Phase 1 Study Of The Novel Pan-Pim Kinase Inhibitor LGH447 In Patients With Relapsed/ Refractory Multiple Myeloma

摘要: Background LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM gene family encodes 3 serine/threonine protein kinases that have roles cell cycle progression survival. In human disease, elevated levels Pim1 Pim2 are associated malignancies, MM showing highest level expression. preclinical studies, majority lines proved sensitive vitro to LGH447-mediated Pim inhibition, exhibiting dose-dependent decrease proliferation. Furthermore, was well tolerated demonstrated significant inhibition tumor growth xenograft mouse models as compared control animals, supporting clinical patients. Methods Patients relapsed/refractory whom no effective options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses single-agent administered orally continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. primary objective estimate maximum dose (MTD) single agent, orally, once daily. Secondary objectives included assessing safety, tolerability, preliminary antimyeloma activity, pharmacokinetic (PK) profiles LGH447. Dose escalation followed Bayesian logistic regression model based dose-limiting toxicities (DLTs) occurring 1. Adverse events (AEs) graded according National Cancer Institute-Common Terminology Criteria Events v4.03. Efficacy assessments made by investigators International Myeloma Working Group (IMWG) uniform response criteria modifications. Following determination MTD LGH447, additional will be an expansion cohort further characterize safety tolerability profile LGH447. Results At data cutoff, 19 been treated at following doses: 70 mg (n = 5), 150 6), 200 4), 250 enrollment ongoing escalation. Median age 66 years (range, 41-75 years). Most (94.7%) presented baseline Eastern Cooperative Oncology performance status 0-1. (73.7%) had received ≥ 2 prior regimens (median 4; range, 1-11), 89.5% bortezomib, 84.2% lenalidomide and/or thalidomide (68.4% 47.4%, respectively). Ten between 150-250 mg, median duration exposure 6 weeks 1-26.6 weeks), 9 discontinued (disease [n 6], AEs 2], withdrawal 1]). There DLT consisting grade thrombocytopenia reported suspected unexpected serious AEs. regardless drug relationship 1/2. common 3/4 (31.6%), anemia (21.1%), neutropenia (15.8%). No deaths occurred study. displayed time-dependent PK 3- 6-fold accumulation from day steady state (day 14). After oral dose, area under curve concentration increased somewhat more than proportion mg. Evidence determined using IMWG criteria, has seen patients, best date being very good partial (VGPR). Conclusion heavily MM, generally exhibited evidence efficacy validating promising therapeutic rationale its updated results presented. Disclosures: Ocio: BMS: Consultancy; Arry-520: Pharmamar: Research Funding; Celgene: Honoraria, Onyx: Consultancy, Novartis: Honoraria. Thomas: Immunomedics: Pharmacyclics: Membership entity’s Board Directors advisory committees; Millenium: Funding. Gunther: Lebovic: Speakers Bureau; Allos/Spectrum: Genentech: Bureau. Kumar: Millennium: Jakubowiak: Honoraria; Song: Employment. Xiang: Hynds: Vanasse: Goh: Jannsen: Gilead: Hospira: committees,