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Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated – NIVACOR trial (GOIRC-03-2018)

BACKGROUND: FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab has shown to be one of the therapeutic regimens in first line with the highest activity in patients (pts.) with metastatic colorectal cancer (mCRC) unselected for biomolecular alterations. Generally, tumor...

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Autores principales: Damato, Angela, Iachetta, Francesco, Antonuzzo, Lorenzo, Nasti, Guglielmo, Bergamo, Francesca, Bordonaro, Roberto, Maiello, Evaristo, Zaniboni, Alberto, Tonini, Giuseppe, Romagnani, Alessandra, Berselli, Annalisa, Normanno, Nicola, Pinto, Carmine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457535/
https://www.ncbi.nlm.nih.gov/pubmed/32867715
http://dx.doi.org/10.1186/s12885-020-07268-4
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author Damato, Angela
Iachetta, Francesco
Antonuzzo, Lorenzo
Nasti, Guglielmo
Bergamo, Francesca
Bordonaro, Roberto
Maiello, Evaristo
Zaniboni, Alberto
Tonini, Giuseppe
Romagnani, Alessandra
Berselli, Annalisa
Normanno, Nicola
Pinto, Carmine
author_facet Damato, Angela
Iachetta, Francesco
Antonuzzo, Lorenzo
Nasti, Guglielmo
Bergamo, Francesca
Bordonaro, Roberto
Maiello, Evaristo
Zaniboni, Alberto
Tonini, Giuseppe
Romagnani, Alessandra
Berselli, Annalisa
Normanno, Nicola
Pinto, Carmine
author_sort Damato, Angela
collection PubMed
description BACKGROUND: FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab has shown to be one of the therapeutic regimens in first line with the highest activity in patients (pts.) with metastatic colorectal cancer (mCRC) unselected for biomolecular alterations. Generally, tumors co-opt the programmed death-1/ligand 1 (PD-1/PD-L1) signaling pathway as one key mechanism to evade immune surveillance. As today, anti-PD-1 monoclonal antibodies are FDA approved only for DNA mismatch repair deficient/microsatellite instability-high (MMRd/MSI-H), which represent only about 5% among all mCRC. Nowadays, there are no data demonstrating anti PD-1 activity in proficient and stable disease (MMRp/MSS). A different target in mCRC is also the Vascular Endothelial Growth Factor A (VEGF-A), which acts on endothelial cells to stimulate angiogenesis. VEGF-A inhibition with bevacizumab has shown to increase the immune cell infiltration, providing a solid rationale for combining VEGF targeted agents with immune checkpoint inhibitors. Based on these evidences, we explore the combination of triplet chemotherapy (FOLFOXIRI) with bevacizumab and nivolumab in pts. with mCRC RAS/BRAF mutant regardless of microsatellite status. METHODS/DESIGN: This is a prospective, open-label, multicentric phase II trial where pts. with mCRC RAS/BRAF mutated, in first line will receive nivolumab in combination with FOLFOXIRI/bevacizumab every 2 weeks for 8 cycles followed by maintenance with bevacizumab plus nivolumab every 2 weeks. Bevacizumab will be administered intravenously at dose of 5 mg/kg every 2 weeks and nivolumab intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint is the overall response rate (ORR). This study hypothesis is that the treatment is able to improve the ORR from 66 to 80%. Secondary endpoints include OS, safety, time to progression, duration of response. Collateral translational studies evaluate the i) tumor mutational burden, and ii) genetic alterations by circulating free DNA (cfDNA) obtained from plasma samples. The trial is open to enrollment, 9 of planned 70 pts. have been enrolled. TRIAL REGISTRATION: NIVACOR is registered at ClinicalTrials.gov: NCT04072198, August 28, 2019.
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spelling pubmed-74575352020-08-31 Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated – NIVACOR trial (GOIRC-03-2018) Damato, Angela Iachetta, Francesco Antonuzzo, Lorenzo Nasti, Guglielmo Bergamo, Francesca Bordonaro, Roberto Maiello, Evaristo Zaniboni, Alberto Tonini, Giuseppe Romagnani, Alessandra Berselli, Annalisa Normanno, Nicola Pinto, Carmine BMC Cancer Study Protocol BACKGROUND: FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab has shown to be one of the therapeutic regimens in first line with the highest activity in patients (pts.) with metastatic colorectal cancer (mCRC) unselected for biomolecular alterations. Generally, tumors co-opt the programmed death-1/ligand 1 (PD-1/PD-L1) signaling pathway as one key mechanism to evade immune surveillance. As today, anti-PD-1 monoclonal antibodies are FDA approved only for DNA mismatch repair deficient/microsatellite instability-high (MMRd/MSI-H), which represent only about 5% among all mCRC. Nowadays, there are no data demonstrating anti PD-1 activity in proficient and stable disease (MMRp/MSS). A different target in mCRC is also the Vascular Endothelial Growth Factor A (VEGF-A), which acts on endothelial cells to stimulate angiogenesis. VEGF-A inhibition with bevacizumab has shown to increase the immune cell infiltration, providing a solid rationale for combining VEGF targeted agents with immune checkpoint inhibitors. Based on these evidences, we explore the combination of triplet chemotherapy (FOLFOXIRI) with bevacizumab and nivolumab in pts. with mCRC RAS/BRAF mutant regardless of microsatellite status. METHODS/DESIGN: This is a prospective, open-label, multicentric phase II trial where pts. with mCRC RAS/BRAF mutated, in first line will receive nivolumab in combination with FOLFOXIRI/bevacizumab every 2 weeks for 8 cycles followed by maintenance with bevacizumab plus nivolumab every 2 weeks. Bevacizumab will be administered intravenously at dose of 5 mg/kg every 2 weeks and nivolumab intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint is the overall response rate (ORR). This study hypothesis is that the treatment is able to improve the ORR from 66 to 80%. Secondary endpoints include OS, safety, time to progression, duration of response. Collateral translational studies evaluate the i) tumor mutational burden, and ii) genetic alterations by circulating free DNA (cfDNA) obtained from plasma samples. The trial is open to enrollment, 9 of planned 70 pts. have been enrolled. TRIAL REGISTRATION: NIVACOR is registered at ClinicalTrials.gov: NCT04072198, August 28, 2019. BioMed Central 2020-08-31 /pmc/articles/PMC7457535/ /pubmed/32867715 http://dx.doi.org/10.1186/s12885-020-07268-4 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Study Protocol
Damato, Angela
Iachetta, Francesco
Antonuzzo, Lorenzo
Nasti, Guglielmo
Bergamo, Francesca
Bordonaro, Roberto
Maiello, Evaristo
Zaniboni, Alberto
Tonini, Giuseppe
Romagnani, Alessandra
Berselli, Annalisa
Normanno, Nicola
Pinto, Carmine
Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated – NIVACOR trial (GOIRC-03-2018)
title Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated – NIVACOR trial (GOIRC-03-2018)
title_full Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated – NIVACOR trial (GOIRC-03-2018)
title_fullStr Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated – NIVACOR trial (GOIRC-03-2018)
title_full_unstemmed Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated – NIVACOR trial (GOIRC-03-2018)
title_short Phase II study on first-line treatment of NIVolumab in combination with folfoxiri/bevacizumab in patients with Advanced COloRectal cancer RAS or BRAF mutated – NIVACOR trial (GOIRC-03-2018)
title_sort phase ii study on first-line treatment of nivolumab in combination with folfoxiri/bevacizumab in patients with advanced colorectal cancer ras or braf mutated – nivacor trial (goirc-03-2018)
topic Study Protocol
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457535/
https://www.ncbi.nlm.nih.gov/pubmed/32867715
http://dx.doi.org/10.1186/s12885-020-07268-4
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