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An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors
PURPOSE: To evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab. EXPERIMENTAL DESIGN: PD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colo...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406114/ https://www.ncbi.nlm.nih.gov/pubmed/32753546 http://dx.doi.org/10.1136/jitc-2020-000883 |
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author | Taylor, Kirsty Loo Yau, Helen Chakravarthy, Ankur Wang, Ben Shen, Shu Yi Ettayebi, Ilias Ishak, Charles A Bedard, Philippe L Abdul Razak, Albiruni R Hansen, Aaron Spreafico, Anna Cescon, Dave Butler, Marcus O Oza, Amit M Lheureux, Stephanie Stjepanovic, Neda Van As, Brendan Boross-Harmer, Sarah Wang, Lisa Pugh, Trevor J Ohashi, Pamela S Siu, Lillian L De Carvalho, Daniel D |
author_facet | Taylor, Kirsty Loo Yau, Helen Chakravarthy, Ankur Wang, Ben Shen, Shu Yi Ettayebi, Ilias Ishak, Charles A Bedard, Philippe L Abdul Razak, Albiruni R Hansen, Aaron Spreafico, Anna Cescon, Dave Butler, Marcus O Oza, Amit M Lheureux, Stephanie Stjepanovic, Neda Van As, Brendan Boross-Harmer, Sarah Wang, Lisa Pugh, Trevor J Ohashi, Pamela S Siu, Lillian L De Carvalho, Daniel D |
author_sort | Taylor, Kirsty |
collection | PubMed |
description | PURPOSE: To evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab. EXPERIMENTAL DESIGN: PD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colorectal cancer; platinum resistant ovarian cancer; and estrogen receptor positive, HER2 negative breast cancer were enrolled in this single-institution, investigator-initiated trial. Two 28 day regimens, regimen A (CC-486 300 mg QD Days 1–14 (cycles 1–3 only) in combination with durvalumab 1500 mg intravenous day 15) and regimen B (CC-486 100 mg QD days 1–21 (cycle 1 and beyond), vitamin C 500 mg once a day continuously and durvalumab 1500 mg intravenous day 15) were investigated. Patients underwent paired tumor biopsies and serial peripheral blood mononuclear cells (PBMCs) collection for immune-profiling, transcriptomic and epigenomic analyzes. RESULTS: A total of 28 patients were enrolled, 19 patients treated on regimen A and 9 on regimen B. The combination of CC-486 and durvalumab was tolerable. Regimen B, with a lower dose of CC-486 extended over a longer treatment course, showed less grade 3/4 adverse effects. Global LINE-1 methylation assessment of serial PBMCs and genome-wide DNA methylation profile in paired tumor biopsies demonstrated minimal changes in global methylation in both regimens. The lack of robust tumor DNA demethylation was accompanied by an absence of the expected ‘viral mimicry’ inflammatory response, and consequently, no clinical responses were observed. The disease control rate was 7.1%. The median progression-free survival was 1.9 months (95% CI 1.5 to 2.3) and median overall survival was 5 months (95% CI 4.5 to 10). CONCLUSIONS: The evaluated treatment schedules of CC-486 in combination with durvalumab did not demonstrate robust pharmacodynamic or clinical activity in selected immunologically cold solid tumors. Lessons learned from this biomarker-rich study should inform continued drug development efforts using these agents. TRIAL REGISTRATION NUMBER: NCT02811497. |
format | Online Article Text |
id | pubmed-7406114 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-74061142020-08-17 An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors Taylor, Kirsty Loo Yau, Helen Chakravarthy, Ankur Wang, Ben Shen, Shu Yi Ettayebi, Ilias Ishak, Charles A Bedard, Philippe L Abdul Razak, Albiruni R Hansen, Aaron Spreafico, Anna Cescon, Dave Butler, Marcus O Oza, Amit M Lheureux, Stephanie Stjepanovic, Neda Van As, Brendan Boross-Harmer, Sarah Wang, Lisa Pugh, Trevor J Ohashi, Pamela S Siu, Lillian L De Carvalho, Daniel D J Immunother Cancer Clinical/Translational Cancer Immunotherapy PURPOSE: To evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab. EXPERIMENTAL DESIGN: PD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colorectal cancer; platinum resistant ovarian cancer; and estrogen receptor positive, HER2 negative breast cancer were enrolled in this single-institution, investigator-initiated trial. Two 28 day regimens, regimen A (CC-486 300 mg QD Days 1–14 (cycles 1–3 only) in combination with durvalumab 1500 mg intravenous day 15) and regimen B (CC-486 100 mg QD days 1–21 (cycle 1 and beyond), vitamin C 500 mg once a day continuously and durvalumab 1500 mg intravenous day 15) were investigated. Patients underwent paired tumor biopsies and serial peripheral blood mononuclear cells (PBMCs) collection for immune-profiling, transcriptomic and epigenomic analyzes. RESULTS: A total of 28 patients were enrolled, 19 patients treated on regimen A and 9 on regimen B. The combination of CC-486 and durvalumab was tolerable. Regimen B, with a lower dose of CC-486 extended over a longer treatment course, showed less grade 3/4 adverse effects. Global LINE-1 methylation assessment of serial PBMCs and genome-wide DNA methylation profile in paired tumor biopsies demonstrated minimal changes in global methylation in both regimens. The lack of robust tumor DNA demethylation was accompanied by an absence of the expected ‘viral mimicry’ inflammatory response, and consequently, no clinical responses were observed. The disease control rate was 7.1%. The median progression-free survival was 1.9 months (95% CI 1.5 to 2.3) and median overall survival was 5 months (95% CI 4.5 to 10). CONCLUSIONS: The evaluated treatment schedules of CC-486 in combination with durvalumab did not demonstrate robust pharmacodynamic or clinical activity in selected immunologically cold solid tumors. Lessons learned from this biomarker-rich study should inform continued drug development efforts using these agents. TRIAL REGISTRATION NUMBER: NCT02811497. BMJ Publishing Group 2020-08-04 /pmc/articles/PMC7406114/ /pubmed/32753546 http://dx.doi.org/10.1136/jitc-2020-000883 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Clinical/Translational Cancer Immunotherapy Taylor, Kirsty Loo Yau, Helen Chakravarthy, Ankur Wang, Ben Shen, Shu Yi Ettayebi, Ilias Ishak, Charles A Bedard, Philippe L Abdul Razak, Albiruni R Hansen, Aaron Spreafico, Anna Cescon, Dave Butler, Marcus O Oza, Amit M Lheureux, Stephanie Stjepanovic, Neda Van As, Brendan Boross-Harmer, Sarah Wang, Lisa Pugh, Trevor J Ohashi, Pamela S Siu, Lillian L De Carvalho, Daniel D An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors |
title | An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors |
title_full | An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors |
title_fullStr | An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors |
title_full_unstemmed | An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors |
title_short | An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors |
title_sort | open-label, phase ii multicohort study of an oral hypomethylating agent cc-486 and durvalumab in advanced solid tumors |
topic | Clinical/Translational Cancer Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406114/ https://www.ncbi.nlm.nih.gov/pubmed/32753546 http://dx.doi.org/10.1136/jitc-2020-000883 |
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