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Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma

BACKGROUND: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. METHODS: We employed a 3+3 dose es...

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Autores principales: Harvey, R. Donald, Carthon, Bradley C., Lewis, Colleen, Hossain, Mohammad S., Zhang, Chao, Chen, Zhengjia, Harris, Wayne B., Alese, Olatunji B., Shaib, Walid, Bilen, Mehmet A., Lawson, David H., Wu, Christina, Steuer, Conor E., El-Rayes, Bassel F., Khuri, Fadlo R., Lonial, Sagar, Waller, Edmund K., Ramalingam, Suresh S., Owonikoko, Taofeek K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553949/
https://www.ncbi.nlm.nih.gov/pubmed/32704173
http://dx.doi.org/10.1038/s41416-020-0988-2
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author Harvey, R. Donald
Carthon, Bradley C.
Lewis, Colleen
Hossain, Mohammad S.
Zhang, Chao
Chen, Zhengjia
Harris, Wayne B.
Alese, Olatunji B.
Shaib, Walid
Bilen, Mehmet A.
Lawson, David H.
Wu, Christina
Steuer, Conor E.
El-Rayes, Bassel F.
Khuri, Fadlo R.
Lonial, Sagar
Waller, Edmund K.
Ramalingam, Suresh S.
Owonikoko, Taofeek K.
author_facet Harvey, R. Donald
Carthon, Bradley C.
Lewis, Colleen
Hossain, Mohammad S.
Zhang, Chao
Chen, Zhengjia
Harris, Wayne B.
Alese, Olatunji B.
Shaib, Walid
Bilen, Mehmet A.
Lawson, David H.
Wu, Christina
Steuer, Conor E.
El-Rayes, Bassel F.
Khuri, Fadlo R.
Lonial, Sagar
Waller, Edmund K.
Ramalingam, Suresh S.
Owonikoko, Taofeek K.
author_sort Harvey, R. Donald
collection PubMed
description BACKGROUND: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. METHODS: We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. RESULTS: The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. CONCLUSIONS: The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. CLINICAL TRIAL REGISTRATION: NCT01218555
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spelling pubmed-75539492021-07-24 Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma Harvey, R. Donald Carthon, Bradley C. Lewis, Colleen Hossain, Mohammad S. Zhang, Chao Chen, Zhengjia Harris, Wayne B. Alese, Olatunji B. Shaib, Walid Bilen, Mehmet A. Lawson, David H. Wu, Christina Steuer, Conor E. El-Rayes, Bassel F. Khuri, Fadlo R. Lonial, Sagar Waller, Edmund K. Ramalingam, Suresh S. Owonikoko, Taofeek K. Br J Cancer Article BACKGROUND: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. METHODS: We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. RESULTS: The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. CONCLUSIONS: The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. CLINICAL TRIAL REGISTRATION: NCT01218555 Nature Publishing Group UK 2020-07-24 2020-10-13 /pmc/articles/PMC7553949/ /pubmed/32704173 http://dx.doi.org/10.1038/s41416-020-0988-2 Text en © The Author(s), under exclusive licence to Cancer Research UK 2020 https://creativecommons.org/licenses/by/4.0/Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
spellingShingle Article
Harvey, R. Donald
Carthon, Bradley C.
Lewis, Colleen
Hossain, Mohammad S.
Zhang, Chao
Chen, Zhengjia
Harris, Wayne B.
Alese, Olatunji B.
Shaib, Walid
Bilen, Mehmet A.
Lawson, David H.
Wu, Christina
Steuer, Conor E.
El-Rayes, Bassel F.
Khuri, Fadlo R.
Lonial, Sagar
Waller, Edmund K.
Ramalingam, Suresh S.
Owonikoko, Taofeek K.
Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma
title Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma
title_full Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma
title_fullStr Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma
title_full_unstemmed Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma
title_short Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma
title_sort phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553949/
https://www.ncbi.nlm.nih.gov/pubmed/32704173
http://dx.doi.org/10.1038/s41416-020-0988-2
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