Delving into the Latest Updates on Domatinostat tosylate with Synapse

DONIMI is a phase 1b trial testing the combination of domatinostat + nivolumab or nivolumab monotherapy in IFN-gamma signature high patients and of domatinostat + nivolumab or domatinostat + nivolumab + ipilimumab in IFN-gamma signature low patients with de-novo or recurrent macroscopic stage III cutaneous or unknown primary melanoma.
The trial will include 45 stage III cutaneous or unknown primary melanoma patients with RECIST 1.1 measurable de-novo or recurrent disease (short axis lymph node metastasis ≥1.5cm).
NanoString IFN-gamma signature high patients will be randomized to be treated pre-surgically for 6 weeks with nivolumab (arm A; 10 patients) or domatinostat + nivolumab (arm B; 10 patients).
IFN-gamma signature low patients will be randomized to be treated pre-surgically for 6 weeks with domatinostat + nivolumab (arm C; 10 patients) or domatinostat + nivolumab + ipilimumab (arm D; 15 patients). Patients will be stratified according to center.
Post-surgery (starting at week 12), the patients will start with adjuvant nivolumab or pembrolizumab for 52 weeks according to institute's standard. BRAF V600E/K mutation positive patients with no pathologic response after neoadjuvant therapy may also receive adjuvant BRAF + MEK inhibition if commercially available and according to the patient's and the treating physician's decision.
Follow-up after the adjuvant therapy will be for 2 years, according to the institutes' standard.
Toxicity and pathologic response rates will be descriptive. In case of 2/5 or 4/10 patients not undergoing their lymph node dissection at week 6 +/- 1 week due to treatment related toxicity, this arm will be declared unfeasible.

Start Date07 Jan 2020

Sponsor / Collaborator

Netherlands Cancer Insitute

[+1]

100 Clinical Results associated with Domatinostat tosylate

Login to view more data

100 Translational Medicine associated with Domatinostat tosylate

Login to view more data

100 Patents (Medical) associated with Domatinostat tosylate

Login to view more data

32

Literatures (Medical) associated with Domatinostat tosylate

01 Apr 2024·ESMO Open

Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE

Article

Author: Smyth, E ; Rao, S ; Terlizzo, M ; Kohoutova, D ; Fribbens, C ; Mansoor, W ; Cartwright, E ; Slater, S ; Turkes, F ; Starling, N ; Tran, A ; Chau, I ; Saffery, C ; Sanna, I ; Rana, I ; Zhitkov, O ; Aresu, M ; Smith, G ; Johnston, E W ; Cunningham, D

BACKGROUNDMost oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC.PATIENTS AND METHODSEligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively.RESULTSPatients (n = 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n = 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D.CONCLUSIONSResponses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2.TRIAL REGISTRATIONNCT03812796 (registered 23^rd January 2019).

25 Jan 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

Q1 · MEDICINE

Review

Author: Hou, Wen-Qing ; Wang, Shu-Wu ; Ji, Shi-Kun ; Liu, Hong-Min ; Wang, Shao-Peng ; Shen, Liang ; Wang, Bo ; Dai, Xing-Jie ; Fu, Meng-Jie

Lysine specific demethylase 1 (LSD1), a transcriptional modulator that represses or activates target gene expression, is overexpressed in many cancer and causes imbalance in the expression of normal gene networks. Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577). Most clinical LSD1 inhibitors demonstrated enhanced efficacy in combination with other agents. LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents.

01 Sep 2023·Journal of cancer research and clinical oncology

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression.

Article

Author: Furtmann, Frauke ; Gambichler, Thilo ; Lei, Kuan Cheok ; Sriram, Ashwin ; Gravemeyer, Jan ; Becker, Jürgen C ; Srinivas, Nalini ; Song, Lina

BACKGROUNDClass I selective histone deacetylase inhibitors (HDACi) have been previously demonstrated to not only increase major histocompatibility complex class I surface expression in Merkel cell carcinoma (MCC) cells by restoring the antigen processing and presentation machinery, but also exert anti-tumoral effect by inducing apoptosis. Both phenomena could be due to induction of type I interferons (IFN), as has been described for HDACi. However, the mechanism of IFN induction under HDACi is not fully understood because the expression of IFNs is regulated by both activating and inhibitory signaling pathways. Our own preliminary observations suggest that this may be caused by suppression of HES1.METHODSThe effect of the class I selective HDACi domatinostat and IFNα on cell viability and the apoptosis of MCPyV-positive (WaGa, MKL-1) and -negative (UM-MCC 34) MCC cell lines, as well as, primary fibroblasts were assessed by colorimetric methods or measuring mitochondrial membrane potential and intracellular caspase-3/7, respectively. Next, the impact of domatinostat on IFNA and HES1 mRNA expression was measured by RT-qPCR; intracellular IFNα production was detected by flow cytometry. To confirm that the expression of IFNα induced by HDACi was due to the suppression of HES1, it was silenced by RNA interference and then mRNA expression of IFNA and IFN-stimulated genes was assessed.RESULTSOur studies show that the previously reported reduction in viability of MCC cell lines after inhibition of HDAC by domatinostat is accompanied by an increase in IFNα expression, both of mRNA and at the protein level. We confirmed that treatment of MCC cells with external IFNα inhibited their proliferation and induced apoptosis. Re-analysis of existing single-cell RNA sequencing data indicated that induction of IFNα by domatinostat occurs through repression of HES1, a transcriptional inhibitor of IFNA; this was confirmed by RT-qPCR. Finally, siRNA-mediated silencing of HES1 in the MCC cell line WaGa not only increased mRNA expression of IFNA and IFN-stimulated genes but also decreased cell viability.CONCLUSIONOur results demonstrate that the direct anti-tumor effect of HDACi domatinostat on MCC cells is at least in part mediated via decreased HES1 expression allowing the induction of IFNα, which in turn causes apoptosis.

1

News (Medical) associated with Domatinostat tosylate

30 Sep 2019

·www.bioportfolio.com

4SC AG: First domatinostat combination data from Phase Ib/II SENSITIZE study presented at ESMO

DGAP-News: 4SC AG / Key word(s): Study 30.09.2019 / 12:00 The issuer is solely responsible for the content of this announcement.

100 Deals associated with Domatinostat tosylate

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB13101

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Merkel Cell Carcinoma	Phase 2	BE	4SC AG	13 Oct 2020
Metastatic Merkel Cell Carcinoma	Phase 2	DE	4SC AG	13 Oct 2020
Metastatic Merkel Cell Carcinoma	Phase 2	FR	4SC AG	13 Oct 2020
Metastatic Merkel Cell Carcinoma	Phase 2	NL	4SC AG	13 Oct 2020
Metastatic Merkel Cell Carcinoma	Phase 2	IT	4SC AG	13 Oct 2020
Melanoma	Phase 2	NL	Netherlands Cancer Insitute	07 Jan 2020
Gastrointestinal Neoplasms	Phase 2	-	Takeda Pharmaceutical Co., Ltd.	-
Colorectal Cancer	Discovery	GB	4SC AG	03 Jan 2019
Esophageal Carcinoma	Discovery	GB	4SC AG	25 Dec 2018
Metastatic melanoma	Discovery	DE	4SC AG	21 Aug 2017

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03812796 (EMERGE, Pubmed) Manual	Phase 2	Gastrointestinal Neoplasms \| \|	31	Domatinostat + avelumab (dose escalation phase)	(naubufktbu) = crvrhjsjvi qatuxhrmms (zjlxlbhwop )	Positive	21 Mar 2024
NCT04133948 (DONIMI, ESMO2022) Manual	Phase 1/2	Melanoma Neoadjuvant IFN-γ	44	nivolumab (IFN-γ sign high + Arm A)	(hoylhaevlg) = zgepdwvvpa wkixptskdj (wkuzmcxfzm ) View more	Positive	10 Sep 2022
NCT04133948 (DONIMI, ESMO2022) Manual	Phase 1/2	Melanoma Neoadjuvant IFN-γ	44	nivolumab +domatinostat (IFN-γ sign high + Arm B)	(hoylhaevlg) = jdafcxglks wkixptskdj (wkuzmcxfzm ) View more	Positive	10 Sep 2022
NCT03812796 (PD-2 EMERGE, ESMO_GI2022)	Phase 2	Advanced Colorectal Adenocarcinoma MMRp	21	Domatinostat plus Avelumab	(ljmjlsblte) = svlaqlkyaa uodaxcdyrr (mlrbeopwjq, 2.8 - 60.0) View more	Positive	02 Jul 2022
NCT04133948 (DONIMI, ESMO2021)	Phase 1	Melanoma Neoadjuvant	40	Nivolumab	(ejeyvmxmkd) = ppgfrdqvaz ehnjkzhjxz (nwczzieckg )	-	20 Sep 2021
NCT04133948 (DONIMI, ESMO2021)	Phase 1	Melanoma Neoadjuvant	40	Ipilimumab	(ejeyvmxmkd) = ybejllzvdt ehnjkzhjxz (nwczzieckg )	-	20 Sep 2021
NCT03278665 (SENSITIZE, ASCO2021) Manual	Phase 1	Locally Advanced Melanoma	40	pembrolizumab+domatinostat	(vbbjthealr) = kctmsixexu vwgenqceur (bfqowifcee ) View more	Positive	28 May 2021
NCT01344707 (Pubmed \| Eur J Haematol) Manual	Phase 1	Hematologic Neoplasms	24	4SC-202	(sgzrzdvjyo) = 200 mg BID，grade 4 hypercalcemia sqtuheesyy (fzjmtizfjf ) View more	Positive	01 Feb 2019
NCT01344707 (TOPAS, ASCO2014)	Phase 1	Hematologic Neoplasms	24	4SC-202	(zhlzzwoguo) = Treatment was very well tolerated by heavily pre-treated patients up to the highest dose group. Possibly drug-related AE were less frequent, e.g. low-grade GI complaints such as nausea. Higher-grade hematological toxicity e.g. leading to treatment changes was not observed. Elevation of liver enzymes was observed at 200mg BID during continuous dosing. ldwedcsfen (pqztzyidvp )	-	20 May 2014