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

Alexander N Shoushtari,Shahnaz Singh-Kandah,Shaheer Khan,Nicolas Acquavella,Richard D Carvajal,Alexandra Nesson,Kelly Abbate,Lynn Feun,Serge Cremers,Tiffany Negri,Grazia Ambrosini,Kimberly Komatsubara,Elgilda Musi,Shing Lee,Gary K Schwartz

doi:10.3390/cancers13215504

Abstract

Simple SummaryUveal melanoma is a rare subset of melanoma characterized by the presence of early initiating GNAQ/11 mutations, with downstream activation of several pathways which are thought to contribute to cell growth. Based on clinical and preclinical data supporting targeting of protein kinase C (PKC) and the phosphatidylinositol 3-kinase (PI3K) pathway, we conducted a phase Ib study to assess the safety of combined sotrastaurin, a PKC inhibitor, and alpelisib, a PI3K inhibitor. We found that sotrastaurin and alpelisib can be safely administered, however there was no evidence of clinical efficacy.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.

Highlights

Uveal melanoma is a rare subtype of melanoma that accounts for approximately 3–5% of all melanomas [1,2]
We previously demonstrated the induction of phospho-AKT with exposure to sotrastaurin in preclinical uveal melanoma models, suggesting upregulation of the PI3K/AKT pathway as a mechanism of resistance to protein kinase C (PKC) inhibition [13]
The primary objective of this study was to determine the maximum tolerated dose (MTD) for the combination of sotrastaurin and alpelisib in patients with metastatic uveal melanoma or other melanoma subtypes harboring a mutation in GNAQ or GNA11

Summary

Introduction

Uveal melanoma is a rare subtype of melanoma that accounts for approximately 3–5% of all melanomas [1,2]. Treatment approaches that have demonstrated efficacy in advanced cutaneous melanoma have been less effective in uveal melanoma due to its distinct biology and clinical behavior. The recently reported data of tebentafusp, a bifunctional fusion protein targeting gp100 in an HLA-restricted fashion, as well as CD3, in HLA-A0201 positive patients with metastatic uveal melanoma demonstrates that immune-based treatment approaches meaningfully impact overall survival, to date, no molecularly targeted approach has been found to do the same in a randomized controlled setting [3,4]. Uveal melanomas generally harbor early initiating mutations in genes encoding for the G-α-protein-subunits, GNAQ or GNA11, with the remainder of cases harboring other alterations, such as mutations in CYSLTR2 or PLCB4, which functionally activate the G-α pathway [5,6]. A number of preclinical studies have demonstrated significant anti-tumor effects of inhibition of various PKC isoforms in uveal melanoma models [10,11]

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