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Aurora B/C Kinase Inhibitor GSK1070916A in Treating Patients With Advanced Solid Tumors

2014-08-27 03:13:53 | BioPortfolio

Summary

RATIONALE: Aurora B/C kinase inhibitor GSK1070916A (GSK1070916A) may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of GSK1070916A in treating patients with advanced solid tumors.

Description

OBJECTIVES:

Primary

- To determine and establish the safety profile of Aurora B/C kinase inhibitor GSK1070916A and define the dose-limiting toxicity in patients with advanced solid tumors.

- To determine the maximum-tolerated dose of Aurora B/C kinase inhibitor GSK1070916A in these patients.

Secondary

- To determine plasma pharmacokinetic (PK) parameters following administration of Aurora B/C kinase inhibitor GSK1070916A in these patients.

- To evaluate tumor response after at least 1 cycle of treatment with Aurora B/C kinase inhibitor GSK1070916A in these patients.

- To propose a safe dose for Phase II evaluation.

Tertiary

- To investigate the effects of Aurora B/C kinase inhibitor GSK1070916A on markers of mitosis/cell proliferation and apoptosis in humans.

- To investigate the metabolism of Aurora B/C kinase inhibitor GSK1070916A in humans.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive Aurora B/C kinase inhibitor GSK1070916A IV over 1 hour once daily on days 1-5. Courses repeat every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients receive escalating doses of Aurora B/C kinase inhibitor GSK1070916A until the maximum-tolerated dose (MTD) is determined. Once the MTD has been defined, 15-18 additional patients are recruited for an expanded MTD cohort in which patients receive Aurora B/C kinase inhibitor GSK1070916A at the MTD. Patients at the expanded MTD cohort must consent to have either tumor biopsies taken or FDG-PET/CT and DW-MRI scans performed.

Patients may undergo tissue, blood, and urine sample collection periodically for pharmacokinetic, pharmacodynamic, and other correlative laboratory studies.

After completion of study therapy, patients are followed up for 28 days.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

Study Design

Primary Purpose: Treatment

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Intervention

Aurora B/C kinase inhibitor GSK1070916A, laboratory biomarker analysis, pharmacological study, diffusion-weighted magnetic resonance imaging, fludeoxyglucose F 18

Location

Leeds Cancer Centre at St. James's University Hospital
Leeds
England
United Kingdom
LS9 7TF

Status

Recruiting

Source

National Cancer Institute (NCI)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:13:53-0400

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PubMed Articles [23981 Associated PubMed Articles listed on BioPortfolio]

Design and synthesis of BPR1K653 derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition.

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Changes in cell morphology guide identification of tubulin as the off-target for protein kinase inhibitors.

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Medical and Biotech [MESH] Definitions

Aurora kinase C is a chromosomal passenger protein that interacts with aurora kinase B in the regulation of MITOSIS. It is found primarily in GERM CELLS in the TESTIS, and may mediate CHROMOSOME SEGREGATION during SPERMATOGENESIS.

An aurora kinase that localizes to the CENTROSOME during MITOSIS and is involved in centrosome regulation and formation of the MITOTIC SPINDLE. Aurora A overexpression in many malignant tumor types suggests that it may be directly involved in NEOPLASTIC CELL TRANSFORMATION.

An aurora kinase that is a component of the chromosomal passenger protein complex and is involved in the regulation of MITOSIS. It mediates proper CHROMOSOME SEGREGATION and contractile ring function during CYTOKINESIS.

A key regulator of CELL CYCLE progression. It partners with CYCLIN E to regulate entry into S PHASE and also interacts with CYCLIN A to phosphorylate RETINOBLASTOMA PROTEIN. Its activity is inhibited by CYCLIN-DEPENDENT KINASE INHIBITOR P27 and CYCLIN-DEPENDENT KINASE INHIBITOR P21.

An INK4 cyclin-dependent kinase inhibitor containing four ANKYRIN-LIKE REPEATS. INK4B is often inactivated by deletions, mutations, or hypermethylation in HEMATOLOGIC NEOPLASMS.

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