Behind the Development of Ivaltinostat in Metastatic PDAC

Mohamad Adham Salkeni, MD, FRCPC, medical oncologist and clinical trial investigator at the Virginia Cancer Specialists Research Institute, discusses the mechanism of action of ivaltinostat and what rationalizes its use in combination with capecitabine as a potential treatment option for patients with metastatic pancreatic adenocarcinoma (PDAC).

Ivaltinostat is a histone deacetylase (HDAC) inhibitor. The agent is currently under investigation in a phase 1b/2, dose-escalation, randomized, multicenter study (NCT05249101) where it is being studied in combination with capecitabine vs capecitabine monotherapy in patients with metastatic PDAC whose disease has not progressed on a first-line fluoropyrimidine-based chemotherapy.

Transcription

0:10 | Ivaltinostat is an HDAC inhibitor. That means it works at the epigenetic level. Epigenetics is machinery of post-translational modification of gene expression. It's been found that in some cancers, epigenetic silencing of a tumor suppressor gene plays a role in oncogenesis. By inhibiting that process, we hope to achieve success in halting tumor growth and reducing risk of progression. Ivaltinostat is an HDAC inhibitor [and] HDAC is an enzyme that typically works to silence those tumor suppressor genes. By inhibiting that sort of enzyme, it makes the histone more accessible and the DNA more accessible to translation, and allows suppressed genes to regain activity and increase translation and transcription.

1:22 | It is a novel drug, it has been granted an orphan drug designation by the FDA for pancreatic adenocarcinoma. In preclinical models, it has been shown to reduce tumor growth and was found to be synergistic with other chemotherapies, particularly with capecitabine. There was a small early phase trial of ivaltinostat which demonstrated good clinical activity [when combined with gemcitabine and erlotinib [Tarceva]]. Based on that encouraging preclinical and early phase clinical data, the trial was designed so that it may be an additional therapy for patients who have advanced or metastatic pancreatic adenocarcinoma.