4SC AG: 4SC & NKI Collaborate on Clinical Evaluation of Domatinostat in the Neoadjuvant Setting in Urothelial Cancer

40 patient Phase Ib study to start in Q3, 2021

Planegg-Martinsried (pta009/17.06.2021/07:30 UTC+2)

4SC today announced the initiation of a second clinical collaboration with the Netherlands Cancer Institute (NKI) on a phase Ib trial in Stage II-III Resectable Urothelial Cancer to explore biomarker-driven pre-operative administration of Domatinostat, Nivolumab and Ipilimumab – TURANDOT.

Neoadjuvant immunotherapy is currently one of the most promising areas of clinical development in solid tumor oncology with potential to improve treatment options for patients. The ultimate goal for neoadjuvant therapy is to prevent relapses after definitive surgery and – depending on the indication – consecutive adjuvant therapy, to promote durable disease-free survival. 

Domatinostat´s immune-modulating capabilities have been demonstrated both preclinically and clinically and led to the interest of the principle investigator, Dr. Michiel van der Heijden (NKI), who is one of the pioneers of neoadjuvant treatment approaches in urothelial carcinoma, to propose and conduct the neoadjuvant TURANDOT study supported by 4SC.

The Investigator-sponsored TURANDOT study investigates the neoadjuvant combination of domatinostat, ipilimumab and nivolumab in stage II-III resectable urothelial carcinoma patients. The primary objective of the phase Ib is to demonstrate feasibility and safety of the respective combination(s) in up to 40 patients. Secondary, pathological response and relapse-free survival will be investigated for clinical activity purposes and both will determine any consecutive clinical development activities in this indication and setting.  Importantly, in urothelial carcinoma, the predictive value of analyzing non-vital tumor cells taken at time of surgery has been demonstrated and the surrogate endpoint of complete pathological response is already widely accepted.

Dr. Michiel S. van der Heijden ("Principal Investigator") stated: 

"Domatinostat and its immune-modulating features in cancer, which were shown preclinically, has aroused my great interest to propose and now conduct the TURANDOT study as the sponsor and principal investigator. Immunotherapy has already demonstrated promising impact as an investigational neoadjuvant treatment in urothelial carcinoma to achieve complete pathological remissions of the tumor. However, there is still a long way to go for clinical implementation. Thus, we have proposed combination approaches of domatinostat with immune checkpoint inhibitors, to increase the rate of patients achieving a pathological complete response at surgery and eventually improve relapse-free survival. The TURANDOT study will initially test for feasibility and safety of pre-operative domatinostat in combination with nivolumab and ipilimumab in urothelial cancer."         

Jason Loveridge, Ph.D., CEO of 4SC commented: "In TURANDOT we are expanding our ongoing relationship with the NKI and our interest in the neoadjuvant setting as a place where domatinostat can potentially provide significant clinical benefit in combination with checkpoint inhibition.  Urothelial carcinoma is a new indication for domatinostat and one where there is  significant room for improvement on current immunotherapy approaches, and where we can generate data that is complementary to our other studies in melanoma, merkel cell carcinoma and micro-satellite stable gastrointestinal cancer." 

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Further information

About 4SC

4SC AG is a clinical-stage biopharmaceutical company developing small-molecule drugs that target key indications in cancer with high unmet medical needs. 4SC’s pipeline is protected by a comprehensive portfolio of patents and currently comprises two drug candidates in clinical development: resminostat and domatinostat.

4SC aims to generate future growth and enhance its enterprise value by entering into partnerships with pharmaceutical and biotech companies and/or the eventual marketing and sales of approved drugs in select territories by 4SC itself.

4SC is headquartered in Planegg-Martinsried near Munich, Germany. The Company had 48 employees as of 31 March 2021 and is listed on the Prime Standard of the Frankfurt Stock Exchange (FSE Prime Standard: VSC; ISIN: DE000A14KL72).

About domatinostat

Domatinostat is an orally administered small molecule class I selective HDAC inhibitor. It strengthens the body’s own anti-tumor immune response.  Domatinostat modulates the tumor and tumor microenvironment making it more visible to the immune system, susceptible to concomitant checkpoint inhibition, and facilitating the infiltration of immune cells into the tumor (Bretz et al., 2019).

Domatinostat has been investigated in a Phase I study in 24 heavily pretreated patients with several types of advanced hematologic cancers and was well tolerated (Tresckow et al., 2019). Signs of single-agent anti-tumor efficacy were observed; with one complete remission and one partial responder.

Besides its therapeutic potential as monotherapy, 4SC is focusing its development activities for domatinostat on evaluating domatinostat’s capacity as a partner in combination therapies, specifically in the immuno-oncology area. In this respect, 4SC initiated a Phase Ib/II study of domatinostat in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab in patients with advanced-stage melanoma from which initial data was presented at ESMO 2019 (Hassel et al., abstract #5545) and at ASCO 2021 (Hassel et al., abstract #9545). 

A second Phase II study of domatinostat in combination with the anti-PD-L1 checkpoint inhibitor avelumab in patients with advanced-stage microsatellite-stable gastrointestinal cancer is currently being conducted by Prof. David Cunningham at The Royal Marsden NHS Foundation Trust in London, UK.  

In addition, in a collaboration with the Netherlands Cancer Institute in Amsterdam, the DONIMI Study, a multicenter, investigator-sponsored phase Ib study, is conducted testing the combination of domatinostat, nivolumab and ipilimumab in high risk stage III melanoma in the neoadjuvant setting.

To advance this development program, 4SC has also signed a drug supply agreement with Merck KGaA for avelumab (anti-PD-L1 antibody) to conduct two Phase II clinical trials of domatinostat in combination with avelumab in advanced-stage Merkel cell carcinoma (MCC) patients progressing on previous anti-PD-(L)1 monotherapy (MERKLIN 2) and in metastatic treatment-naïve patients (MERKLIN 1). 

Forward-looking information

Information set forth in this press release contains forward-looking statements, which involve risks and uncertainties. The forward-looking statements contained herein represent the judgement of 4SC as of the date of this press release. Such forward-looking statements are neither promises nor guarantees but are subject to a variety of risks and uncertainties, many of which are beyond 4SC’s control, and which could cause actual results to differ materially from those contemplated in these forward-looking statements. 4SC expressly disclaims any obligation or undertaking to release any updates or revisions to any such statements to reflect any change in its expectations or any change in events, conditions or circumstances on which any such statement is based.

Contact

ir-pr@4sc.com
+49 89 700763-0

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Emitter:	4SC AG Fraunhoferstr. 22 82152 Planegg-Martinsried Germany
Contact Person:	4SC AG
Phone:	+49 89 700763-0
E-Mail:	ir-pr@4sc.com
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