On June 7, 2021 Prof. Dr. Jessica C. Hassel, Principle Investigator of the SENSITIZE study at the University Hospital Heidelberg, Germany, Department of Dermatology and National Center for Tumor Diseases, reported that presents a poster and associated slide presentation at the virtual 2021 ASCO (Free ASCO Whitepaper) Annual Meeting (Jun 4 – Jun 8, 2021) summarizing results from the Phase Ib part of the SENSITIZE study combining domatinostat with pembrolizumab in advanced melanoma patients refractory to prior checkpoint inhibitor therapy (Abstract #9545) (Press release, 4SC, JUN 7, 2021, View Source [SID1234583663]). The poster and slide presentation is available on the ASCO (Free ASCO Whitepaper) 2021 Virtual Meeting platform and will be available on the 4SC homepage after the conference.
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The SENSITIZE study (ClinicalTrials.gov identifier: NCT03278665) 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 (Free ASCO Whitepaper) 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".
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30 September 2019, First domatinostat combination data from Phase Ib/II SENSITIZE study presented at ESMO (Free ESMO Whitepaper)
11 July 2019, 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
6 February 2019, First patient enrolled in Phase II study EMERGE of domatinostat (4SC-202) in gastrointestinal cancer