Foretinib inhibits both Met and VEGFR in a balanced manner

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Foretinib inhibits both Met and VEGFR in a balanced manner

Posted On : Jan-12-2012 | seen (770) times | Article Word Count : 992 |

The role of mesechymal-epithelial transition (Met) tyrosine kinase in various cancers has been discussed in previous posts. Briefly, Met is one of the most frequently dysregulated pathways in human cancers. Patients with constitutively active Met tend of have aggressive cancers that are resistant to chemotherapy and, therefore, carry poor prognoses.

INTRODUCTION

The role of mesechymal-epithelial transition (Met) tyrosine kinase in various cancers has been discussed in previous posts. Briefly, Met is one of the most frequently dysregulated pathways in human cancers. Patients with constitutively active Met tend of have aggressive cancers that are resistant to chemotherapy and, therefore, carry poor prognoses.

A previous post discussed several Met-inhibitors that are currently in development as chemotherapeutics. One such drug is Foretinib, which is an inhibitor of both Met and vascular endothelial growth factor receptor (VEGFR). Foretinib was identified by high-throughput screening and rationally developed to act as both a proliferation inhibitor (Met) and an angiogenesis inhibitor (VEGFR) in order to test the hypothesis that antitumor activity could be combined in a single agent. Results of a phase I trail evaluating the efficacy and safety of foretinib in advanced solid tumors were published in 2010.

PHASE I STUDY

A total of 40 patients were enrolled in the study who had either metastatic or nonresectable solid tumors of various types. The patients were divided into eight cohorts treated with foretinib at levels of 0.1, 0.2, 0.4, 0.8, 1.6, 2.4, 3.6, and 4.5mg/kg for five consecutive days out of every 14days.

The patients underwent a dose-escalation scheme in which the dose was doubled until the first drug-related grade 2 toxicity was observed. Then, doses were increased by 50% until the first instance of grade 3 toxicity was observed. However, 4.5mg/kg was the highest dose administered. Once the maximum tolerated dose was determined, additional patients were treated at that dose to confirm safety.

Thirty-three patients were able to continue the therapy after the initial treatment. Two patients developed brain metastases, an additional four patients discontinued due to progressive disease, and one patient dropped out of the study due to an adverse event.

Dose-dependent toxicities were in 50% of patients receiving the maximum dose, who demonstrated elevated levels of aspartate aminotransferase (AST) and lipase. Toxicity at 3.6mg/kg was tolerable with only one patient out of 14 demonstrating an adverse effect. The most frequent adverse effects at this dosage were grade 1 or 2 hypertension and grade 1 or 2 proteinuria. Fatigue and some reversible cognitive dysfunction were observed with long term exposure. Therefore, 3.6mg/kg was designated as the maximum tolerated dose.

Pharmacokinetic data showed that foretinib has a long half-life in humans, approximating 40 hours. Plasma concentrations after a 9-days-off period were very low and essentially the same as the start of a 14-day cycle, suggesting that investigation of a lower dose administered more frequently throughout a treatment cycle may be warranted. In the expanded cohort of 3.6 mg/kg/d, the average dose that patients actually received was 240 mg. Therefore, the recommended dose of foretinib for use in phase II trials is 240 mg.

Serial tumor biopsies were collected from three patients, each with different tumor types and treated at different doses. Immunohistochemistry of the biopsies revealed minimal changes in total Met after treatment with foretinib. However, Met tyrosine kinase activity, as measured by phosphorylation status as well as downstream signaling molecules, was reduced in the tumors of all three patients. Furthermore, cellular proliferation was decreased and apoptosis was increased post-treatment. However, all three o f these patients demonstrated minor responses (stable disease) to foretinib.

Overall, three confirmed partial responses (7.5%) were observed, two in patient with papillary renal carcinoma and one in a patient with medullary thyroid carcinoma. Twenty-two additional patients had stable disease (55%), which represents a minor response.

SUMMARY

These results were from the first-time-in-human, phase I, dose-escalation trial of oral foretinib. The trial demonstrated that foretinib exposure produces clinical activity in human tumors, as evidenced by three partial responses and 22 cases of disease stabilization.

Foretinib inhibits both Met and VEGFR in a balanced manner. Therefore, the results of this trial support the hypothesis that antitumor activity can be combined in a single agent through inhibition of both tumor proliferation (Met) and angiogenesis (VEGFR2). The clinical activity in this phase I trial supports plans to investigate alternative schedules.

An additional study with daily dosing of foretinib has been completed, but the results have not yet been published. Phase II studies with the intermittent schedule used in this trial have also been completed in papillary renal carcinoma and refractory gastric cancer. Phase II trials with the daily schedule are under way in several tumor types, including hepatocellular carcinoma and lung cancer.

REFERENCES

van Heeckeren WJ, Ortiz J, Cooney MM, et al. (2007) Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: clinical toxicity, therapeutic target, or novel biomarker? J Clin Oncol 25:2993–5.
Eder JP, Shapiro GI, Appleman LJ, et al. (2010) A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2. Clin Cancer Res July 1, 2010 16; 3507

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<h1>Foretinib inhibits both Met and VEGFR in a balanced manner</h1> Author: <a href='http://www.articleseen.com/profile_Dr.Rabia.aspx'>Dr.Rabia</a> INTRODUCTION

A previous post discussed several Met-inhibitors that are currently in development as chemotherapeutics. One such drug is Foretinib, which is an inhibitor of both Met and vascular endothelial growth factor receptor (VEGFR). Foretinib was identified by high-throughput screening and rationally developed to act as both a proliferation inhibitor (Met) and an angiogenesis inhibitor (VEGFR) in order to test the hypothesis that antitumor activity could be combined in a single agent. Results of a phase I trail evaluating the efficacy and safety of foretinib in advanced solid tumors were published in 2010.

PHASE I STUDY

A total of 40 patients were enrolled in the study who had either metastatic or nonresectable solid tumors of various types. The patients were divided into eight cohorts treated with foretinib at levels of 0.1, 0.2, 0.4, 0.8, 1.6, 2.4, 3.6, and 4.5mg/kg for five consecutive days out of every 14days.

The patients underwent a dose-escalation scheme in which the dose was doubled until the first drug-related grade 2 toxicity was observed. Then, doses were increased by 50% until the first instance of grade 3 toxicity was observed. However, 4.5mg/kg was the highest dose administered. Once the maximum tolerated dose was determined, additional patients were treated at that dose to confirm safety.

Thirty-three patients were able to continue the therapy after the initial treatment. Two patients developed brain metastases, an additional four patients discontinued due to progressive disease, and one patient dropped out of the study due to an adverse event.

Dose-dependent toxicities were in 50% of patients receiving the maximum dose, who demonstrated elevated levels of aspartate aminotransferase (AST) and lipase. Toxicity at 3.6mg/kg was tolerable with only one patient out of 14 demonstrating an adverse effect. The most frequent adverse effects at this dosage were grade 1 or 2 hypertension and grade 1 or 2 proteinuria. Fatigue and some reversible cognitive dysfunction were observed with long term exposure. Therefore, 3.6mg/kg was designated as the maximum tolerated dose.

Pharmacokinetic data showed that foretinib has a long half-life in humans, approximating 40 hours. Plasma concentrations after a 9-days-off period were very low and essentially the same as the start of a 14-day cycle, suggesting that investigation of a lower dose administered more frequently throughout a treatment cycle may be warranted. In the expanded cohort of 3.6 mg/kg/d, the average dose that patients actually received was 240 mg. Therefore, the recommended dose of foretinib for use in phase II trials is 240 mg.

Serial tumor biopsies were collected from three patients, each with different tumor types and treated at different doses. Immunohistochemistry of the biopsies revealed minimal changes in total Met after treatment with foretinib. However, Met tyrosine kinase activity, as measured by phosphorylation status as well as downstream signaling molecules, was reduced in the tumors of all three patients. Furthermore, cellular proliferation was decreased and apoptosis was increased post-treatment. However, all three o f these patients demonstrated minor responses (stable disease) to foretinib.

Overall, three confirmed partial responses (7.5%) were observed, two in patient with papillary renal carcinoma and one in a patient with medullary thyroid carcinoma. Twenty-two additional patients had stable disease (55%), which represents a minor response.

SUMMARY

These results were from the first-time-in-human, phase I, dose-escalation trial of oral foretinib. The trial demonstrated that foretinib exposure produces clinical activity in human tumors, as evidenced by three partial responses and 22 cases of disease stabilization.

Foretinib inhibits both Met and VEGFR in a balanced manner. Therefore, the results of this trial support the hypothesis that antitumor activity can be combined in a single agent through inhibition of both tumor proliferation (Met) and angiogenesis (VEGFR2). The clinical activity in this phase I trial supports plans to investigate alternative schedules.

An additional study with daily dosing of foretinib has been completed, but the results have not yet been published. Phase II studies with the intermittent schedule used in this trial have also been completed in papillary renal carcinoma and refractory gastric cancer. Phase II trials with the daily schedule are under way in several tumor types, including hepatocellular carcinoma and lung cancer.

REFERENCES

van Heeckeren WJ, Ortiz J, Cooney MM, et al. (2007) Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: clinical toxicity, therapeutic target, or novel biomarker? J Clin Oncol 25:2993–5.
    Eder JP, Shapiro GI, Appleman LJ, et al. (2010) A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2. Clin Cancer Res July 1, 2010 16; 3507

Met Inhibitors: Targeted therapies for multiple cancers
Two tyrosine kinase inhibitors are the first drugs to be approved for treatment of medullary thyroid cancer
Related to Phase I trail of Foretinib in Metastatic Solid Tumors

Development of Vandetanib to treat Non-small Cell Lung Cancer

INTRODUCTION Several previous posts have discussed lung cancer, which remains the leading cause of cancer related deaths in the US. Despite its prevalence, lung cancer, ...
    Met Inhibitors: Targeted therapies for multiple cancers

INTRODUCTION Mesenchymal-epithelial transition (Met) tyrosine kinase is the receptor for hepatocyte growth factor (HGF), which is normally active in wound healing, liver regeneration, and embryonic ...
    A multitargeted tyrosine kinase inhibitor is a potent angiogenesis inhibitor in several cancers.

INTRODUCTION Angiogenesis, the process of vascularization of tumors, is a critical contributor to the progression of multiple cancers. Specifically, hepatocellular carcinoma, renal cell carcinoma, and ...About the Author: As one of the world leading suppliers of high-performance life-science products. We have over 8,000 products which consist of inhibitors, antibodies, RNAis, proteins and peptides those which focus on signaling pathways such as <a rel="nofollow" href="http://www.selleckchem.com/products/ABT-888.html">veliparib</a>, <a rel="nofollow" href="http://www.selleckchem.com/products/CAL-101.html">CAL-101</a>, <a rel="nofollow" href="http://www.selleckchem.com/products/BEZ235.html">BEZ235</a> and more. Article Source: <a href='http://www.articleseen.com/Article_Foretinib-inhibits-both-Met-and-VEGFR-in-a-balanced-manner_132691.aspx'> http://www.articleseen.com/Article_Foretinib inhibits both Met and VEGFR in a balanced manner_132691.aspx</a>

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As one of the world leading suppliers of high-performance life-science products. We have over 8,000 products which consist of inhibitors, antibodies, RNAis, proteins and peptides those which focus on signaling pathways such as veliparib, CAL-101, BEZ235 and more.

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