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

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.

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

“…LY2157299, also known as galunisertib, is a selective ATP-mimetic inhibitor of TGF-βRI serine/threonine kinase. It displayed antitumor activity, as well as acceptable tolerability and safety profile in cancer patients with advanced tumors, such as glioma (49)(50)(51). In the in vivo study herein, combined treatment of LY2157299 with GEM significantly reduced CSC subpopulation and tumorigenecity compared with either drug alone.…”

Targeting TGF-β Signaling for Therapeutic Gain

“…However, the data may be consistent with the possibility that the two drugs antagonized each other. It is, however, encouraging that 235 cancer patients have now been treated with galunisertib, yet show no remarkable cardiovascular toxicities despite, in some cases, treatment over 3 years (Rodó n et al 2015a). Moreover, outcomes in glioblastoma are at least as good as standard of care lomustine, and manifest less severe side effects than the latter.…”

Molecular Pathways: Targeting the Microenvironment of Liver Metastases

“…Several phase II clinical trials based on targeting the TGFβ axis are, in fact, currently in progress. For example, the NCT01373164 trial (phase 1/2, completed) is assessing the effect of Galunisertib - an inhibitor of the TGFβ receptor I kinase with a favourable toxicity profile in humans (53) in combination with Gemcitabine on the OS of patients with unresectable metastatic PDAC. In the NCT02423343 trial (phase 1/2, recruiting), the effect of this inhibitor is being evaluated in combination with the PD-1 inhibitor Nivolumab in patients with recurrent hepatocellular carcinoma.…”