Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer
Rodón, Jordi (Hospital Universitari Vall d'Hebron)
Carducci, Michael (Johns Hopkins Kimmel Cancer Center)
Sepulveda-Sánchez, Juan M. (Hospital Universitario 12 de Octubre (Madrid))
Azaro, Analía (Hospital Universitari Vall d'Hebron)
Calvo, Emiliano (Centro Integral Oncológico Clara Campal-HM CIOCC (Madrid, Espanya))
Seoane Suárez, Joan (Hospital Universitari Vall d'Hebron)
Braña, Irene (Hospital Universitari Vall d'Hebron)
Sicart, Elisabet (Hospital Universitari Vall d'Hebron)
Gueorguieva, Ivelina (Eli Lilly and Company)
Cleverly, Ann (Eli Lilly and Company)
Pillay, N. Sokalingum (Eli Lilly and Company)
Desaiah, Durisala (Eli Lilly and Company)
Estrem, Shawn T. (Eli Lilly and Company)
Paz-Ares, Luis (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Holdhoff, Matthias (Johns Hopkins Kimmel Cancer Center)
Blakeley, Jaishri (Johns Hopkins University)
Lahn, Michael M.. (Eli Lilly and Company)
Baselga Torres, Josep, 1959-2021, (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Data:	2014
Resum:	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 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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	TGF-β inhibitor ; Galunisertib ; First-in-Human Dose ; Glioma ; Pharmacokinetics ; Pharmacodynamics
Publicat a:	Investigational New Drugs, Vol. 33 (december 2014) , p. 357-370, ISSN 1573-0646

DOI: 10.1007/s10637-014-0192-4
PMID: 25529192

14 p, 1.9 MB

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