2019
Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial
Herbst RS, Arkenau HT, Santana-Davila R, Calvo E, Paz-Ares L, Cassier PA, Bendell J, Penel N, Krebs MG, Martin-Liberal J, Isambert N, Soriano A, Wermke M, Cultrera J, Gao L, Widau RC, Mi G, Jin J, Ferry D, Fuchs CS, Petrylak DP, Chau I. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. The Lancet Oncology 2019, 20: 1109-1123. PMID: 31301962, DOI: 10.1016/s1470-2045(19)30458-9.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAgedAntibodies, Monoclonal, HumanizedAntineoplastic Agents, ImmunologicalAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Non-Small-Cell LungCarcinoma, Transitional CellDose-Response Relationship, DrugEsophageal NeoplasmsFemaleHumansLung NeoplasmsMaleMiddle AgedStomach NeoplasmsConceptsGastro-oesophageal junction adenocarcinomaTreatment-related adverse eventsCell lung cancerPhase 1a/b trialSerious adverse eventsDose-limiting toxicityAdverse eventsJunction adenocarcinomaUrothelial carcinomaLung cancerDay 1VEGF receptor 2Abdominal painPrevious therapyAdvanced gastricEastern Cooperative Oncology Group performance statusAntigen-specific T-cell migrationMore treatment-related adverse eventsTreatment-related serious adverse eventsAdditional dose-limiting toxicitiesCell lung cancer cohortGrade 3 abdominal painSingle-agent checkpoint inhibitorsB trialAntitumour activityRandomized, double-blind, phase 3 trial of first-line pembrolizumab + platinum doublet chemotherapy (chemo) ± lenvatinib in patients (pts) with metastatic nonsquamous non–small-cell lung cancer (NSCLC): LEAP-006.
Hui R, Nishio M, Reck M, Rodriguez-Abreu D, Fouad T, Flaim D, Yin L, Dang T, Herbst R. Randomized, double-blind, phase 3 trial of first-line pembrolizumab + platinum doublet chemotherapy (chemo) ± lenvatinib in patients (pts) with metastatic nonsquamous non–small-cell lung cancer (NSCLC): LEAP-006. Journal Of Clinical Oncology 2019, 37: tps9118-tps9118. DOI: 10.1200/jco.2019.37.15_suppl.tps9118.Peer-Reviewed Original ResearchPrimary endpointPD-L1 tumor proportion scoreFirst-line lenvatinibMetastatic nonsquamous NSCLCNCI CTCAE v4.0Platinum-doublet chemotherapyFirst-line pembrolizumabPhase 3 trialTumor proportion scoreDose-limiting toxicityKaplan-Meier methodCell lung cancerLog-rank testQuality of lifeDoublet chemotherapyECOG PSMaintenance pembrolizumabAdvanced NSCLCNonsquamous NSCLCSecondary endpointsStudy withdrawalCTCAE v4.0Carboplatin AUCNew cancer therapiesLung cancer
2012
Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours
Kozloff MF, Martin LP, Krzakowski M, Samuel TA, Rado TA, Arriola E, De Castro Carpeño J, Herbst RS, Tarazi J, Kim S, Rosbrook B, Tortorici M, Olszanski AJ, Cohen RB. Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours. British Journal Of Cancer 2012, 107: 1277-1285. PMID: 22990652, PMCID: PMC3494447, DOI: 10.1038/bjc.2012.406.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerPaclitaxel/carboplatinAdvanced non-small cell lung cancerPharmacokinetics of axitinibGemcitabine/cisplatinCell lung cancerAxitinib 5Platinum doubletsLung cancerSolid tumorsSquamous cell non-small cell lung cancerTreatment-related adverse eventsSelective second-generation inhibitorVascular endothelial growth factor receptorObjective response rateDose-limiting toxicityPhase I trialEndothelial growth factor receptorDose-finding trialDrug-drug interactionsPhase I dose-finding trialsCisplatin regimensFebrile neutropeniaGrowth factor receptorExpansion cohortA Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors
Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL, Vo AC, Klucher K, Herbst RS, Eckhardt SG, Peterson S, Hausman DF, Kurzrock R, Jimeno A. A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors. Clinical Cancer Research 2012, 18: 4173-4182. PMID: 22693357, DOI: 10.1158/1078-0432.ccr-12-0714.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAged, 80 and overArea Under CurveDiarrheaDisease ProgressionDose-Response Relationship, DrugDrug Administration ScheduleEnzyme InhibitorsFatigueFemaleGonanesHumansMaleMetabolic Clearance RateMiddle AgedMutationNauseaNeoplasmsPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsTreatment OutcomeVomitingConceptsDose-limiting toxicityArm 1PX-866Stable diseaseArm 2Frequent study drug-related adverse eventsSolid tumorsStudy drug-related adverse eventsDrug-related adverse eventsMulticenter phase I trialGrade III diarrheaAdvanced solid tumorsDose-escalation studyResponse Evaluation CriteriaContinuous dosing scheduleElevated aspartate aminotransferasePhase I trialEvaluable patientsIrreversible small-molecule inhibitorAdverse eventsDosing schedulesI trialAdditional patientsGastrointestinal disordersIncurable cancer
2011
A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors
Infante JR, Kurzrock R, Spratlin J, Burris HA, Eckhardt SG, Li J, Wu K, Skolnik JM, Hylander-Gans L, Osmukhina A, Huszar D, Herbst RS. A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors. Cancer Chemotherapy And Pharmacology 2011, 69: 165-172. PMID: 21638123, DOI: 10.1007/s00280-011-1667-z.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityPrimary dose-limiting toxicityPhase IAcceptable safety profileAdvanced solid malignanciesAdvanced solid tumorsRelated adverse eventsSeverity of neutropeniaConclusionThe MTDAdverse eventsIntravenous infusionSafety profileSolid malignanciesAZD4877Intermediate doseDose reductionPart BPharmacokinetic profileDay 1Solid tumorsPart ANeutropeniaTolerabilityPatientsMTD
2009
Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors
Herbst RS, Hong D, Chap L, Kurzrock R, Jackson E, Silverman JM, Rasmussen E, Sun YN, Zhong D, Hwang YC, Evelhoch JL, Oliner JD, Le N, Rosen LS. Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors. Journal Of Clinical Oncology 2009, 27: 3557-3565. PMID: 19546406, DOI: 10.1200/jco.2008.19.6683.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAngiogenesis InhibitorsAngiopoietinsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntimetabolites, AntineoplasticBevacizumabDose-Response Relationship, DrugDrug-Related Side Effects and Adverse ReactionsFatigueFemaleHumansInfusions, IntravenousMaleMaximum Tolerated DoseMiddle AgedNeoplasm StagingNeoplasmsTreatment OutcomeConceptsAMG 386Advanced solid tumorsPartial responseAntitumor activitySolid tumorsElimination half-life valuesPatients 48 hoursMaximum-tolerated doseTreatment-related toxicityDose-limiting toxicityRefractory ovarian cancerWeeks of treatmentPeptide-Fc fusion proteinVolume transfer constantAngiopoietin inhibitorsCommon toxicitiesStable diseasePeripheral edemaAdult patientsClinical sequelaeMethods PatientsWeekly dosesTumor burdenRespiratory arrestSafety profilePhase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor
Jimeno A, Hong D, Hecker S, Clement R, Kurzrock R, Pestano L, Hiscox A, Leos R, Kirkpatrick D, Eckhardt S, Herbst R. Phase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor. Journal Of Clinical Oncology 2009, 27: 3542-3542. DOI: 10.1200/jco.2009.27.15_suppl.3542.Peer-Reviewed Original ResearchPX-866Stable diseaseClinical trialsDay 1Drug-related severe adverse eventsMild side effect profilePhase 1 clinical trialStabilization of diseaseSevere adverse eventsDose-limiting toxicityPhase I trialSide effect profileAdvanced metastatic cancerP-mTOR levelsDose-dependent inhibitionLower drug dosesPhosphoinositide-3 kinase inhibitorPD endpointsExpansion cohortLast doseAbdominal discomfortAdverse eventsI trialEffect profileLoss of PTEN
2008
Dose Escalation of Gemcitabine Is Possible With Concurrent Chest Three-Dimensional Rather Than Two-Dimensional Radiotherapy: A Phase I Trial in Patients With Stage III Non–Small-Cell Lung Cancer
Zinner RG, Komaki R, Cox JD, Glisson BS, Pisters KM, Herbst RS, Kies M, Liao Z, Hong WK, Fossella FV. Dose Escalation of Gemcitabine Is Possible With Concurrent Chest Three-Dimensional Rather Than Two-Dimensional Radiotherapy: A Phase I Trial in Patients With Stage III Non–Small-Cell Lung Cancer. International Journal Of Radiation Oncology • Biology • Physics 2008, 73: 119-127. PMID: 18556142, DOI: 10.1016/j.ijrobp.2008.03.069.Peer-Reviewed Original ResearchMeSH KeywordsAbdomenAdultAgedAged, 80 and overAntimetabolites, AntineoplasticCarcinoma, Non-Small-Cell LungCombined Modality TherapyDeoxycytidineDose-Response Relationship, DrugDose-Response Relationship, RadiationFeasibility StudiesFemaleGemcitabineHumansLung NeoplasmsMaleMiddle AgedRadiation-Sensitizing AgentsRadiotherapy, ConformalTreatment OutcomeConceptsGrade 3 esophagitisDose of gemcitabineCell lung cancerTwo-dimensional radiotherapyLung cancerThree-dimensional conformal radiotherapySevere acute esophagitisWeekly gemcitabine concurrentCycles of gemcitabinePhase II doseStage III NSCLCDose-limiting toxicityPhase I trialThree-dimensional CRTChest radiotherapyConcurrent chestConcurrent radiotherapySevere esophagitisAcute esophagitisI trialDose escalationConformal radiotherapyEsophagitisApparent diseaseStage III
2007
First-in-human study of AMG 386, a selective angiopoietin1/2-neutralizing peptibody, in adult patients with advanced solid tumors
Rosen L, Hong D, Chap L, Kurzrock R, Garcia A, Rasmussen E, Nguyen L, Hwang Y, Storgard C, Herbst R. First-in-human study of AMG 386, a selective angiopoietin1/2-neutralizing peptibody, in adult patients with advanced solid tumors. Journal Of Clinical Oncology 2007, 25: 3522-3522. DOI: 10.1200/jco.2007.25.18_suppl.3522.Peer-Reviewed Original ResearchAMG 386Advanced solid tumorsAdverse eventsStable diseaseTumor responseHuman studiesGrade 2Solid tumorsDCE-MRIMinor clinical responseSignificant vascular effectsSerum CA 125Treatment-related toxicityDose-limiting toxicityFurther clinical studiesEvaluable patientsEvaluable subjectsPeripheral edemaRECIST criteriaAdult patientsClinical responseProgressive diseaseWeekly administrationVascular effectsCA 125
2006
Phase I Dose Escalation and Pharmacokinetic Study of Enzastaurin, an Oral Protein Kinase C Beta Inhibitor, in Patients With Advanced Cancer
Carducci MA, Musib L, Kies MS, Pili R, Truong M, Brahmer JR, Cole P, Sullivan R, Riddle J, Schmidt J, Enas N, Sinha V, Thornton DE, Herbst RS. Phase I Dose Escalation and Pharmacokinetic Study of Enzastaurin, an Oral Protein Kinase C Beta Inhibitor, in Patients With Advanced Cancer. Journal Of Clinical Oncology 2006, 24: 4092-4099. PMID: 16943527, DOI: 10.1200/jco.2005.05.3447.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAntineoplastic AgentsDose-Response Relationship, DrugDrug Administration ScheduleFemaleFlow CytometryGene Expression Regulation, EnzymologicGene Expression Regulation, NeoplasticHumansIndolesMaleMiddle AgedNeoplasmsProtein Kinase CProtein Kinase C betaProtein Kinase InhibitorsConceptsMaximum-tolerated doseProtein kinase C beta inhibitorStable diseaseAdvanced cancerEastern Cooperative Oncology Group performance statusSignificant grade 3/4 toxicityBeta inhibitorGrade 3/4 toxicitiesPhase II dosePhase II trialDose-limiting toxicityYears of ageExpansion cohortGI toxicityII trialStarting dosePerformance statusDose escalationAdditional patientsNeck cancerPrevalent malignancySafety dataPatientsSecondary objectiveEnzastaurin
2005
Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results
Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, Wilding G. Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results. Journal Of Clinical Oncology 2005, 23: 5474-5483. PMID: 16027439, DOI: 10.1200/jco.2005.04.192.Peer-Reviewed Original ResearchConceptsAdvanced solid tumorsAG-013736Clinical activityOral receptor tyrosine kinase inhibitorSolid tumorsReceptor tyrosine kinase inhibitorsGrowth factorSingle test dosesMaximum-tolerated dosePhase II doseDose-limiting toxicitySignificant drug interactionsPeak plasma concentrationEndothelial cell growth factorPhase II testingVascular endothelial cell growth factorTyrosine kinase inhibitorsHighest dose levelPlatelet-derived growth factorIndividual PK parametersEffect of foodCell growth factorObserved hypertensionDrug holidayPartial responsePhase I/II Trial Evaluating the Anti-Vascular Endothelial Growth Factor Monoclonal Antibody Bevacizumab in Combination With the HER-1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib for Patients With Recurrent Non–Small-Cell Lung Cancer
Herbst RS, Johnson DH, Mininberg E, Carbone DP, Henderson T, Kim ES, Blumenschein G, Lee JJ, Liu DD, Truong MT, Hong WK, Tran H, Tsao A, Xie D, Ramies DA, Mass R, Seshagiri S, Eberhard DA, Kelley SK, Sandler A. Phase I/II Trial Evaluating the Anti-Vascular Endothelial Growth Factor Monoclonal Antibody Bevacizumab in Combination With the HER-1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib for Patients With Recurrent Non–Small-Cell Lung Cancer. Journal Of Clinical Oncology 2005, 23: 2544-2555. PMID: 15753462, DOI: 10.1200/jco.2005.02.477.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBevacizumabCarcinoma, Non-Small-Cell LungDose-Response Relationship, DrugDrug InteractionsErlotinib HydrochlorideFemaleHumansInfusions, IntravenousLung NeoplasmsMaleMiddle AgedProtein Kinase InhibitorsQuinazolinesSurvival AnalysisTreatment OutcomeConceptsPhase II doseCell lung cancerLung cancerHumanized anti-vascular endothelial growth factor monoclonal antibodyVascular endothelial growth factor monoclonal antibody bevacizumabAnti-vascular endothelial growth factor monoclonal antibodyPhase I/II studyPhase I/II trialStage IIIB/IV NSCLCEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinibTyrosine kinase inhibitor erlotinibReceptor tyrosine kinase inhibitorsCommon adverse eventsMedian overall survivalProgression-free survivalDose-limiting toxicityFactor monoclonal antibodyMonoclonal antibody bevacizumabKinase inhibitor erlotinibTyrosine kinase inhibitorsAdenocarcinoma histologyModerate rashPrior chemotherapy
2004
Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Paclitaxel in Solid Tumors
Khuri FR, Glisson BS, Kim ES, Statkevich P, Thall PF, Meyers ML, Herbst RS, Munden RF, Tendler C, Zhu Y, Bangert S, Thompson E, Lu C, Wang XM, Shin DM, Kies MS, Papadimitrakopoulou V, Fossella FV, Kirschmeier P, Bishop WR, Hong WK. Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Paclitaxel in Solid Tumors. Clinical Cancer Research 2004, 10: 2968-2976. PMID: 15131032, DOI: 10.1158/1078-0432.ccr-03-0412.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerGrade 4 diarrheaCell lung cancerPartial responseLung cancerMetastatic non-small cell lung cancerSolid tumorsGrade 3 peripheral neuropathyPrincipal grade 3/4 toxicitiesDose level 3Durable partial responseGrade 3 hyperbilirubinemiaPrevious taxane therapyGrade 3/4 toxicitiesGrade 4 neutropeniaPhase II trialDose-limiting toxicityPhase I trialFarnesyltransferase inhibitor lonafarnibNovel farnesyltransferase inhibitorPlasma paclitaxelII trialTaxane therapyCombination regimenMedian duration
2003
A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer.
Herbst RS, Hammond LA, Carbone DP, Tran HT, Holroyd KJ, Desai A, Williams JI, Bekele BN, Hait H, Allgood V, Solomon S, Schiller JH. A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Clinical Cancer Research 2003, 9: 4108-15. PMID: 14519633.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAngiogenesis InhibitorsAntineoplastic Combined Chemotherapy ProtocolsCarboplatinCarcinoma, Non-Small-Cell LungCholestanolsDisease-Free SurvivalFemaleHumansInfusions, IntravenousLactatesLung NeoplasmsMaleMiddle AgedNeoplasm StagingPaclitaxelPatient SelectionPleural EffusionSurvival AnalysisTime FactorsConceptsNon-small cell lung cancerCell lung cancerLung cancerDay 1Continuous infusionChemotherapy-naive non-small cell lung cancerAdvanced non-small cell lung cancerPhase I/IIa studyPhase I/IIa trialPhase II doseDose-limiting toxicityPartial tumor responseFive-day infusionEffective therapeutic strategyPatient survival dataEvaluable patientsStable diseaseStage IIIBStarting doseClinical responseCombination regimenCytotoxic chemotherapyIIa studyIIa trialMedian survival
2002
Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial.
Herbst RS, Maddox AM, Rothenberg ML, Small EJ, Rubin EH, Baselga J, Rojo F, Hong WK, Swaisland H, Averbuch SD, Ochs J, LoRusso PM. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. Journal Of Clinical Oncology 2002, 20: 3815-25. PMID: 12228201, DOI: 10.1200/jco.2002.03.038.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAged, 80 and overAntineoplastic AgentsCarcinoma, Non-Small-Cell LungDose-Response Relationship, DrugDrug Administration ScheduleEnzyme InhibitorsFemaleGastrointestinal DiseasesGefitinibHead and Neck NeoplasmsHumansLung NeoplasmsMaleMaximum Tolerated DoseMiddle AgedNeoplasm StagingNeoplasmsProtein-Tyrosine KinasesQuinazolinesSkin DiseasesConceptsDose-limiting toxicityPharmacokinetic analysisEpidermal growth factor receptor tyrosine kinase inhibitor ZD1839Epidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsGrade 1/2 adverse eventsTyrosine kinase inhibitor ZD1839Primary dose-limiting toxicityReceptor tyrosine kinase inhibitorsPrior cancer therapyAntitumor activityDaily oral dosingPhase I trialCell lung cancerTyrosine kinase inhibitorsSolid tumor typesVariability of exposureStable diseaseAdverse eventsPartial responseUndue toxicityI trialTolerability trialCell lungFollicular rashPharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition.
Albanell J, Rojo F, Averbuch S, Feyereislova A, Mascaro J, Herbst R, LoRusso P, Rischin D, Sauleda S, Gee J, Nicholson R, Baselga J. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. Journal Of Clinical Oncology 2002, 20: 110-24. PMID: 11773160, DOI: 10.1200/jco.2002.20.1.110.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAntineoplastic AgentsApoptosisBiomarkersCell Cycle ProteinsCyclin-Dependent Kinase Inhibitor p27Dose-Response Relationship, DrugErbB ReceptorsFemaleGefitinibHumansKeratinocytesMaleMAP Kinase Signaling SystemMiddle AgedNeoplasmsQuinazolinesSkinStatistics, NonparametricTumor Suppressor ProteinsConceptsCancer patientsEpidermal growth factor receptor tyrosine kinase inhibitor ZD1839Tyrosine kinase inhibitor ZD1839Phase I clinical trialMaximum-tolerated doseDose-limiting toxicityEGFR activationReceptor-dependent processUnacceptable toxicityDefinitive efficacyPharmacodynamic assessmentSafety trialPharmacodynamic effectsClinical trialsKeratin plugsReceptor inhibitionMaturation markersSkin biopsiesPharmacodynamic studiesProliferation indexDose levelsOral ZD1839PatientsOptimal dosesZD1839