Studies / Clinical Trials -  E7080 Phase one trial (74 views) Notify me whenever anyone posts in this discussion.Subscribe
 
From: Swampwitch / laura (verlughmina) DelphiPlus Member Icon Posted by host7/12/07 1:17 AM 
To: All  (1 of 3) 
 326.1 
for more information on  E7080
PRIVATELY EMAIL
mimi-olsson@comcast.net


check for clinical trials at
www.clinicaltrials.gov

current Clinical trials in Netherlands, UK,
Japan and
Texas [MDA and Dallas]

multitargeted VEGF, PDGF, Ckit, OTHER
multiple inihibitors.


A phase I dose finding study of E7080 in
patients (pts) with advanced malignancies.
Sub-category: Tyrosine Kinase Inhibitors
Category: Developmental Therapeutics:
Molecular Therapeutics
Meeting: 2007 ASCO Annual Meeting




Abstract No:14073
Citation:Journal of Clinical Oncology, 2007
ASCO Annual Meeting Proceedings Part I. Vol
25, No. 18S (June 20 Supplement), 2007: 14073

Author(s):H. Glen, D. Boss, T. R. Evans, M.
Roelvink, J. M. Saro, P. Bezodis, W. Copalu,
A. Das, G. Crosswell, J. H. Schellens
Abstract:Background: E7080 is a potent
inhibitor of the split-kinase family of
transmembrane growth factor receptors
including Flt-1 and KDR. In addition, E7080
also potently inhibits FGFR1 and PDGFRß
tyrosine kinase activities. In an in vitro
angiogenic model, E7080 inhibited VEGF-driven
umbilical vein endothelial cell (HUVEC)
proliferation and tube formation. Using H460
and Colo205 mouse xenograft models, E7080
significantly inhibited tumor growth at doses
from 1 to 100 mg/kg.

Methods: A Phase I and pharmacologic study
was conducted to determine the Maximum
Tolerated Dose (MTD) and Dose Limiting
Toxicity (DLT) of E7080 in pts with advanced
malignancies. Eligible pts with adequate
hematologic, renal and hepatic function, and
with tumors refractory to standard therapies,
were treated with E7080 administered orally
on a once daily continuous dose schedule in
cycles of 4 weeks. Dose escalation was
performed according to an accelerated design
of 100% dose increases in subsequent cohorts
until the first patient experienced > CTC
grade 2 toxicity.
Results: As of November 17th, 2006, 37 pts
with documented progressive disease (PD) have
been treated at the following dose levels:
0.2 mg/d, 0.4 mg/d, 0.8 mg/d, 1.6 mg/d, 3.2
mg/d, 6.4 mg/d, 12.5 mg/d and 16 mg/d. Median
number of cycles was 1 (0-11). Median age =
60 years (25-84), 20 pts were male, 17 were
female. 37 pts were evaluable for toxicity. 1
patient experienced grade 3 hypertension
(DLT) in the 16 mg/d cohort, other related
toxicities > grade 2 include hemorrhage and
thrombosis (n=1), tachycardia (n=1), febrile
neutropenia (n=1), proteinuria (n=1),
thrombocytopenia (n=1) and hypertension
(n=1). MTD has not been reached and this
study is continuing to recruit. 24 pts were
evaluable for efficacy, 3 are too early to
evaluate. 1 patient had a partial response
(high grade sarcoma) after 2 cycles, and 15
pts experienced stable disease from 2+ to 11
months, and 11 pts continue on therapy.
Pharmacokinetic (PK) studies: preliminary
data suggest that the PK is linear over the
range 0.2 mg/d to 12.5 mg/d.

Conclusions: E7080 is safe and well tolerated
at doses acheived so far and has shown
promising first signs of anti-cancer activity
associated with potent activity in
pre-clinical models. Clinical and PK data
from subsequent doses and follow-up will be
presented.
 
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From: Swampwitch / laura (verlughmina) DelphiPlus Member Icon Posted by host3/19/08 11:09 AM 
To: Swampwitch / laura (verlughmina) DelphiPlus Member Icon  (2 of 3) 
 326.2 in reply to 326.1 

E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. In this study, we show the inhibitory activity of E7080 against SCF-induced angiogenesis in vitro and tumor growth of SCF-producing human small cell lung carcinoma H146 cells in vivo. E7080 inhibits SCF-driven tube formation of HUVEC, which express SCF receptor, KIT at the IC(50) value of 5.2 nM and it was almost identical for VEGF-driven one (IC(50) = 5.1 nM). To assess the role of SCF/KIT signaling in tumor angiogenesis, we evaluated the effect of imatinib, a selective KIT kinase inhibitor, on tumor growth of H146 cells in nude mice. Imatinib did not show the potent antitumor activity in vitro (IC(50) = 2,200 nM), because H146 cells did not express KIT. However, oral administration of imatinib at 160 mg/kg clearly slowed tumor growth of H146 cells in nude mice, accompanied by decreased microvessel density. Oral administration of E7080 inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF-producing H146 cells, and E7080 causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling. E7080 may provide therapeutic benefits in the treatment of SCF-producing tumors. (c) 2007 Wiley-Liss, Inc.

http://www.ncbi.nlm.nih.gov/pubmed/17943726?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVLinkOut

 

 
From: Swampwitch / laura (verlughmina) DelphiPlus Member Icon Posted by host3/19/08 11:40 AM 
To: Swampwitch / laura (verlughmina) DelphiPlus Member Icon  (3 of 3) 
 326.3 in reply to 326.2 

Abstract # 3008-From the lab of Dr. Jonathan Fletcher (Brigham and Women’s Hospital and Harvard Medical School), Meijun Zhu presented a poster on “KIT oncoprotein interactions in GISTs: Therapeutic relevance.” Zhu et al. used frozen GIST tumors and GIST cell lines to evaluate KIT signaling mechanisms. They found that PDGFRA existed in a complex with KIT and that the activated KIT protein also activated (through crossphosphorylation) the PDGFRA protein. They concluded that the response of GIST patients to Gleevec likely involves inhibition of both KIT and PDGFRA (Gleevec inhibits both of these proteins). The poster also noted the major contributions of PI3-K and PKCè (protein kinase C theta), both downstream targets of KIT in GISTs. Inhibition of PI3-K (with LY294002) or PKCè (by lentiviral shRNA infection) resulted in either inhibition of growth or cell death in four GIST cell lines. The poster concluded that PI3-K and PKCè are compelling therapeutic targets that might further improve the GIST therapeutic response to KIT/PDGFRA inhibition.

Note: PI3-K has long been avoided as a drug target because it is commonly expressed in normal cells; thus toxicities are expected to be high. It is one the major proteins involved in tyrosine kinase receptor signaling. One method for targeting PI3-K inhibition to tumor cells (while avoiding inhibiting it in normal cells) is to make a “prodrug” PI3-K inhibitor. This is a drug that is somehow “activated” by the tumor environment (such as be a different pH level in the tumor).

PKCè represents an attractive target because it is only rarely expressed in normal cells. A type of immune cell known as “T cells” signals through PKCè.

Abstract #1328-Prenen et al reported on the cellular uptake of both imatinib (Glivec) and AMN107 in GIST tumor cells. Several studies have reported that P-glycoprotein (PGP) is a transporter of imatinib and that high expression of the MDR1 gene (the gene that makes Pglycoprotein) could confer resistance to imatinib.

The Belgium scientists reported that imatinib uptake into two GIST cell lines, GIST882 and GIST GDG1, was significantly reduced compared to AMN107. Levels of AMN107 were 3 times higher than imatinib in GIST882 cells and 10 times higher in GIST GDG1 cells. Their findings suggest that AMN107 might be less susceptible to resistance caused by multi-drug resistance proteins.

Editor’s note: In a separate paper, White et al. found that AMN107 was also less affected by the influx pump, OCT1. They concluded that OCT-1 influx may be a key determinant of response to imatinib (low expression of OCT-1 may confer resistance), but it is unlikely to affect patient responses to AMN107. The unanswered question is whether it would be more effective to give AMN107 as front-line therapy before resistance developed, or to give it to patients once they become resistant to imatinib.

Abstract #1158-Salto-Tellez et al. from the National University of Singapore, reported that VEGF-A protein is a main biomarker that is able to differentiate low-risk GISTs from high-risk GISTs (p=0.0003). The authors concluded that their study showed VEGF-A status is important in the biological understanding (of GISTs), as well as clinical characterization of GISTs, and may point to an alternative and/or complementary treatment strategy to GIST.

Editor’s note: VEGF-A is one of at least five different growth factors that are able to activate one or more of the three different VEGF receptors (VEGFR-1, VEGFR-2 and VEGFR-3). VEGF-A is known to activate both VEGFR-1 and VEGFR-2. Many of the newer multi-targeted tyrosine kinase inhibitors, such as Sutent, AMG706, and BAY 43-9006, inhibit two or three of the known VEGF receptors. Thus, drugs that inhibit VEGFR-1 and VEGFR-2 would be expected to inhibit signaling caused by the VEGF-A growth factor. Avastin (Bevacizumab) is another drug that blocks the signaling of VEGFR1 and VEGFR2. Avastin is a monoclonal antibody that is given intravenously and has been shown to improve survival in colon cancer when given together with chemotherapy. A new trial is being planned for GIST patients that will test whether the combination of Gleevec and Avastin will be more effective than Gleevec alone. This trial is expected to start this summer.

Abstract #4038-Yamamoto et al. reported on a multi-targeted kinase inhibitor, E7080. E7080 is made by EISAI CO. LTD, Japan. It was tested in a mouse model that had human GIST tumor cells (GIST882). E7080 inhibits VEGFR-1, VEGFR-2, FGFR1, and PDGFRbeta. All of these targets have been implicated in angiogenesis (the growth of new blood vessels that feed tumors). In addition, it also inhibits KIT at slightly higher concentrations. E7080 was able to stabilize the GIST tumors in the mice at doses of 30 mg/kg. Doses of 100 mg/kg caused tumor shrinkage of about 40 percent in this mouse model.

Soluble KIT (s-KIT) was also evaluated as a potential biomarker in the mouse model. Normal mice (no GIST) did not have detectable levels of s-KIT. Mice with implanted GIST tumors did have detectable levels of s-KIT which was correlated with tumor weight. Treatment with E7080 clearly reduced levels of s-KIT. The author’s conclusions were that E7080 has therapeutic potential via inhibition of KIT in GISTs and s-KIT might be useful as a biomarker in GIST patients.

Editor’s note: Three phase I clinical trials for E7080 were listed in the clinicaltrials. gov database. These trials included solid tumors and were located in Amsterdam, Netherlands; Glasgow, United Kingdom; Dallas, Texas (USA) and Tokyo, Japan.

Abstract #1634-Jahn et al. reported that the KIT protein is recruited to lipid rafts at the cell membrane. Inhibition of lipid raft formation prevented KITmediated activation of AKT and blocked KIT mediated cellular proliferation, including KIT mutants that were resistant to Gleevec. They hypothesize that inhibition of receptor tyrosine kinase (RTK) recruitment to lipid rafts may be a useful strategy for control of tumors dependent on RTK activity.

http://www.liferaftgroup.org/news_sci_articles/highlights_AACRmeeting.html

 

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