Case Series of Cancer Patients Treated With Galunisertib, a Transforming Growth Factor-Beta Receptor I Kinase Inhibitor in a First-in-Human Dose Study

Abstract

Galunisertib (LY2157299 monohydrate) is a first-in-class small molecule inhibitor (SMI) of the transforming growth factor-beta (TGF-β) signaling pathway. Some adverse events were associated with galunisertib during the first-in-human dose (FHD) study. Among these adverse events (n = 11) were four cases of infection, two cases of thromboembolic events and two cases of thrombocytopenia. In one of the patients with thromboembolic events, an autopsy was also performed to examine possible changes of the aorta. No significant histopathologic changes were observed. Single cases of grade 2 diarrhea (only associated with drug intake), stroke (after resection for relapsed glioma), and pre-existing co-primary tumor (possible colorectal cancer) were observed. Because TGF-β plays an important role in tissue homeostasis and in immune response regulation, the present case series may serve as a future reference for adverse events observed in subsequent clinical trials with galunisertib.

Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway

“…The case was also peer reviewed by an external vascular pathologist who found the changes to be consistent with routine degenerative findings in age-matched patients. 101 …”

Pre-Existing and Acquired Resistance to PARP Inhibitor-Induced Synthetic Lethality

“…This finding suggests potential clinical applications of TGFβR kinase inhibitors in PARPi-mediated interventions against hematopoietic malignancies. In fact, the inhibition of TGFβR kinase by galunisertib, which has been applied in clinical trials of several cancers [ 153 , 154 , 155 , 156 , 157 , 158 ], restored the PARPi sensitivity of leukemia cells in the BMM. Therefore, we postulate that the addition of galunisertib to PARPi treatment should improve the therapeutic outcome.…”