Delving into the Latest Updates on AZD-4877 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

KIF11

Mechanism

KIF11 inhibitors(Kinesin-like protein 1 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Solid tumor

Inactive Indication

Acute Promyelocytic LeukemiaAdvanced Malignant Solid NeoplasmBladder Cancer+ [8]

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization

University of Colorado Health Sciences CenterAstraZeneca, Inc.

Sarah Cannon Research Institute LLC

Inactive Organization

AstraZeneca PLC

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC28H33N5O2S

InChIKeySMFXSYMLJDHGIE-UHFFFAOYSA-N

CAS Registry758722-49-5

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

BACKGROUNDAZD4877 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 METHODSAZD4877 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.RESULTSNone 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.CONCLUSIONSAZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

01 Apr 2013·Investigational New DrugsQ3 · MEDICINE

A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies

Q3 · MEDICINE

Article

Author: Dennis Huszar ; Joe J. Stephenson ; Anna Osmukhina ; Jianguo Li ; Jeffrey M. Skolnik ; Gary K. Schwartz ; John F. Gerecitano ; Kaida Wu ; Nancy L. Lewis ; Zhiping You

BACKGROUNDThis Phase I study assessed the safety and maximum tolerated dose (MTD) of the kinesin spindle protein inhibitor AZD4877 in patients with relapsed/refractory solid tumors and lymphoma.METHODSIn this multicenter study, a standard 3 + 3 dose-escalation design was used. AZD4877 was given as an intravenous infusion on days 1, 4, 8 and 11 of each 21-day cycle. Responses were assessed with CT scans +/- PET after 6 and 12 weeks, then every 12 weeks while on therapy. An additional four patients with lymphoma were enrolled at the MTD.RESULTS29 patients were enrolled and 22 patients received at least one dose of AZD4877 and were evaluable for safety. The MTD was 11 mg. Dose-limiting toxicity was neutropenia (n = 2 patients, 15 mg cohort). The most common adverse events were grade 1/2 fatigue, nausea, neutropenia and dyspnea. AZD4877 exposure generally increased with dose, with mean elimination half-life approximately 16 h at the MTD. Pharmacodynamic analyses demonstrated moderate correlation between plasma drug concentrations at 6 or 24 h and monoaster formation in peripheral blood mononuclear cells (PBMCs).CONCLUSIONSAZD4877 is generally well-tolerated with pharmacodynamic evidence of target inhibition in circulating PBMCs.

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
Urethral Neoplasms	Discovery	CA	AstraZeneca PLC	01 May 2008
Urethral Neoplasms	Discovery	DE	AstraZeneca PLC	01 May 2008
Urethral Neoplasms	Discovery	ES	AstraZeneca PLC	01 May 2008
Urethral Neoplasms	Discovery	GB	AstraZeneca PLC	01 May 2008
Urethral Neoplasms	Discovery	US	AstraZeneca PLC	01 May 2008
Urothelial Carcinoma of the Urinary Bladder	Discovery	GB	AstraZeneca PLC	01 May 2008
Urothelial Carcinoma of the Urinary Bladder	Discovery	DE	AstraZeneca PLC	01 May 2008
Urothelial Carcinoma of the Urinary Bladder	Discovery	US	AstraZeneca PLC	01 May 2008
Urothelial Carcinoma of the Urinary Bladder	Discovery	ES	AstraZeneca PLC	01 May 2008
Urothelial Carcinoma of the Urinary Bladder	Discovery	CA	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


NCT00486265 (Pubmed \| Invest New Drugs)	Phase 1/2	Refractory acute myeloid leukemia	47	AZD4877	(eqzhoynawy) = jemmlwvpji abvebnvidk (ynxzjxpxvn )	Negative	01 Jun 2012
NCT00661609 (CTgov)	Phase 2	Ureteral Neoplasms \| Renal Pelvis Carcinoma \| Urothelial Carcinoma of the Urinary Bladder \| Urothelial carcinoma recurrent \| Bladder Cancer \| Urethral Neoplasms	54	AZD4877	kryuauiehv(oarpbizfhx) = mcymxuhxhu eccpzqncbs (gbypxapqvd, eplyymwomt - osrbpxwtdc) View more	-	12 Jan 2011
ASCO2009	Phase 1	Refractory acute myeloid leukemia Consolidation	24	AZD4877	(pmkgylsfhd) = Mucositis was the DLT at 18 mg/day; with 1 pt developing Gr 3 palmar-plantar syndrome at this dose gcfngoyxtb (icuxntbbng ) View more	-	20 May 2009
ASCO2008	Phase 1	Advanced Malignant Solid Neoplasm	-	AZD4877	(mhrszjxwdg) = xmpuycyrcy dzamnikiww (qmbubocmxt ) View more	-	20 May 2008