A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma

Uveal melanoma (UM) is a rare subset of melanoma characterized by the presence of early initiating GNAQ/11 mutations, with downstream activation of the PKC, MAPK, and PI3Kα pathways. Activity has been observed with the PKC inhibitors sotrastaurin (AEB071) and darovasertib (IDE196) in patients with U...

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Autores principales:	Alexander N. Shoushtari, Shaheer Khan, Kimberly Komatsubara, Lynn Feun, Nicolas Acquavella, Shahnaz Singh-Kandah, Tiffany Negri, Alexandra Nesson, Kelly Abbate, Serge Cremers, Elgilda Musi, Grazia Ambrosini, Shing Lee, Gary K. Schwartz, Richard D. Carvajal
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	uveal melanoma targeted therapy sotrastaurin alpelisib PKC PI3K Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/ca14021bac2d473688895d4925fe502f
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spelling	oai:doaj.org-article:ca14021bac2d473688895d4925fe502f2021-11-11T15:33:46ZA Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma10.3390/cancers132155042072-6694https://doaj.org/article/ca14021bac2d473688895d4925fe502f2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5504https://doaj.org/toc/2072-6694Uveal melanoma (UM) is a rare subset of melanoma characterized by the presence of early initiating GNAQ/11 mutations, with downstream activation of the PKC, MAPK, and PI3Kα pathways. Activity has been observed with the PKC inhibitors sotrastaurin (AEB071) and darovasertib (IDE196) in patients with UM. Inhibition of the PI3K pathway enhances PKC inhibition in in vivo models. We therefore conducted a phase Ib study of sotrastaurin in combination with the PI3Kα inhibitor alpelisib to identify a tolerable regimen that may enhance the activity of PKC inhibition alone. Patients with metastatic uveal melanoma (n = 24) or GNAQ/11 mutant cutaneous melanoma (n = 1) were enrolled on escalating dose levels of sotrastaurin (100–400 mg BID) and alpelisib (200–350 mg QD). The primary objective was to identify the maximum tolerated dose (MTD) of these agents when administered in combination. Treatment-related adverse events (AE) occurred in 86% (any grade) and 29% (Grade 3). No Grade 4–5-related AEs occurred. Dose Level 4 (sotrastaurin 200 mg BID and alpelisib 350 mg QD) was identified as the maximum tolerated dose. Pharmacokinetic analysis demonstrated increasing concentration levels with increasing doses of sotrastaurin and alpelisib, without evidence of interaction between agents. Pharmacodynamic assessment of pMARCKS and pAKT protein expression with drug exposure suggested modest target inhibition that did not correlate with clinical response. No objective responses were observed, and median progression-free survival was 8 weeks (range, 3–51 weeks). Although a tolerable dose of sotrastaurin and alpelisib was identified with pharmacodynamic evidence of target inhibition and without evidence of a corresponding immunosuppressive effect, limited clinical activity was observed.Alexander N. ShoushtariShaheer KhanKimberly KomatsubaraLynn FeunNicolas AcquavellaShahnaz Singh-KandahTiffany NegriAlexandra NessonKelly AbbateSerge CremersElgilda MusiGrazia AmbrosiniShing LeeGary K. SchwartzRichard D. CarvajalMDPI AGarticleuveal melanomatargeted therapysotrastaurinalpelisibPKCPI3KNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5504, p 5504 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	uveal melanoma targeted therapy sotrastaurin alpelisib PKC PI3K Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	uveal melanoma targeted therapy sotrastaurin alpelisib PKC PI3K Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Alexander N. Shoushtari Shaheer Khan Kimberly Komatsubara Lynn Feun Nicolas Acquavella Shahnaz Singh-Kandah Tiffany Negri Alexandra Nesson Kelly Abbate Serge Cremers Elgilda Musi Grazia Ambrosini Shing Lee Gary K. Schwartz Richard D. Carvajal A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma
description	Uveal melanoma (UM) is a rare subset of melanoma characterized by the presence of early initiating GNAQ/11 mutations, with downstream activation of the PKC, MAPK, and PI3Kα pathways. Activity has been observed with the PKC inhibitors sotrastaurin (AEB071) and darovasertib (IDE196) in patients with UM. Inhibition of the PI3K pathway enhances PKC inhibition in in vivo models. We therefore conducted a phase Ib study of sotrastaurin in combination with the PI3Kα inhibitor alpelisib to identify a tolerable regimen that may enhance the activity of PKC inhibition alone. Patients with metastatic uveal melanoma (n = 24) or GNAQ/11 mutant cutaneous melanoma (n = 1) were enrolled on escalating dose levels of sotrastaurin (100–400 mg BID) and alpelisib (200–350 mg QD). The primary objective was to identify the maximum tolerated dose (MTD) of these agents when administered in combination. Treatment-related adverse events (AE) occurred in 86% (any grade) and 29% (Grade 3). No Grade 4–5-related AEs occurred. Dose Level 4 (sotrastaurin 200 mg BID and alpelisib 350 mg QD) was identified as the maximum tolerated dose. Pharmacokinetic analysis demonstrated increasing concentration levels with increasing doses of sotrastaurin and alpelisib, without evidence of interaction between agents. Pharmacodynamic assessment of pMARCKS and pAKT protein expression with drug exposure suggested modest target inhibition that did not correlate with clinical response. No objective responses were observed, and median progression-free survival was 8 weeks (range, 3–51 weeks). Although a tolerable dose of sotrastaurin and alpelisib was identified with pharmacodynamic evidence of target inhibition and without evidence of a corresponding immunosuppressive effect, limited clinical activity was observed.
format	article
author	Alexander N. Shoushtari Shaheer Khan Kimberly Komatsubara Lynn Feun Nicolas Acquavella Shahnaz Singh-Kandah Tiffany Negri Alexandra Nesson Kelly Abbate Serge Cremers Elgilda Musi Grazia Ambrosini Shing Lee Gary K. Schwartz Richard D. Carvajal
author_facet	Alexander N. Shoushtari Shaheer Khan Kimberly Komatsubara Lynn Feun Nicolas Acquavella Shahnaz Singh-Kandah Tiffany Negri Alexandra Nesson Kelly Abbate Serge Cremers Elgilda Musi Grazia Ambrosini Shing Lee Gary K. Schwartz Richard D. Carvajal
author_sort	Alexander N. Shoushtari
title	A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma
title_short	A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma
title_full	A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma
title_fullStr	A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma
title_full_unstemmed	A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma
title_sort	phase ib study of sotrastaurin, a pkc inhibitor, and alpelisib, a pi3kα inhibitor, in patients with metastatic uveal melanoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ca14021bac2d473688895d4925fe502f
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A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma

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