Delving into the Latest Updates on Gartisertib with Synapse

Study will include 3 parts. Aim of Part 1 of this study is to establish the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) for M4344 (is an Ataxia Telangiectasia Mutated and Rad3-related [ATR] inhibitors) in combination with niraparib in participants with advanced solid tumors. Aim of Parts 2 and 3 of the study is to provide clinical proof-of-concept for the preclinically predicted synergistic efficacy of ATR and poly(ADP-Ribose) polymerase (PARP) inhibitors (PARPi) in defined populations of participants with advanced breast cancer (aBC) with DDR mutations with an unmet medical need.

Start Date01 Dec 2020

Sponsor / Collaborator

EMD Serono Research & Development Institute, Inc.

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NCT02278250 / CompletedPhase 1

An Open-Label Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of M4344 (Formerly VX-803) as a Single Agent and in Combination With Cytotoxic Chemotherapy in Participants With Advanced Solid Tumors

The purpose of this study was to evaluate the safety and tolerability of multiple ascending doses of single-agent M4344 administered twice-weekly (BIW), twice daily (BID) or once daily dose schedule in participants with advanced solid tumors. This investigation is a three part study examining M4344 alone and in combination with carboplatin to determine the safety and maximum tolerated dose.

Start Date26 Jan 2015

Sponsor / Collaborator

EMD Serono Research & Development Institute, Inc.

[+1]

100 Clinical Results associated with Gartisertib

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100 Translational Medicine associated with Gartisertib

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100 Patents (Medical) associated with Gartisertib

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Literatures (Medical) associated with Gartisertib

01 Aug 2024·Molecular & Cellular Proteomics

Chemo-Phosphoproteomic Profiling with ATR Inhibitors Berzosertib and Gartisertib Uncovers New Biomarkers and DNA Damage Response Regulators

Article

Author: Hastie, C James ; Weiland, Florian ; Alabert, Constance ; Brown, Fiona ; van Attikum, Haico ; Carroll, Thomas ; Rouse, John ; Noordermeer, Sylvie M ; Zhou, Houjiang ; Lamoliatte, Frederic ; Gao, Yuandi ; Jadav, Rathan ; Masson, Jean-Yves ; Macartney, Thomas ; Zenke, Frank ; Wang, Jianming ; Toth, Rachel

The ATR kinase protects cells against DNA damage and replication stress and represents a promising anti-cancer drug target. The ATR inhibitors (ATRi) berzosertib and gartisertib are both in clinical trials for the treatment of advanced solid tumors as monotherapy or in combination with genotoxic agents. We carried out quantitative phospho-proteomic screening for ATR biomarkers that are highly sensitive to berzosertib and gartisertib, using an optimized mass spectrometry pipeline. Screening identified a range of novel ATR-dependent phosphorylation events, which were grouped into three broad classes: (i) targets whose phosphorylation is highly sensitive to ATRi and which could be the next generation of ATR biomarkers; (ii) proteins with known genome maintenance roles not previously known to be regulated by ATR; (iii) novel targets whose cellular roles are unclear. Class iii targets represent candidate DNA damage response proteins and, with this in mind, proteins in this class were subjected to secondary screening for recruitment to DNA damage sites. We show that one of the proteins recruited, SCAF1, interacts with RNAPII in a phospho-dependent manner and recruitment requires PARP activity and interaction with RNAPII. We also show that SCAF1 deficiency partly rescues RAD51 loading in cells lacking the BRCA1 tumor suppressor. Taken together these data reveal potential new ATR biomarkers and new genome maintenance factors.

20 Apr 2024·British Journal of Cancer

A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours

Article

Author: Bolleddula, Jayaprakasam ; Berlin, Jordan ; Gounaris, Ioannis ; Locatelli, Giuseppe ; Kalapur, Anup ; Lolkema, Martijn P ; Ferrer-Playan, Jordi ; Burris, Howard A ; Arkenau, Tobias ; Cote, Gregory M ; Goddemeier, Thomas ; de Bono, Johann

AbstractBackgroundGartisertib is an oral inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a key kinase of the DNA damage response. We aimed to determine the safety and tolerability of gartisertib ± carboplatin in patients with advanced solid tumours.MethodsThis phase I open-label, multicenter, first-in-human study comprised four gartisertib cohorts: A (dose escalation [DE]; Q2W); A2 (DE; QD/BID); B1 (DE+carboplatin); and C (biomarker-selected patients).ResultsOverall, 97 patients were enroled into cohorts A (n = 42), A2 (n = 26), B1 (n = 16) and C (n = 13). The maximum tolerated dose and recommended phase II dose (RP2D) were not declared for cohorts A or B1. In cohort A2, the RP2D for gartisertib was determined as 250 mg QD. Gartisertib was generally well-tolerated; however, unexpected increased blood bilirubin in all study cohorts precluded further DE. Investigations showed that gartisertib and its metabolite M26 inhibit UGT1A1-mediated bilirubin glucuronidation in human but not dog or rat liver microsomes. Prolonged partial response (n = 1 [cohort B1]) and stable disease >6 months (n = 3) did not appear to be associated with biomarker status. Exposure generally increased dose-dependently without accumulation.ConclusionGartisertib was generally well-tolerated at lower doses; however, unexpected liver toxicity prevented further DE, potentially limiting antitumour activity. Gartisertib development was subsequently discontinued.ClinicalTrials.govNCT02278250.

16 Jan 2024·Oncotarget

ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines

Article

Author: Tooney, Paul A ; Graves, Moira C ; Lozinski, Mathew ; Day, Bryan W ; Stringer, Brett W ; Fay, Michael ; Bowden, Nikola A

Glioblastoma cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation causing downstream DDR activation. Here, we investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with TMZ and/or RT in 12 patient-derived glioblastoma cell lines. We showed that gartisertib alone potently reduced the cell viability of glioblastoma cell lines, where sensitivity was associated with the frequency of DDR mutations and higher expression of the G2 cell cycle pathway. ATR inhibition significantly enhanced cell death in combination with TMZ and RT and was shown to have higher synergy than TMZ+RT treatment. MGMT promoter unmethylated and TMZ+RT resistant glioblastoma cells were also more sensitive to gartisertib. Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways. Overall, this study identifies ATR inhibition as a strategy to enhance the DNA-damaging ability of glioblastoma standard treatment, while providing preliminary evidence that ATR inhibition induces an innate immune gene signature that warrants further investigation.

100 Deals associated with Gartisertib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 3	-	EMD Serono Research & Development Institute, Inc.	01 Dec 2020
Lymphoma	Phase 1	-	Merck Serono SA	-
Lymphoma	Phase 1	-	Vertex Pharmaceuticals, Inc.	-
Advanced Malignant Solid Neoplasm	Preclinical	-	EMD Serono Research & Development Institute, Inc.	01 Dec 2020
Advanced Malignant Solid Neoplasm	Preclinical	-	EMD Serono Research & Development Institute, Inc.	01 Dec 2020
Breast Cancer	Preclinical	US	EMD Serono Research & Development Institute, Inc.	01 Dec 2020
Breast Cancer	Preclinical	-	EMD Serono Research & Development Institute, Inc.	01 Dec 2020
Breast Cancer	Preclinical	CA	EMD Serono Research & Development Institute, Inc.	01 Dec 2020
Breast Cancer	Discovery	CA	EMD Serono Research & Development Institute, Inc.	01 Dec 2020
Breast Cancer	Discovery	US	EMD Serono Research & Development Institute, Inc.	01 Dec 2020

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Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02278250 (Pubmed) Manual	Phase 1	Advanced Malignant Solid Neoplasm	97	gartisertib	(cvhwqxjyic) = unexpected liver toxicity prevented further DE, potentially limiting antitumour activity polktuwnxg (jfzhtyabhu )	Negative	29 Jan 2024
				Gartisertib (dose escalation [DE]; Q2W)