Phase 1/2 precision medicine study of the next-generation BRAF inhibitor PLX8394.
2018; Lippincott Williams & Wilkins; Volume: 36; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2018.36.15_suppl.2583
ISSN1527-7755
AutoresFilip Janků, Ulka N. Vaishampayan, Vivek Khemka, Minny Bhatty, Eric J. Sherman, Jessica J. Tao, Jonathan Whisenant, David S. Hong, Nam Q. Bui, Shivaani Kummar, Lynn G. Feun, Aparna R. Parikh, Chao Zhang, Glenn Michelson, Eric S. Martin, Rafe Shellooe, Paul Severson, Michael Pelayo, David A. Karlin, Sunil Sharma,
Tópico(s)Computational Drug Discovery Methods
Resumo2583 Background: First-generation BRAF inhibitors (BRAFi) show high response rates and prolonged survival in some BRAFV600-mutant cancers; however, paradoxical activation of the RAF/MEK/ERK pathway promotes resistance and development of skin malignancies. PLX8394 is a next-generation, orally available small-molecule BRAFi that does not induce the RAF/MEK/ERK paradoxical activation and blocks signaling from both monomeric BRAFV600 and dimeric BRAFnon-V600 protein. Methods: This is a phase 1/2 study of PLX8394 and cobicistat (cstat,150mg), a CYP3A4 inhibitor used to enhance PLX8394 exposure, to determine the safety, tolerability in subjects with refractory solid tumors (phase 1) and RECIST response rate in BRAFV600 and dimer-dependent, RAS-independent BRAFnon-V600 mutant patients (phase 2). A hot-melt extrusion (HME) formulation of PLX8394 was used for this study. Results are reported as of January 8, 2018. Results: Phase 1: The RP2D was 900mg BID + cstat (Proc AACR-NCI-EORTC 2017, abst B176). A single DLT of reversible grade (G) 3 transaminitis occurred in a subject treated with PLX8394 900mg BID + cstat. Cstat co-administration resulted in a 2-3-fold increase in PLX8394 systemic exposure. Of 13 evaluable BRAFV600-mutated subjects, 3 (23%) achieved partial responses [colorectal cancer (42%), glioma (65%); both BRAFi naïve, and ovarian cancer (62%) previously treated with 3 lines of BRAF/MEKi]. Phase 2: Of 18 patients enrolled, 13 had BRAFV600 mutation [melanoma (n = 5), colorectal (n = 4), glioblastoma (n = 2), thyroid (n = 2)] and 5 BRAFnon-V600 mutation [pancreatic (n = 2), and prostate, thyroid, and colorectal (each n = 1)]. No prior MAPK pathway inhibitors were permitted for non-melanoma subjects. G≥3 AEs included G3 transaminitis and hyperbilirubinemia in one patient. Of 10 evaluable patients, 3 (30%, all with BRAFV600 mutations) had stable disease (+7%, -10%, -14%, respectively). Efficacy and exploratory biomarker analysis including transcriptome and ctDNA analysis is on-going. Conclusions: PLX8394 + cstat has been well tolerated and shows promising activity in refractory solid tumors with BRAF mutations. This work was sponsored by Plexxikon Inc. Clinical trial information: NCT02428712.
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