[HTML][HTML] Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in …

J Rodón, M Carducci, JM Sepulveda-Sánchez… - Investigational new …, 2015 - Springer
J Rodón, M Carducci, JM Sepulveda-Sánchez, A Azaro, E Calvo, J Seoane, I Braña, E Sicart…
Investigational new drugs, 2015Springer
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 …
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 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.
Springer