The SENSITIZE study (ClinicalTrials.gov identifier: NCT03278665 (https://clinicaltrials.gov/ct2/show/NCT03278665?term=4sc-202&rank=1)) enrolled 40 patients suffering from unresectable or metastatic advanced-stage cutaneous melanoma who were refractory prior treatment with anti-PD-1 antibodies (checkpoint inhibitor) into this Phase Ib part of the study. Different dose levels and schedules for domatinostat were applied to evaluate safety and tolerability, and to define the Phase II dose and schedule. Tumor assessments for clinical activity were performed according to irRECIST criteria and sequential tumor biopsies were taken for translational research.

Conclusions from the data presented were:

* Domatinostat (a selective class I HDAC inhibitor) in combination with pembrolizumab was safely administered at all dose levels tested up to 200 mg BID (twice daily)
* Domatinostat 200 mg BID was determined as the Phase II dose and schedule in combination with pembrolizumab
* Clinical activity was observed in this heavily-pretreated patient population, primary refractory to prior anti-PD-1 therapy (i.e. stable disease or progressive disease as best response to previous therapy), with a Disease Control Rate (DCR) of 34% (12/35) in patients with at least one post-baseline tumor assessment
* Translational research results support the immune-modulating mode of action of domatinostat to synergize with checkpoint inhibition.

4SC would like to sincerely thank the patients who volunteered to participate in the SENSITIZE study and the investigators and staff members at the study sites who cared for them.

Prof. Jessica Hassel stated: „Metastatic Melanoma patients progressing on anti-PD1 therapy urgently need new treatment options especially if the melanoma is not BRAF mutated. The SENSITIZE study investigates an innovative combination therapy intending to overcome resistance to the anti-PD1 therapy. The phase Ib data of the HDAC inhibitor domatinostat in combination with the anti-PD1 antibody pembrolizumab in patients resistant to anti-PD1 therapy that I am presenting on behalf of my co-investigators of the study at the Annual ASCO meeting 2021 are encouraging. Several doses and schedules of domatinostat in this combination were safely administered and a Phase II dose defined. For the first time the immune-modulating features of domatinostat could be confirmed in patients, further supporting the scientific rationale for the combination with checkpoint inhibition. Approximately one third of these refractory melanoma patients achieved disease control, some of them for up to 2 years, which is remarkable and justifies further investigation of domatinostat in combination with anti-PD-1 therapies."

Jason Loveridge, Ph.D., CEO of 4SC: "SENSITIZE is the first clinical study of domatinostat in combination with checkpoint inhibition. The primary objective of the Phase Ib part of the study was to investigate the safety and tolerability of domatinostat, and to establish a Phase II dose and regime. This goal has been achieved and builds the basis for our ongoing clinical program in other indications in combination with checkpoint inhibition.

In terms of efficacy, a disease control rate of 34% is good, especially in such a difficult to treat population, where surprisingly, the analysis of patient tumor samples showed them to be inflamed, but immunosuppressed and populated by exhausted T-cells.

Overall, the SENSITIZE study data gives us plenty of encouragement for our ongoing clinical development program in Merkel Cell Carcinoma with the MERKLIN 1 and 2 studies in combination with avelumab where we expect to see less immunosuppressed tumors, and where the upregulation of antigen presentation by domatinostat is more likely to be a key contributor to clinical activity (of the combination) in this cancer type".

Related articles

30 September 2019, First domatinostat combination data from Phase Ib/II SENSITIZE study presented at ESMO (https://www.4sc.com/news/first-domatinostat-combination-data-from-phase-ib-ii-sensitize-study-presented-at-esmo/)

11 July 2019, 4SC AG: Positive safety review of Phase Ib/II SENSITIZE study of domatinostat + pembrolizumab in melanoma (https://www.4sc.com/news/4sc-ag-positive-safety-review-of-phase-ib-ii-sensitize-study-of-domatinostat-pembrolizumab-in-melanoma/)

8 April 2019, 4SC AG: Domatinostat’s mode of action in Merkel cell carcinoma (https://www.4sc.com/news/4sc-ag-domatinostats-mode-of-action-in-merkel-cell-carcinoma/)

6 February 2019, First patient enrolled in Phase II study EMERGE of domatinostat (4SC-202) in gastrointestinal cancer (https://www.4sc.com/news/first-patient-enrolled-in-phase-ii-study-emerge-of-domatinostat-4sc-202-in-gastrointestinal-cancer/)

About domatinostat

Domatinostat (http://www.4sc.com/product-pipeline/4sc-202/) 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).

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).

About the SENSITIZE study – Domatinostat (4SC-202) + pembrolizumab for treatment of melanoma

The SENSITIZE study (ClinicalTrials.gov identifier: NCT03278665 (https://clinicaltrials.gov/ct2/show/NCT03278665?term=4sc-202&rank=1)) was opened for recruitment in September 2017 and patients were enrolled at 6 certified skin cancer centers in Germany and at one center in Italy. A total of 40 patients suffering from unresectable or metastatic advanced-stage cutaneous melanoma who are refractory or non-responding to prior treatment with anti-PD-1 antibodies (checkpoint inhibitors) were enrolled into the phase Ib part. Five cohorts were treated at different dose levels of domatinostat in combination with pembrolizumab. In the second part, additional patients will be treated with the recommended dosing regimen defined in the first part of the study.

The primary goal of the phase Ib part is to determine the safety and tolerability of domatinostat in combination with pembrolizumab and define a phase 2 dose and regime. Key secondary endpoints aim to assess the anti-tumor activity of the combination treatment. Additionally, the study will investigate changes in key immunological biomarkers to better understand how domatinostat renders patients more susceptible to treatment with checkpoint inhibitors.

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.