title: Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer.
abstract: 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.
authors.affiliation: Medical Oncology, Vall d'Hebron University Hospital and Universitat Autonoma de Barcelona, Barcelona, Spain, jrodon@vhio.net.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodón
authors.forename: Michael
authors.initials: M
authors.lastname: Carducci
authors.forename: Juan M
authors.initials: JM
authors.lastname: Sepulveda-Sánchez
authors.forename: Analía
authors.initials: A
authors.lastname: Azaro
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.forename: Joan
authors.initials: J
authors.lastname: Seoane
authors.forename: Irene
authors.initials: I
authors.lastname: Braña
authors.forename: Elisabet
authors.initials: E
authors.lastname: Sicart
authors.forename: Ivelina
authors.initials: I
authors.lastname: Gueorguieva
authors.forename: Ann
authors.initials: A
authors.lastname: Cleverly
authors.forename: N Sokalingum
authors.initials: NS
authors.lastname: Pillay
authors.forename: Durisala
authors.initials: D
authors.lastname: Desaiah
authors.forename: Shawn T
authors.initials: ST
authors.lastname: Estrem
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.forename: Matthias
authors.initials: M
authors.lastname: Holdhoff
authors.forename: Jaishri
authors.initials: J
authors.lastname: Blakeley
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lahn
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
mesh_terms: D051722:ADAM Proteins; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000494:pharmacology; D019540:Area Under Curve; D001772:Blood Cell Count; D054422:Chemokine CCL22; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008130:Lomustine; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D011720:Pyrazoles; D011804:Quinolines; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D051899:Smad2 Protein / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins
chemical_list: D000927:Anticonvulsants; D054422:Chemokine CCL22; D054328:Proton Pump Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D025521:Tumor Suppressor Proteins; C557799:LY-2157299; D008130:Lomustine; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D051722:ADAM Proteins; C090222:ADAM11 protein, human