Cmax

Neutropenia

Gene

Quantum mechanics

Phase (matter)

Methyltransferase

Amino acid

Adverse effect

Biology

Dosing

Pharmacokinetics

Arginine

Response Evaluation Criteria in Solid Tumors

Biochemistry

Anemia

Phases of clinical research

Meteor (satellite)

Physics

Pharmacodynamics

Toxicity

Astronomy

Methylation

Internal medicine

Pharmacology

Dysgeusia

Tolerability

Nausea

Oncology

Medicine

Protein arginine methyltransferase 5

Gastroenterology

Annals of Oncology

Background null 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. null null null Methods null 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). null null null Results null 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. null null null Conclusions null 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. null null null Clinical trial identification null NCT02783300. null null null Legal entity responsible for the study null GlaxoSmithKline. null null null Funding null GlaxoSmithKline. null null null Disclosure null L.L. Siu: Advisory / Consultancy: Merck (compensated), Pfizer (compensated), Celgene (compensated), AstraZeneca/Medimmune (compensated), Morphosys (compensated), Roche (compensated), GeneSeeq (compensated), Loxo (compensated), Oncorus (compensated), Symphogen (compensated), Seattle Geneti; Research grant / Funding (institution): Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks; Shareholder / Stockholder / Stock options, Spouse: agios. D.W. Rasco: Research grant / Funding (institution): gsk. S. Postel Vinay: Research grant / Funding (institution): Boehringer Ingelheim, Roche and Merck KGaA; Advisory / Consultancy: Merck KGaA; Travel / Accommodation / Expenses: AstraZeneca; Leadership role, Principal/sub-investigator of clinical trials: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol. P. Martin Romano: Research grant / Funding (institution): AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-remunerated activity/ies, Drug supplied: AstraZeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche; Non-remunerated activity/ies, Courses, trainings for: AstraZeneca, Roche. J.L. Egger: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. S.A. Gorman: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. R. Parasrampuria: Full / Part-time employment: GlaxoSmithKline. K. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. B.E. Kremer: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. M.M. Gounder: Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self): Epizyme, Tracon, Amgen, Daiichi Sankyo, Springwork Therapeutics, Bayer, Karyopharm. All other authors have declared no conflicts of interest.

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