head and Neck Neoplasms
Immunotherapy
Cyclophosphamide
Radiotherapy
Platinum
Tumor Escape
Tumor Microenvironment
Regulatory T-Lymphocytes
Clinical Protocols
Fluorouracil
Survivors
Vaccination
Therapeutics
Quality of Life
Clinical Trials
T-Lymphocytes
Safety
Drug Therapy
Survival
avelumab

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Activation of immune responses in patients with relapsed-metastatic head and neck cancer (CONFRONT phase I-II trial) : Multimodality immunotherapy with avelumab, short-course radiotherapy, and cyclophosphamide. / Merlano, Marco C; Merlotti, Anna M; Licitra, Lisa; Denaro, Nerina; Fea, Elena; Galizia, Danilo; Di Maio, Massimo; Fruttero, Claudia; Curcio, Paola; Vecchio, Stefania; Russi, Elvio G; Corvò, Renzo.

In: Clinical and translational radiation oncology, Vol. 12, 08.2018, p. 47-52.

Research output: Contribution to journalArticle

Merlano, Marco C ; Merlotti, Anna M ; Licitra, Lisa ; Denaro, Nerina ; Fea, Elena ; Galizia, Danilo ; Di Maio, Massimo ; Fruttero, Claudia ; Curcio, Paola ; Vecchio, Stefania ; Russi, Elvio G ; Corvò, Renzo. / Activation of immune responses in patients with relapsed-metastatic head and neck cancer (CONFRONT phase I-II trial) : Multimodality immunotherapy with avelumab, short-course radiotherapy, and cyclophosphamide. In: Clinical and translational radiation oncology. 2018 ; Vol. 12. pp. 47-52.
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abstract = "Introduction and background: Second-line treatment of platinum-resistant relapsed/metastatic (R/M) head and neck cancer (HNC) is a currently unmet clinical need. Clinical trials showed improvement in overall survival and quality of life of R/M-HNC patients treated with anti-PD-1 regardless of the number of prior chemotherapy lines; however, the percentage of long-term survivors remains limited.This study aims to test the hypothesis that attacking the tumor microenvironment at multiple levels can increase immunogenicity of R/M-HNC without worsening the safety profile of immune checkpoint inhibitors.Methods/design: In this open label, multi-center, single-arm, Phase Ib/II, R/M-HNC patients pretreated with at least one line of therapy containing platinum, fluorouracil, and cetuximab will receive a daily metronomic dose of 50 mg cyclophosphamide without a drug-free break, 10 mg/kg avelumab on day 1 and every other week until progression, and a single fraction of 8 Gy radiotherapy on day 8.Discussion: The treatment protocol aims to reverse immune evasion of the tumor through a radiotherapy-induced self-vaccination effect, suppression of CD4+ CD25+ FoxP3+ regulatory T-cell function by metronomic cyclophosphamide, and effector T-cell reactivation owing to the inhibition of the PD-1-PD-L1 axis by avelumab.The immunologic interplay induced by the proposed combined treatment may theoretically improve the activity of avelumab without increasing its toxicity profile.Finally, an ancillary translational study will be extended to all the patients' population.Trial registration: EudraCT n. 2017-000353-39.",
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T1 - Activation of immune responses in patients with relapsed-metastatic head and neck cancer (CONFRONT phase I-II trial)

T2 - Multimodality immunotherapy with avelumab, short-course radiotherapy, and cyclophosphamide

AU - Merlano, Marco C

AU - Merlotti, Anna M

AU - Licitra, Lisa

AU - Denaro, Nerina

AU - Fea, Elena

AU - Galizia, Danilo

AU - Di Maio, Massimo

AU - Fruttero, Claudia

AU - Curcio, Paola

AU - Vecchio, Stefania

AU - Russi, Elvio G

AU - Corvò, Renzo

PY - 2018/8

Y1 - 2018/8

N2 - Introduction and background: Second-line treatment of platinum-resistant relapsed/metastatic (R/M) head and neck cancer (HNC) is a currently unmet clinical need. Clinical trials showed improvement in overall survival and quality of life of R/M-HNC patients treated with anti-PD-1 regardless of the number of prior chemotherapy lines; however, the percentage of long-term survivors remains limited.This study aims to test the hypothesis that attacking the tumor microenvironment at multiple levels can increase immunogenicity of R/M-HNC without worsening the safety profile of immune checkpoint inhibitors.Methods/design: In this open label, multi-center, single-arm, Phase Ib/II, R/M-HNC patients pretreated with at least one line of therapy containing platinum, fluorouracil, and cetuximab will receive a daily metronomic dose of 50 mg cyclophosphamide without a drug-free break, 10 mg/kg avelumab on day 1 and every other week until progression, and a single fraction of 8 Gy radiotherapy on day 8.Discussion: The treatment protocol aims to reverse immune evasion of the tumor through a radiotherapy-induced self-vaccination effect, suppression of CD4+ CD25+ FoxP3+ regulatory T-cell function by metronomic cyclophosphamide, and effector T-cell reactivation owing to the inhibition of the PD-1-PD-L1 axis by avelumab.The immunologic interplay induced by the proposed combined treatment may theoretically improve the activity of avelumab without increasing its toxicity profile.Finally, an ancillary translational study will be extended to all the patients' population.Trial registration: EudraCT n. 2017-000353-39.

AB - Introduction and background: Second-line treatment of platinum-resistant relapsed/metastatic (R/M) head and neck cancer (HNC) is a currently unmet clinical need. Clinical trials showed improvement in overall survival and quality of life of R/M-HNC patients treated with anti-PD-1 regardless of the number of prior chemotherapy lines; however, the percentage of long-term survivors remains limited.This study aims to test the hypothesis that attacking the tumor microenvironment at multiple levels can increase immunogenicity of R/M-HNC without worsening the safety profile of immune checkpoint inhibitors.Methods/design: In this open label, multi-center, single-arm, Phase Ib/II, R/M-HNC patients pretreated with at least one line of therapy containing platinum, fluorouracil, and cetuximab will receive a daily metronomic dose of 50 mg cyclophosphamide without a drug-free break, 10 mg/kg avelumab on day 1 and every other week until progression, and a single fraction of 8 Gy radiotherapy on day 8.Discussion: The treatment protocol aims to reverse immune evasion of the tumor through a radiotherapy-induced self-vaccination effect, suppression of CD4+ CD25+ FoxP3+ regulatory T-cell function by metronomic cyclophosphamide, and effector T-cell reactivation owing to the inhibition of the PD-1-PD-L1 axis by avelumab.The immunologic interplay induced by the proposed combined treatment may theoretically improve the activity of avelumab without increasing its toxicity profile.Finally, an ancillary translational study will be extended to all the patients' population.Trial registration: EudraCT n. 2017-000353-39.

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JF - Clinical and translational radiation oncology

SN - 2405-6308

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