Domatinostat is an orally administered small molecule for the treatment of cancer. The compound inhibits the enzymes histone deacetylase (HDAC) 1, 2, and 3, which are believed to play important roles in the regulation of aberrant cancer signaling.
Preclinical studies have shown that domatinostat is able to modulate the tumor microenvironment to make it more susceptible to anti-tumor inflammatory processes and as such domatinostat is potentially an excellent candidate for combination with checkpoint inhibitors that enhance the body’s immune response.
Clinical development profile
Domatinostat has been evaluated in a Phase I clinical trial TOPAS in 24 heavily pre-treated patients with different types of blood cancer. Domatinostat was well tolerated with few and/or manageable adverse events. Positive signs of anti-tumor efficacy were observed with one complete remission for 28 months and one partial responder for 8 months. Findings also exhibited disease control in 83% of the patients and long-term stabilization in 50% of patients.
In addition to its therapeutic potential in cancer monotherapy, 4SC is evaluating domatinostat’s capacity as a partner in combination therapies, specifically in the immuno-oncology area. Toward this end, 4SC initiated the Phase Ib/II study SENSITIZE of domatinostat in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab in patients with advanced-stage melanoma. A second Phase II study (EMERGE) of domatinostat in combination with the anti-PD-L1 checkpoint inhibitor avelumab in patients with advanced-stage microsatellite-stable gastrointestinal cancer is conducted by Prof. David Cunningham of The Royal Marsden NHS Foundation Trust (London, UK).
A multicenter Phase Ib study DONIMI which is testing the combination of domatinostat, nivolumab, and ipilimumab, in high risk stage III melanoma in the neoadjuvant setting is conducted by Prof. Christian Blank, MD, Staff Member at the Department of Medical Oncology, and Group Leader at the Division of Immunology, The Netherlands Cancer Institute, Amsterdam.
4SC is currently preparing two Phase II clinical trials of domatinostat in combination with a checkpoint inhibitor in advanced-stage Merkel cell carcinoma either in first or in second line. Collaboration partners of 4SC are preparing two additional studies of domatinostat in different combinations and treatment lines in melanoma.
One of the most promising therapeutic concepts in oncology drug development is the modification of chromatin. Domatinostat inhibits the enzymes histone deacetylase (HDAC) 1, 2, and 3.
Preclinical experiments have demonstrated that domatinostat has the ability to modulate the tumor microenvironment resulting in immunologically advantageous cellular differentiation patterns – for example, by increasing favorable populations of immune cells in the tumor. Specifically, domatinostat can drive anti-tumor immunity by increasing the expression of tumor-associated antigens (TAAs) and immunomodulatory molecules in cancer cell lines. And in animal models, the infiltration of CD8 positive cytotoxic T cells into the tumor was enhanced and the presence of myeloid-derived suppressor cells (MDSCs) was reduced. Importantly, the combination of domatinostat with checkpoint inhibitors had additive effects on tumor growth inhibition presumably due to a domatinostat-mediated shift in the tumor microenvironment resulting in anti-tumor immunity.
The immune modulating effects of domatinostat have been shown to contribute to the anti-tumor activity of checkpoint inhibitors and as such, domatinostat has unique characteristics as a therapeutic partner in malignancies where the anti-tumoral T-cell response plays a role.