Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer

• DOI: 10.1007/s10637-014-0192-4
• Publication Date: 2014-12-22T02:10:28Z
• Authors: Jordi Rodón; Michael Carducci; Juan M. Sepulveda...; Analía Azaro; Emiliano Calvo; Joan Seoane; Irene Braña; Elisabet Sicart; Ivelina Gueorguieva; Ann Cleverly; N. Sokalingum Pillay; Durisala Desaiah; Shawn T. Estrem; Luis Paz-Ares; Matthias Holdhoff; Jaishri Blakeley; Michael M. Lahn; Jose Baselga
• Keywords: Pharmacodynamics

Summary Purpose Transforming growth factor-beta (TGF-β) signaling plays a key role in epithelial-mesenchymal transition (EMT) of tumors, including malignant glioma. Small molecule inhibitors (SMI) blocking TGF-β reverse EMT and arrest tumor progression. Several SMIs were developed, but currently only LY2157299 monohydrate (galunisertib) was advanced to clinical investigation. Design The first-in-human dose study had three parts (Part A, escalation, n = 39; Part B, safety combination with lomustine, 26; C, relative bioavailability study, 14). Results A preclinical pharmacokinetic/pharmacodynamic (PK/PD) model predicted therapeutic window up 300 mg/day confirmed after continuous PK/PD. PK not affected by co-medications such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors. Changes pSMAD2 levels peripheral blood mononuclear cells associated exposure indicating target-related pharmacological activity galunisertib. Twelve (12/79; 15 %) patients refractory/relapsed glioma durable stable disease (SD) for 6 more cycles, partial responses (PR), complete (CR). These benefit high plasma baseline MDC/CCL22 low protein expression their tumors. Of the 5 IDH1/2 mutation, 4 defined CR/PR SD ≥6 cycles. Galunisertib favorable toxicity profile no cardiac adverse events. Conclusion Based on PK, PD, biomarker evaluations, intermittent administration galunisertib at is safe future