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: Adult; Male; 0301 basic medicine; Maximum Tolerated Dose; Enzyme-Linked Immunosorbent Assay; Protein Serine-Threonine Kinases; Drug Administration Schedule; 03 medical and health sciences; Lomustine; Phase I Studies; Neoplasms; Humans; Pharmacology (medical); Drug Interactions; Aged; Pharmacology; Chemokine CCL22; Dose-Response Relationship, Drug; Middle Aged; Blood Cell Count; 3. Good health; ADAM Proteins; Oncology; Area Under Curve; Leukocytes, Mononuclear; Anticonvulsants; Female

SummaryPurpose 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 signaling 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, dose escalation, n = 39; Part B, safety combination with lomustine, n = 26; Part C, relative bioavailability study, n = 14). Results A preclinical pharmacokinetic/pharmacodynamic (PK/PD) model predicted a therapeutic window up to 300 mg/day and was confirmed in Part A after continuous PK/PD. PK was not affected by co-medications such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors. Changes in pSMAD2 levels in peripheral blood mononuclear cells were associated with exposure indicating target-related pharmacological activity of galunisertib. Twelve (12/79; 15 %) patients with refractory/relapsed malignant glioma had durable stable disease (SD) for 6 or more cycles, partial responses (PR), or complete responses (CR). These patients with clinical benefit had high plasma baseline levels of MDC/CCL22 and low protein expression of pSMAD2 in their tumors. Of the 5 patients with IDH1/2 mutation, 4 patients had a clinical benefit as defined by CR/PR and SD ≥6 cycles. Galunisertib had a favorable toxicity profile and no cardiac adverse events. Conclusion Based on the PK, PD, and biomarker evaluations, the intermittent administration of galunisertib at 300 mg/day is safe for future clinical investigation.