Delving into the Latest Updates on AZD-4877 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

AZD 4877, AZD4877

Target

KIF11

Action

inhibitors

Mechanism

KIF11 inhibitors(Kinesin-like protein 1 inhibitors)

Therapeutic Areas

NeoplasmsUrogenital DiseasesImmune System Diseases+ [2]

Active Indication-

Inactive Indication

Acute Promyelocytic LeukemiaAdvanced Malignant Solid NeoplasmB-Cell Lymphoma+ [10]

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization-

Inactive Organization

AstraZeneca PLC

University of Colorado Health Sciences CenterAstraZeneca, Inc.

+ [1]

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC28H33N5O2S

InChIKeySMFXSYMLJDHGIE-UHFFFAOYSA-N

CAS Registry758722-49-5

Acute infectious mononucleosis (AIM) is associated with Epstein-Barr virus (EBV) infection. We explored molecular mechanisms regarding the expression of CD8+T cells in convalescence stage (CONV). Differentially expressed genes (DEGs) were identified by analyzing GEO expression profiles. Subsequently, Gene Set Enrichment Analysis (GSEA), Protein-Protein Interactions (PPI) network, and gene-micro RNAs networks were used to identify hub genes and associated pathways. GSEA provided evidence that the top 3 gene sets in GSEA were all related to integrins. We identified ten hub genes in the PPI network and DGIdb was applied to predict potential targets that might reverse the expression of hub genes. Our study enhances a mechanistic understanding of the CD8+T cells expansion in acute EBV infection and provides potential treatment targets for further research. Keywords: acute infectious mononucleosis; bioinformatics; CD8+T cells; differentially expressed genes; EBV.

01 Dec 2021·BMC cancerQ2 · MEDICINE

Assessment of various continual reassessment method models for dose-escalation phase 1 oncology clinical trials: using real clinical data and simulation studies

Q2 · MEDICINE

ArticleOA

Author: James, G D ; Symeonides, S ; Marshall, J ; Young, J ; Clack, G

Abstract:

Background:

The continual reassessment method (CRM) identifies the maximum tolerated dose (MTD) more efficiently and identifies the true MTD more frequently compared to standard methods such as the 3 + 3 method. An initial estimate of the dose-toxicity relationship (prior skeleton) is required, and there is limited guidance on how to select this. Previously, we compared the CRM with six different skeletons to the 3 + 3 method by conducting post-hoc analysis on a phase 1 oncology study (AZD3514), each CRM model reduced the number of patients allocated to suboptimal and toxic doses. This manuscript extends this work by assessing the ability of the 3 + 3 method and the CRM with different skeletons in determining the true MTD of various “true” dose-toxicity relationships.

Methods:

One thousand studies were simulated for each “true” dose toxicity relationship considered, four were based on clinical trial data (AZD3514, AZD1208, AZD1480, AZD4877), and four were theoretical. The 3 + 3 method and 2-stage extended CRM with six skeletons were applied to identify the MTD, where the true MTD was considered as the largest dose where the probability of experiencing a dose limiting toxicity (DLT) is ≤33%.

Results:

For every true dose-toxicity relationship, the CRM selected the MTD that matched the true MTD in a higher proportion of studies compared to the 3 + 3 method. The CRM overestimated the MTD in a higher proportion of simulations compared to the 3 + 3 method.The proportion of studies where the correct MTD was selected varied considerably between skeletons. For some true dose-toxicity relationships, some skeletons identified the true MTD in a higher proportion of scenarios compared to the skeleton that matched the true dose-toxicity relationship.

Conclusion:

Through simulation, the CRM generally outperformed the 3 + 3 method for the clinical and theoretical true dose-toxicity relationships. It was observed that accurate estimates of the true skeleton do not always outperform a generic skeleton, therefore the application of wide confidence intervals may enable a generic skeleton to be used. Further work is needed to determine the optimum skeleton.

01 Aug 2013·Investigational new drugsQ3 · MEDICINE

Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer

Q3 · MEDICINE

Article

Author: Simon Chowdhury ; Arkadiusz Z. Dudek ; Tony Elliott ; Volker Muller-Mattheis ; Marc-Oliver Grimm ; Graham Mead ; John D. Chester ; Jacqueline Vuky ; Peter Albers ; Jianguo Li ; Jose Angel Arranz ; Anna Osmukhina ; Jurgen E. Gschwend ; Jeffrey Skolnik ; Gary Hudes ; Robert Jones ; Christian Wulfing

BACKGROUND:

AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (Cmax) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609).

PATIENTS AND METHODS:

AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if ≤ 2 of the first 20 evaluable patients achieved an objective tumor response. Cmax was assessed on days 1 and 8 of cycle 1.

RESULTS:

None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for ≥ 8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade ≥ 3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively.

CONCLUSIONS:

AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

100 Deals associated with AZD-4877

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11671

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Bladder Cancer	Phase 2	United States	AstraZeneca PLC	01 May 2008
Bladder Cancer	Phase 2	Canada	AstraZeneca PLC	01 May 2008
Bladder Cancer	Phase 2	Germany	AstraZeneca PLC	01 May 2008
Bladder Cancer	Phase 2	Spain	AstraZeneca PLC	01 May 2008
Bladder Cancer	Phase 2	United Kingdom	AstraZeneca PLC	01 May 2008
Renal Pelvis Carcinoma	Phase 2	United States	AstraZeneca PLC	01 May 2008
Renal Pelvis Carcinoma	Phase 2	Canada	AstraZeneca PLC	01 May 2008
Renal Pelvis Carcinoma	Phase 2	Germany	AstraZeneca PLC	01 May 2008
Renal Pelvis Carcinoma	Phase 2	Spain	AstraZeneca PLC	01 May 2008
Renal Pelvis Carcinoma	Phase 2	United Kingdom	AstraZeneca PLC	01 May 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00661609 (Pubmed \| Invest New Drugs)	Phase 2	Urothelial carcinoma recurrent	39	AZD4877 25 mg	xoptrfxkww(pyfcqjlvko) = 6 patients jcdzawtngv (wjkjbeugwx ) View more	Negative	01 Aug 2013
NCT00486265 (Pubmed \| Invest New Drugs)	Phase 1/2	Refractory acute myeloid leukemia	47	AZD4877	ntduirnlcy(rdkichwpan) = sjeohjlbsr mhsarglfho (imbhvahmwt )	Negative	01 Jun 2012
NCT00661609 (CTgov)	Phase 2	Ureteral Neoplasms \| Urothelial carcinoma bladder stage IV \| Urothelial Carcinoma of the Urinary Bladder ... View more	54	AZD4877	djibykiqtb = yuyutxaxkv godiowerhm (tbzoizufrd, lvjhbihjkr - ctdujpimer) View more	-	12 Jan 2011
ASCO2009	Phase 1	Refractory acute myeloid leukemia Consolidation	24	AZD4877	dpxdpgqdpo(klpqlrimgi) = Mucositis was the DLT at 18 mg/day; with 1 pt developing Gr 3 palmar-plantar syndrome at this dose dlpfcybsij (zwjckqshgw ) View more	-	20 May 2009
ASCO2008	Phase 1	Advanced Malignant Solid Neoplasm	-	AZD4877	uepekwlqez(ttninefqth) = xuexxqgxsl wqdekbbwum (lbmptcxiaw ) View more	-	20 May 2008