438OMETEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours

Abstract Background PRMT5 is an enzyme that methylates arginines in proteins important for tumor growth and development. GSK3326595 is a potent and selective PRMT5 inhibitor that demonstrates efficacy in multiple tumor models. METEOR-1 is a phase I study to assess the safety, pharmacokinetics (PK),...

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Veröffentlicht in:Annals of oncology 2019-10, Vol.30 (Supplement_5)
Hauptverfasser: Siu, L L, Rasco, D W, Vinay, S Postel, Romano, P Martin, Menis, J, Opdam, F L, Heinhuis, K M, Egger, J L, Gorman, S A, Parasrampuria, R, Wang, K, Kremer, B E, Gounder, M M
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Sprache:eng
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Zusammenfassung:Abstract Background PRMT5 is an enzyme that methylates arginines in proteins important for tumor growth and development. GSK3326595 is a potent and selective PRMT5 inhibitor that demonstrates efficacy in multiple tumor models. METEOR-1 is a phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of GSK3326595 in adults with solid tumors. Methods Eligible participants (pts) were >18 years with advanced or metastatic solid tumors. Pts were enrolled in a modified toxicity probability interval design. Safety, tolerability, PK, PD, and efficacy data were used to identify the recommended phase 2 dose (RP2D). Results Fifty-four pts with a median age of 60 (range 21 – 81) received at least one dose of drug. The most common tumor types were adenoid cystic carcinoma (ACC; n = 14 [26%]), colorectal cancer (n = 9 [17%]), and breast cancer (n = 3 [6%]). Dosing proceeded from 12.5 mg to 600 mg once daily (QD), and from 50 mg to 200 mg twice daily. Median time on treatment was 1.8 months (range 1 day to 18.7 months). Overall, 48 pts (89%) experienced at least one adverse event (AE) that was deemed treatment-related. The most common related AEs were fatigue (n = 21 [39%]), anemia (n = 17 [31%]), nausea (n = 17 [31%]), alopecia (n = 15 [28%]), and dysgeusia (n = 14 [26%]). Grade 3/4 related AEs included anemia (n = 8 [15%]), thrombocytopenia, neutropenia, and fatigue (each n = 4 [7%]). There were no Grade 5 related AEs. Twenty-two pts (41%) had ≥1 dose reduction. GSK3326595 Cmax and AUC were dose-dependent after single and repeat dosing. PD analyses showed robust target engagement, as measured by dimethylated arginine in plasma and tumor samples. Clinical activity was observed in several tumor types, with partial responses in patients with HPV+ cervical cancer (1 response/1 subject) and ACC (3 responses/14 subjects). Durable stable disease was achieved in bladder cancer and other tumors. 400 mg QD was selected as the RP2D. Conclusions This is the first study evaluating a PRMT5 inhibitor. Overall, AEs were common but manageable. Patients with multiple tumor types responded to therapy. Part 2 of the study is open for subjects with predefined solid tumors and non-Hodgkin’s lymphoma. Clinical trial identification NCT02783300. Legal entity responsible for the study GlaxoSmithKline. Funding GlaxoSmithKline. Disclosure L.L. Siu: Advisory / Consultancy: Merck (compensated), Pfizer (compensated), Celgene (compensated), AstraZeneca/Medimmune (c
ISSN:0923-7534
1569-8041
DOI:10.1093/annonc/mdz244