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Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

BACKGROUND: Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy. OBJECTIVE: This phase 1b trial investigated the safety, maximum tolerated dose (MTD), recommended phase II dose, pharmacokinetics, tumor response, fluorodeoxyglucose positron emission tomography (F...

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Autores principales: Ramanathan, Ramesh K., Von Hoff, Daniel D., Eskens, Ferry, Blumenschein, George, Richards, Donald, Genvresse, Isabelle, Reschke, Susanne, Granvil, Camille, Skubala, Adam, Peña, Carol, Mross, Klaus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591420/
https://www.ncbi.nlm.nih.gov/pubmed/32314268
http://dx.doi.org/10.1007/s11523-020-00714-0
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author Ramanathan, Ramesh K.
Von Hoff, Daniel D.
Eskens, Ferry
Blumenschein, George
Richards, Donald
Genvresse, Isabelle
Reschke, Susanne
Granvil, Camille
Skubala, Adam
Peña, Carol
Mross, Klaus
author_facet Ramanathan, Ramesh K.
Von Hoff, Daniel D.
Eskens, Ferry
Blumenschein, George
Richards, Donald
Genvresse, Isabelle
Reschke, Susanne
Granvil, Camille
Skubala, Adam
Peña, Carol
Mross, Klaus
author_sort Ramanathan, Ramesh K.
collection PubMed
description BACKGROUND: Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy. OBJECTIVE: This phase 1b trial investigated the safety, maximum tolerated dose (MTD), recommended phase II dose, pharmacokinetics, tumor response, fluorodeoxyglucose positron emission tomography (FDG-PET) pharmacodynamics, and biomarker explorations for the combination of pan-PI3K inhibitor copanlisib and allosteric MEK inhibitor refametinib in patients with advanced solid tumors. PATIENTS AND METHODS: This was an adaptive trial with eight dose cohorts combining dose escalation and varying schedules in repeated 28-day cycles. Patients received copanlisib (0.2–0.8 mg/kg intravenously) intermittently (days 1, 8, 15) or weekly (days 1, 8, 15, 22) each cycle, and refametinib (30–50 mg twice daily orally) continuously or 4 days on/3 days off. Patients with KRAS, NRAS, BRAF, or PI3KCA mutations were eligible for the expansion cohort. RESULTS: In the dose-escalation (n = 49) and expansion (n = 15) cohorts, the most common treatment-emergent adverse events included diarrhea (59.4%), nausea, acneiform rash, and fatigue (51.6% each). Dose-limiting toxicities included oral mucositis (n = 4), increased alanine aminotransferase/aspartate aminotransferase (n = 3), acneiform rash, hypertension (n = 2 each), and diarrhea (n = 1). MTD was copanlisib 0.4 mg/kg weekly and refametinib 30 mg twice daily. No pharmacokinetic interactions were identified. Decreased tumor FDG uptake and MEK-ERK signaling inhibition were demonstrated during treatment. Best response was stable disease (n = 21); median treatment duration was 6 weeks. CONCLUSIONS: Despite sound rationale and demonstrable pharmacodynamic tumor activity in relevant tumor populations, a dose and schedule could not be identified for this drug combination that were both tolerable and offered clear efficacy in the population assessed. CLINICALTRIALS.GOV IDENTIFIER: NCT01392521. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11523-020-00714-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-75914202020-10-29 Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer Ramanathan, Ramesh K. Von Hoff, Daniel D. Eskens, Ferry Blumenschein, George Richards, Donald Genvresse, Isabelle Reschke, Susanne Granvil, Camille Skubala, Adam Peña, Carol Mross, Klaus Target Oncol Original Research Article BACKGROUND: Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy. OBJECTIVE: This phase 1b trial investigated the safety, maximum tolerated dose (MTD), recommended phase II dose, pharmacokinetics, tumor response, fluorodeoxyglucose positron emission tomography (FDG-PET) pharmacodynamics, and biomarker explorations for the combination of pan-PI3K inhibitor copanlisib and allosteric MEK inhibitor refametinib in patients with advanced solid tumors. PATIENTS AND METHODS: This was an adaptive trial with eight dose cohorts combining dose escalation and varying schedules in repeated 28-day cycles. Patients received copanlisib (0.2–0.8 mg/kg intravenously) intermittently (days 1, 8, 15) or weekly (days 1, 8, 15, 22) each cycle, and refametinib (30–50 mg twice daily orally) continuously or 4 days on/3 days off. Patients with KRAS, NRAS, BRAF, or PI3KCA mutations were eligible for the expansion cohort. RESULTS: In the dose-escalation (n = 49) and expansion (n = 15) cohorts, the most common treatment-emergent adverse events included diarrhea (59.4%), nausea, acneiform rash, and fatigue (51.6% each). Dose-limiting toxicities included oral mucositis (n = 4), increased alanine aminotransferase/aspartate aminotransferase (n = 3), acneiform rash, hypertension (n = 2 each), and diarrhea (n = 1). MTD was copanlisib 0.4 mg/kg weekly and refametinib 30 mg twice daily. No pharmacokinetic interactions were identified. Decreased tumor FDG uptake and MEK-ERK signaling inhibition were demonstrated during treatment. Best response was stable disease (n = 21); median treatment duration was 6 weeks. CONCLUSIONS: Despite sound rationale and demonstrable pharmacodynamic tumor activity in relevant tumor populations, a dose and schedule could not be identified for this drug combination that were both tolerable and offered clear efficacy in the population assessed. CLINICALTRIALS.GOV IDENTIFIER: NCT01392521. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11523-020-00714-0) contains supplementary material, which is available to authorized users. Springer International Publishing 2020-10-27 2020 /pmc/articles/PMC7591420/ /pubmed/32314268 http://dx.doi.org/10.1007/s11523-020-00714-0 Text en © The Author(s) 2020, corrected publication 2020 Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial 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-nc/4.0/.
spellingShingle Original Research Article
Ramanathan, Ramesh K.
Von Hoff, Daniel D.
Eskens, Ferry
Blumenschein, George
Richards, Donald
Genvresse, Isabelle
Reschke, Susanne
Granvil, Camille
Skubala, Adam
Peña, Carol
Mross, Klaus
Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer
title Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer
title_full Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer
title_fullStr Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer
title_full_unstemmed Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer
title_short Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer
title_sort phase ib trial of the pi3k inhibitor copanlisib combined with the allosteric mek inhibitor refametinib in patients with advanced cancer
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591420/
https://www.ncbi.nlm.nih.gov/pubmed/32314268
http://dx.doi.org/10.1007/s11523-020-00714-0
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