A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer

Summary Purpose To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castratio...

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Veröffentlicht in:Investigational new drugs 2014-08, Vol.32 (4), p.746-752
Hauptverfasser: Azad, Arun A., Beardsley, Emma K., Hotte, Sebastian J., Ellard, Susan L., Klotz, Lawrence, Chin, Joseph, Kollmannsberger, Christian, Mukherjee, Som D., Chi, Kim N.
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container_end_page 752
container_issue 4
container_start_page 746
container_title Investigational new drugs
container_volume 32
creator Azad, Arun A.
Beardsley, Emma K.
Hotte, Sebastian J.
Ellard, Susan L.
Klotz, Lawrence
Chin, Joseph
Kollmannsberger, Christian
Mukherjee, Som D.
Chi, Kim N.
description Summary Purpose To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-naïve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (≥ 50 % decline from baseline). Results Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p  = 0.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels. Conclusion The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone. Further evaluation of this combination is not warranted in mCRPC.
doi_str_mv 10.1007/s10637-014-0091-8
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Methods This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-naïve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (≥ 50 % decline from baseline). Results Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p  = 0.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels. Conclusion The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone. Further evaluation of this combination is not warranted in mCRPC.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-014-0091-8</identifier><identifier>PMID: 24671507</identifier><identifier>CODEN: INNDDK</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject><![CDATA[Aged ; Androgens ; Anilides - administration & dosage ; Anilides - adverse effects ; Antineoplastic agents ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biological and medical sciences ; Cancer therapies ; Chemotherapy ; Correlation analysis ; Drug dosages ; Drug therapy ; Epidermal growth factor ; FDA approval ; Gynecology. Andrology. Obstetrics ; Health sciences ; Humans ; Inhibitor drugs ; Kinases ; Male ; Male genital diseases ; Medical sciences ; Medicine ; Medicine & Public Health ; Metastasis ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Nephrology. Urinary tract diseases ; Nitriles - administration & dosage ; Nitriles - adverse effects ; Oncology ; Patients ; Pharmaceuticals ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Phase II Studies ; Piperidines - administration & dosage ; Plasma ; Prostate cancer ; Prostate-Specific Antigen - metabolism ; Prostatic Neoplasms, Castration-Resistant - drug therapy ; Prostatic Neoplasms, Castration-Resistant - metabolism ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - adverse effects ; Quinazolines - administration & dosage ; Scintigraphy ; Statistical analysis ; Testosterone ; Tosyl Compounds - administration & dosage ; Tosyl Compounds - adverse effects ; Toxicity ; Tumors ; Tumors of the urinary system ; Urinary tract. Prostate gland ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - metabolism ; Vascular Endothelial Growth Factor Receptor-2 - metabolism]]></subject><ispartof>Investigational new drugs, 2014-08, Vol.32 (4), p.746-752</ispartof><rights>Springer Science+Business Media New York 2014</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3878-932aba700dd5a1b18a900eb51c7d0e5c6d605da46cb20b9380b883395c64a46c3</citedby><cites>FETCH-LOGICAL-c3878-932aba700dd5a1b18a900eb51c7d0e5c6d605da46cb20b9380b883395c64a46c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10637-014-0091-8$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10637-014-0091-8$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=28641915$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24671507$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Azad, Arun A.</creatorcontrib><creatorcontrib>Beardsley, Emma K.</creatorcontrib><creatorcontrib>Hotte, Sebastian J.</creatorcontrib><creatorcontrib>Ellard, Susan L.</creatorcontrib><creatorcontrib>Klotz, Lawrence</creatorcontrib><creatorcontrib>Chin, Joseph</creatorcontrib><creatorcontrib>Kollmannsberger, Christian</creatorcontrib><creatorcontrib>Mukherjee, Som D.</creatorcontrib><creatorcontrib>Chi, Kim N.</creatorcontrib><title>A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary Purpose To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-naïve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (≥ 50 % decline from baseline). Results Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p  = 0.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels. Conclusion The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone. Further evaluation of this combination is not warranted in mCRPC.</description><subject>Aged</subject><subject>Androgens</subject><subject>Anilides - administration &amp; dosage</subject><subject>Anilides - adverse effects</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - administration &amp; dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Cancer therapies</subject><subject>Chemotherapy</subject><subject>Correlation analysis</subject><subject>Drug dosages</subject><subject>Drug therapy</subject><subject>Epidermal growth factor</subject><subject>FDA approval</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Health sciences</subject><subject>Humans</subject><subject>Inhibitor drugs</subject><subject>Kinases</subject><subject>Male</subject><subject>Male genital diseases</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine &amp; Public Health</subject><subject>Metastasis</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Nitriles - administration &amp; dosage</subject><subject>Nitriles - adverse effects</subject><subject>Oncology</subject><subject>Patients</subject><subject>Pharmaceuticals</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Phase II Studies</subject><subject>Piperidines - administration &amp; dosage</subject><subject>Plasma</subject><subject>Prostate cancer</subject><subject>Prostate-Specific Antigen - metabolism</subject><subject>Prostatic Neoplasms, Castration-Resistant - drug therapy</subject><subject>Prostatic Neoplasms, Castration-Resistant - metabolism</subject><subject>Protein Kinase Inhibitors - administration &amp; dosage</subject><subject>Protein Kinase Inhibitors - adverse effects</subject><subject>Quinazolines - administration &amp; dosage</subject><subject>Scintigraphy</subject><subject>Statistical analysis</subject><subject>Testosterone</subject><subject>Tosyl Compounds - administration &amp; dosage</subject><subject>Tosyl Compounds - adverse effects</subject><subject>Toxicity</subject><subject>Tumors</subject><subject>Tumors of the urinary system</subject><subject>Urinary tract. 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Andrology. Obstetrics</topic><topic>Health sciences</topic><topic>Humans</topic><topic>Inhibitor drugs</topic><topic>Kinases</topic><topic>Male</topic><topic>Male genital diseases</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine &amp; Public Health</topic><topic>Metastasis</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Nitriles - administration &amp; dosage</topic><topic>Nitriles - adverse effects</topic><topic>Oncology</topic><topic>Patients</topic><topic>Pharmaceuticals</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Phase II Studies</topic><topic>Piperidines - administration &amp; dosage</topic><topic>Plasma</topic><topic>Prostate cancer</topic><topic>Prostate-Specific Antigen - metabolism</topic><topic>Prostatic Neoplasms, Castration-Resistant - drug therapy</topic><topic>Prostatic Neoplasms, Castration-Resistant - metabolism</topic><topic>Protein Kinase Inhibitors - administration &amp; dosage</topic><topic>Protein Kinase Inhibitors - adverse effects</topic><topic>Quinazolines - administration &amp; dosage</topic><topic>Scintigraphy</topic><topic>Statistical analysis</topic><topic>Testosterone</topic><topic>Tosyl Compounds - administration &amp; dosage</topic><topic>Tosyl Compounds - adverse effects</topic><topic>Toxicity</topic><topic>Tumors</topic><topic>Tumors of the urinary system</topic><topic>Urinary tract. Prostate gland</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Azad, Arun A.</creatorcontrib><creatorcontrib>Beardsley, Emma K.</creatorcontrib><creatorcontrib>Hotte, Sebastian J.</creatorcontrib><creatorcontrib>Ellard, Susan L.</creatorcontrib><creatorcontrib>Klotz, Lawrence</creatorcontrib><creatorcontrib>Chin, Joseph</creatorcontrib><creatorcontrib>Kollmannsberger, Christian</creatorcontrib><creatorcontrib>Mukherjee, Som D.</creatorcontrib><creatorcontrib>Chi, Kim N.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing &amp; Allied Health Database</collection><collection>Access via ABI/INFORM (ProQuest)</collection><collection>ABI/INFORM Global (PDF only)</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ABI/INFORM Global (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ABI/INFORM Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Business Premium Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Business Premium Collection (Alumni)</collection><collection>Health Research Premium Collection</collection><collection>ABI/INFORM Global (Corporate)</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Business Collection (Alumni Edition)</collection><collection>ProQuest Business Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>ABI/INFORM Professional Advanced</collection><collection>ABI/INFORM Global</collection><collection>Consumer Health Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Business</collection><collection>ProQuest One Business (Alumni)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Azad, Arun A.</au><au>Beardsley, Emma K.</au><au>Hotte, Sebastian J.</au><au>Ellard, Susan L.</au><au>Klotz, Lawrence</au><au>Chin, Joseph</au><au>Kollmannsberger, Christian</au><au>Mukherjee, Som D.</au><au>Chi, Kim N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2014-08</date><risdate>2014</risdate><volume>32</volume><issue>4</issue><spage>746</spage><epage>752</epage><pages>746-752</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><coden>INNDDK</coden><abstract>Summary Purpose To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-naïve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (≥ 50 % decline from baseline). Results Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p  = 0.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels. Conclusion The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone. Further evaluation of this combination is not warranted in mCRPC.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>24671507</pmid><doi>10.1007/s10637-014-0091-8</doi><tpages>7</tpages></addata></record>
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language eng
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source MEDLINE; SpringerNature Journals
subjects Aged
Androgens
Anilides - administration & dosage
Anilides - adverse effects
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - adverse effects
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological and medical sciences
Cancer therapies
Chemotherapy
Correlation analysis
Drug dosages
Drug therapy
Epidermal growth factor
FDA approval
Gynecology. Andrology. Obstetrics
Health sciences
Humans
Inhibitor drugs
Kinases
Male
Male genital diseases
Medical sciences
Medicine
Medicine & Public Health
Metastasis
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Nephrology. Urinary tract diseases
Nitriles - administration & dosage
Nitriles - adverse effects
Oncology
Patients
Pharmaceuticals
Pharmacology. Drug treatments
Pharmacology/Toxicology
Phase II Studies
Piperidines - administration & dosage
Plasma
Prostate cancer
Prostate-Specific Antigen - metabolism
Prostatic Neoplasms, Castration-Resistant - drug therapy
Prostatic Neoplasms, Castration-Resistant - metabolism
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - adverse effects
Quinazolines - administration & dosage
Scintigraphy
Statistical analysis
Testosterone
Tosyl Compounds - administration & dosage
Tosyl Compounds - adverse effects
Toxicity
Tumors
Tumors of the urinary system
Urinary tract. Prostate gland
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - metabolism
Vascular Endothelial Growth Factor Receptor-2 - metabolism
title A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T20%3A36%3A02IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20randomized%20phase%20II%20efficacy%20and%20safety%20study%20of%20vandetanib%20(ZD6474)%20in%20combination%20with%20bicalutamide%20versus%20bicalutamide%20alone%20in%20patients%20with%20chemotherapy%20na%C3%AFve%20castration-resistant%20prostate%20cancer&rft.jtitle=Investigational%20new%20drugs&rft.au=Azad,%20Arun%20A.&rft.date=2014-08&rft.volume=32&rft.issue=4&rft.spage=746&rft.epage=752&rft.pages=746-752&rft.issn=0167-6997&rft.eissn=1573-0646&rft.coden=INNDDK&rft_id=info:doi/10.1007/s10637-014-0091-8&rft_dat=%3Cproquest_cross%3E3374803071%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1545397032&rft_id=info:pmid/24671507&rfr_iscdi=true