Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types
Identifieur interne : 005505 ( PascalFrancis/Corpus ); précédent : 005504; suivant : 005506Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types
Auteurs : J. Baselga ; D. Rischin ; M. Ranson ; H. Calvert ; E. Raymond ; D. G. Kieback ; S. B. Kaye ; L. Gianni ; A. Harris ; T. Bjork ; S. D. Averbuch ; A. Feyereislova ; H. Swaisland ; F. Rojo ; J. AlbanellSource :
- Journal of clinical oncology [ 0732-183X ] ; 2002.
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Abstract
Purpose: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. Patients and Methods: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. Results: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD 1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. Conclusion: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.
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Format Inist (serveur)
| NO : | PASCAL 03-0039169 INIST |
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| ET : | Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types |
| AU : | BASELGA (J.); RISCHIN (D.); RANSON (M.); CALVERT (H.); RAYMOND (E.); KIEBACK (D. G.); KAYE (S. B.); GIANNI (L.); HARRIS (A.); BJORK (T.); AVERBUCH (S. D.); FEYEREISLOVA (A.); SWAISLAND (H.); ROJO (F.); ALBANELL (J.) |
| AF : | Vall d'Hebron University Hospital/Barcelona/Espagne; Peter MacCollum Institute/Melbourne/Australie; Christie Hospital Notional Health Service Trust/Manchester/Etats-Unis; Northern Centre for Cancer Treatment/Newcastle-upon-Tyne/Royaume-Uni; The Royal Marsden Hospital/Sutton/Etats-Unis; Churchill Hospital/Oxford/Etats-Unis; AstraZeneca/Alderley Park/Royaume-Uni; Institut Gustave Roussy/Villejuif/France; Maastricht University Medical Center/Maastricht/Pays-Bas; Istituto Nazionale Tumori/Milan/Italie; Universitetssjukhuset/Malmö/Suède; AstraZeneca/Wilmington, DE/Etats-Unis |
| DT : | Publication en série; Niveau analytique |
| SO : | Journal of clinical oncology; ISSN 0732-183X; Etats-Unis; Da. 2002; Vol. 20; No. 21; Pp. 4292-4302; Bibl. 43 ref. |
| LA : | Anglais |
| EA : | Purpose: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. Patients and Methods: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. Results: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD 1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. Conclusion: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839. |
| CC : | 002B02R02 |
| FD : | Tumeur solide; Essai clinique phase I; Homme; Facteur croissance épiderme; Récepteur membranaire; Inhibiteur enzyme; Toxicité; Pharmacocinétique; Pharmacologie; Relation dose réponse; Dose croissante; Dose maximale; Tolérance |
| ED : | Solid tumor; Phase I trial; Human; Epidermal growth factor; Membrane receptor; Enzyme inhibitor; Toxicity; Pharmacokinetics; Pharmacology; Dose activity relation; Increasing dose; Maximal dose; Tolerance |
| SD : | Tumor sólido; Ensayo clínico fase I; Hombre; Factor crecimiento epidermi; Receptor membrana; Inhibidor enzima; Toxicidad; Farmacocinética; Farmacología; Relación dosis respuesta; Dosis creciente; Dosis máxima; Tolerancia |
| LO : | INIST-20094.354000105410280050 |
| ID : | 03-0039169 |
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Albanell</name></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">03-0039169</idno><date when="2002">2002</date><idno type="stanalyst">PASCAL 03-0039169 INIST</idno><idno type="RBID">Pascal:03-0039169</idno><idno type="wicri:Area/PascalFrancis/Corpus">005505</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types</title><author><name sortKey="Baselga, J" sort="Baselga, J" uniqKey="Baselga J" first="J." last="Baselga">J. Baselga</name><affiliation><inist:fA14 i1="01"><s1>Vall d'Hebron University Hospital</s1><s2>Barcelona</s2><s3>ESP</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Peter MacCollum Institute</s1><s2>Melbourne</s2><s3>AUS</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="03"><s1>Christie Hospital Notional Health Service Trust</s1><s2>Manchester</s2><s3>USA</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="04"><s1>Northern Centre for Cancer Treatment</s1><s2>Newcastle-upon-Tyne</s2><s3>GBR</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="05"><s1>The Royal Marsden Hospital</s1><s2>Sutton</s2><s3>USA</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="06"><s1>Churchill Hospital</s1><s2>Oxford</s2><s3>USA</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="07"><s1>AstraZeneca</s1><s2>Alderley Park</s2><s3>GBR</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="08"><s1>Institut Gustave Roussy</s1><s2>Villejuif</s2><s3>FRA</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="09"><s1>Maastricht University Medical Center</s1><s2>Maastricht</s2><s3>NLD</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="10"><s1>Istituto Nazionale Tumori</s1><s2>Milan</s2><s3>ITA</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="11"><s1>Universitetssjukhuset</s1><s2>Malmö</s2><s3>SWE</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="12"><s1>AstraZeneca</s1><s2>Wilmington, DE</s2><s3>USA</s3></inist:fA14></affiliation></author><author><name sortKey="Rischin, D" sort="Rischin, D" uniqKey="Rischin D" first="D." last="Rischin">D. Rischin</name></author><author><name sortKey="Ranson, M" sort="Ranson, M" uniqKey="Ranson M" first="M." last="Ranson">M. Ranson</name></author><author><name sortKey="Calvert, H" sort="Calvert, H" uniqKey="Calvert H" first="H." last="Calvert">H. Calvert</name></author><author><name sortKey="Raymond, E" sort="Raymond, E" uniqKey="Raymond E" first="E." last="Raymond">E. Raymond</name></author><author><name sortKey="Kieback, D G" sort="Kieback, D G" uniqKey="Kieback D" first="D. G." last="Kieback">D. G. Kieback</name></author><author><name sortKey="Kaye, S B" sort="Kaye, S B" uniqKey="Kaye S" first="S. B." last="Kaye">S. B. Kaye</name></author><author><name sortKey="Gianni, L" sort="Gianni, L" uniqKey="Gianni L" first="L." last="Gianni">L. Gianni</name></author><author><name sortKey="Harris, A" sort="Harris, A" uniqKey="Harris A" first="A." last="Harris">A. Harris</name></author><author><name sortKey="Bjork, T" sort="Bjork, T" uniqKey="Bjork T" first="T." last="Bjork">T. Bjork</name></author><author><name sortKey="Averbuch, S D" sort="Averbuch, S D" uniqKey="Averbuch S" first="S. D." last="Averbuch">S. D. Averbuch</name></author><author><name sortKey="Feyereislova, A" sort="Feyereislova, A" uniqKey="Feyereislova A" first="A." last="Feyereislova">A. Feyereislova</name></author><author><name sortKey="Swaisland, H" sort="Swaisland, H" uniqKey="Swaisland H" first="H." last="Swaisland">H. Swaisland</name></author><author><name sortKey="Rojo, F" sort="Rojo, F" uniqKey="Rojo F" first="F." last="Rojo">F. Rojo</name></author><author><name sortKey="Albanell, J" sort="Albanell, J" uniqKey="Albanell J" first="J." last="Albanell">J. Albanell</name></author></analytic><series><title level="j" type="main">Journal of clinical oncology</title><title level="j" type="abbreviated">J. clin. oncol.</title><idno type="ISSN">0732-183X</idno><imprint><date when="2002">2002</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of clinical oncology</title><title level="j" type="abbreviated">J. clin. oncol.</title><idno type="ISSN">0732-183X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Dose activity relation</term><term>Enzyme inhibitor</term><term>Epidermal growth factor</term><term>Human</term><term>Increasing dose</term><term>Maximal dose</term><term>Membrane receptor</term><term>Pharmacokinetics</term><term>Pharmacology</term><term>Phase I trial</term><term>Solid tumor</term><term>Tolerance</term><term>Toxicity</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Tumeur solide</term><term>Essai clinique phase I</term><term>Homme</term><term>Facteur croissance épiderme</term><term>Récepteur membranaire</term><term>Inhibiteur enzyme</term><term>Toxicité</term><term>Pharmacocinétique</term><term>Pharmacologie</term><term>Relation dose réponse</term><term>Dose croissante</term><term>Dose maximale</term><term>Tolérance</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. Patients and Methods: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. Results: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD 1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. Conclusion: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0732-183X</s0></fA01><fA03 i2="1"><s0>J. clin. oncol.</s0></fA03><fA05><s2>20</s2></fA05><fA06><s2>21</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types</s1></fA08><fA11 i1="01" i2="1"><s1>BASELGA (J.)</s1></fA11><fA11 i1="02" i2="1"><s1>RISCHIN (D.)</s1></fA11><fA11 i1="03" i2="1"><s1>RANSON (M.)</s1></fA11><fA11 i1="04" i2="1"><s1>CALVERT (H.)</s1></fA11><fA11 i1="05" i2="1"><s1>RAYMOND (E.)</s1></fA11><fA11 i1="06" i2="1"><s1>KIEBACK (D. G.)</s1></fA11><fA11 i1="07" i2="1"><s1>KAYE (S. B.)</s1></fA11><fA11 i1="08" i2="1"><s1>GIANNI (L.)</s1></fA11><fA11 i1="09" i2="1"><s1>HARRIS (A.)</s1></fA11><fA11 i1="10" i2="1"><s1>BJORK (T.)</s1></fA11><fA11 i1="11" i2="1"><s1>AVERBUCH (S. D.)</s1></fA11><fA11 i1="12" i2="1"><s1>FEYEREISLOVA (A.)</s1></fA11><fA11 i1="13" i2="1"><s1>SWAISLAND (H.)</s1></fA11><fA11 i1="14" i2="1"><s1>ROJO (F.)</s1></fA11><fA11 i1="15" i2="1"><s1>ALBANELL (J.)</s1></fA11><fA14 i1="01"><s1>Vall d'Hebron University Hospital</s1><s2>Barcelona</s2><s3>ESP</s3></fA14><fA14 i1="02"><s1>Peter MacCollum Institute</s1><s2>Melbourne</s2><s3>AUS</s3></fA14><fA14 i1="03"><s1>Christie Hospital Notional Health Service Trust</s1><s2>Manchester</s2><s3>USA</s3></fA14><fA14 i1="04"><s1>Northern Centre for Cancer Treatment</s1><s2>Newcastle-upon-Tyne</s2><s3>GBR</s3></fA14><fA14 i1="05"><s1>The Royal Marsden Hospital</s1><s2>Sutton</s2><s3>USA</s3></fA14><fA14 i1="06"><s1>Churchill Hospital</s1><s2>Oxford</s2><s3>USA</s3></fA14><fA14 i1="07"><s1>AstraZeneca</s1><s2>Alderley Park</s2><s3>GBR</s3></fA14><fA14 i1="08"><s1>Institut Gustave Roussy</s1><s2>Villejuif</s2><s3>FRA</s3></fA14><fA14 i1="09"><s1>Maastricht University Medical Center</s1><s2>Maastricht</s2><s3>NLD</s3></fA14><fA14 i1="10"><s1>Istituto Nazionale Tumori</s1><s2>Milan</s2><s3>ITA</s3></fA14><fA14 i1="11"><s1>Universitetssjukhuset</s1><s2>Malmö</s2><s3>SWE</s3></fA14><fA14 i1="12"><s1>AstraZeneca</s1><s2>Wilmington, DE</s2><s3>USA</s3></fA14><fA20><s1>4292-4302</s1></fA20><fA21><s1>2002</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>20094</s2><s5>354000105410280050</s5></fA43><fA44><s0>0000</s0><s1>© 2003 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>43 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>03-0039169</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Journal of clinical oncology</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>Purpose: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. Patients and Methods: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. Results: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD 1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. Conclusion: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02R02</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Tumeur solide</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Solid tumor</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Tumor sólido</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Essai clinique phase I</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Phase I trial</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Ensayo clínico fase I</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Homme</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Human</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Hombre</s0><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Facteur croissance épiderme</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Epidermal growth factor</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Factor crecimiento epidermi</s0><s5>04</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Récepteur membranaire</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Membrane receptor</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Receptor membrana</s0><s5>05</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Inhibiteur enzyme</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Enzyme inhibitor</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Inhibidor enzima</s0><s5>06</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Toxicité</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Toxicity</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Toxicidad</s0><s5>07</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Pharmacocinétique</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Pharmacokinetics</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Farmacocinética</s0><s5>08</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Pharmacologie</s0><s5>09</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Pharmacology</s0><s5>09</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Farmacología</s0><s5>09</s5></fC03><fC03 i1="10" i2="X" l="FRE"><s0>Relation dose réponse</s0><s5>10</s5></fC03><fC03 i1="10" i2="X" l="ENG"><s0>Dose activity relation</s0><s5>10</s5></fC03><fC03 i1="10" i2="X" l="SPA"><s0>Relación dosis respuesta</s0><s5>10</s5></fC03><fC03 i1="11" i2="X" l="FRE"><s0>Dose croissante</s0><s5>11</s5></fC03><fC03 i1="11" i2="X" l="ENG"><s0>Increasing dose</s0><s5>11</s5></fC03><fC03 i1="11" i2="X" l="SPA"><s0>Dosis creciente</s0><s5>11</s5></fC03><fC03 i1="12" i2="X" l="FRE"><s0>Dose maximale</s0><s5>12</s5></fC03><fC03 i1="12" i2="X" l="ENG"><s0>Maximal dose</s0><s5>12</s5></fC03><fC03 i1="12" i2="X" l="SPA"><s0>Dosis máxima</s0><s5>12</s5></fC03><fC03 i1="13" i2="X" l="FRE"><s0>Tolérance</s0><s5>13</s5></fC03><fC03 i1="13" i2="X" l="ENG"><s0>Tolerance</s0><s5>13</s5></fC03><fC03 i1="13" i2="X" l="SPA"><s0>Tolerancia</s0><s5>13</s5></fC03><fN21><s1>020</s1></fN21><fN82><s1>PSI</s1></fN82></pA></standard><server><NO>PASCAL 03-0039169 INIST</NO><ET>Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types</ET><AU>BASELGA (J.); RISCHIN (D.); RANSON (M.); CALVERT (H.); RAYMOND (E.); KIEBACK (D. G.); KAYE (S. B.); GIANNI (L.); HARRIS (A.); BJORK (T.); AVERBUCH (S. D.); FEYEREISLOVA (A.); SWAISLAND (H.); ROJO (F.); ALBANELL (J.)</AU><AF>Vall d'Hebron University Hospital/Barcelona/Espagne; Peter MacCollum Institute/Melbourne/Australie; Christie Hospital Notional Health Service Trust/Manchester/Etats-Unis; Northern Centre for Cancer Treatment/Newcastle-upon-Tyne/Royaume-Uni; The Royal Marsden Hospital/Sutton/Etats-Unis; Churchill Hospital/Oxford/Etats-Unis; AstraZeneca/Alderley Park/Royaume-Uni; Institut Gustave Roussy/Villejuif/France; Maastricht University Medical Center/Maastricht/Pays-Bas; Istituto Nazionale Tumori/Milan/Italie; Universitetssjukhuset/Malmö/Suède; AstraZeneca/Wilmington, DE/Etats-Unis</AF><DT>Publication en série; Niveau analytique</DT><SO>Journal of clinical oncology; ISSN 0732-183X; Etats-Unis; Da. 2002; Vol. 20; No. 21; Pp. 4292-4302; Bibl. 43 ref.</SO><LA>Anglais</LA><EA>Purpose: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. Patients and Methods: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. Results: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD 1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. Conclusion: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.</EA><CC>002B02R02</CC><FD>Tumeur solide; Essai clinique phase I; Homme; Facteur croissance épiderme; Récepteur membranaire; Inhibiteur enzyme; Toxicité; Pharmacocinétique; Pharmacologie; Relation dose réponse; Dose croissante; Dose maximale; Tolérance</FD><ED>Solid tumor; Phase I trial; Human; Epidermal growth factor; Membrane receptor; Enzyme inhibitor; Toxicity; Pharmacokinetics; Pharmacology; Dose activity relation; Increasing dose; Maximal dose; Tolerance</ED><SD>Tumor sólido; Ensayo clínico fase I; Hombre; Factor crecimiento epidermi; Receptor membrana; Inhibidor enzima; Toxicidad; Farmacocinética; Farmacología; Relación dosis respuesta; Dosis creciente; Dosis máxima; Tolerancia</SD><LO>INIST-20094.354000105410280050</LO><ID>03-0039169</ID></server></inist></record>Pour manipuler ce document sous Unix (Dilib)
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