2013
Phase I–IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours
Soria JC, Baselga J, Hanna N, Laurie SA, Bahleda R, Felip E, Calvo E, Armand JP, Shepherd FA, Harbison CT, Berman D, Park JS, Zhang S, Vakkalagadda B, Kurland JF, Pathak AK, Herbst RS. Phase I–IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours. European Journal Of Cancer 2013, 49: 1815-1824. PMID: 23490650, DOI: 10.1016/j.ejca.2013.02.012.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedArea Under CurveCarcinoma, Non-Small-Cell LungDiarrheaDose-Response Relationship, DrugDrug Resistance, NeoplasmErbB ReceptorsErlotinib HydrochlorideExanthemaFemaleHumansLung NeoplasmsMaleMetabolic Clearance RateMiddle AgedNeoplasm MetastasisNeoplasmsPiperidinesProtein Kinase InhibitorsPyrrolesQuinazolinesReceptor, ErbB-2Treatment OutcomeTriazinesVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth Factor Receptor-3ConceptsIIa studyBMS-690514Growth factor receptorPhase IAdverse eventsEGFR mutationsHER-2Phase IIaFrequent treatment-related adverse eventsSolid tumorsTreatment-related adverse eventsOral tyrosine kinase inhibitorDisease controlVascular endothelial growth factor receptorManageable safety profileObjective response rateAdvanced solid tumorsFactor receptorMetastatic solid tumorsEndothelial growth factor receptorCell lung cancerTyrosine kinase inhibitorsInhibition of VEGFREpidermal growth factor receptorWild-type EGFR
2012
A 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
2010
Pharmacokinetic study of the phase III, randomized, double-blind, multicenter trial (TRIBUTE) of paclitaxel and carboplatin combined with erlotinib or placebo in patients with advanced Non-small Cell Lung Cancer (NSCLC)
Tran HT, Zinner RG, Blumenschein GR, Oh YW, Papadimitrakopoulou VA, Kim ES, Lu C, Malik M, Lum BL, Herbst RS. Pharmacokinetic study of the phase III, randomized, double-blind, multicenter trial (TRIBUTE) of paclitaxel and carboplatin combined with erlotinib or placebo in patients with advanced Non-small Cell Lung Cancer (NSCLC). Investigational New Drugs 2010, 29: 499-505. PMID: 20094773, DOI: 10.1007/s10637-009-9380-z.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerAdvanced non-small cell lung cancerDrug-drug interactionsErlotinib groupPlacebo groupPotential drug-drug interactionsErlotinib treatment groupPlacebo-treated patientsPossible drug-drug interactionsStandard chemotherapy regimenPhase III trialsCell lung cancerAddition of erlotinibPharmacokinetics of erlotinibMetabolite OSI-420Non-compartmental modelingAUC 6Erlotinib 150Paclitaxel 200Resultant paclitaxelChemotherapy regimenIII trialsUntreated patientsConcomitant administrationMulticenter trial
2008
Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer
Oh Y, Herbst RS, Burris H, Cleverly A, Musib L, Lahn M, Bepler G. Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer. Journal Of Clinical Oncology 2008, 26: 1135-1141. PMID: 18309949, DOI: 10.1200/jco.2007.14.3685.Peer-Reviewed Original ResearchConceptsOral serine/threonine kinase inhibitorCell lung cancerPFS ratesMetastatic NSCLCOverall survivalLung cancerEastern Cooperative Oncology Group performance statusSix-month PFS rateProgression-free survival ratesEpidermal growth factor inhibitorsSerine/threonine kinase inhibitorProtein kinase CKinase inhibitorsPrior systemic regimensMedian overall survivalPrimary end pointThird-line therapyPhase II trialGrowth factor inhibitorsTumor cell apoptosisMedian PFSStable diseaseCommon toxicitiesPrior therapySystemic regimens
2007
Randomized, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel in Previously Treated Non–Small-Cell Lung Cancer
Heymach JV, Johnson BE, Prager D, Csada E, Roubec J, Pešek M, Špásová I, Belani CP, Bodrogi I, Gadgeel S, Kennedy SJ, Hou J, Herbst RS. Randomized, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel in Previously Treated Non–Small-Cell Lung Cancer. Journal Of Clinical Oncology 2007, 25: 4270-4277. PMID: 17878479, DOI: 10.1200/jco.2006.10.5122.Peer-Reviewed Original ResearchConceptsProgression-free survivalRandomized phaseOverall survivalLung cancerFirst-line platinum-based chemotherapyNon-small cell lung cancerMedian progression-free survivalActivity of vandetanibCommon adverse eventsDaily oral inhibitorObjective response rateOpen-label runPhase II studyGrowth factor receptor 2Platinum-based chemotherapyCell lung cancerOne-sided significance levelEndothelial growth factor receptor 2Second-line NSCLCVascular endothelial growth factor receptor 2Factor receptor 2Asymptomatic prolongationEligible patientsMetastatic NSCLCII studyVandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis
Herbst RS, Heymach JV, O’Reilly M, Onn A, Ryan AJ. Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opinion On Investigational Drugs 2007, 16: 239-249. PMID: 17243944, DOI: 10.1517/13543784.16.2.239.Peer-Reviewed Original ResearchConceptsTumor typesHereditary medullary thyroid cancerReceptor tyrosine kinase inhibitorsPhase III trialsProgression-free survivalDaily oral administrationPhase II evaluationPhase I studiesMedullary thyroid cancerTyrosine kinase inhibitorsSolid tumor typesTumor cell proliferationRefractory NSCLCAdvanced NSCLCIII trialsI studiesII evaluationThyroid cancerOral administrationAvailable agentsClinical developmentPharmacokinetic profileTumor growthVandetanibTumor angiogenesis
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
TRIBUTE: A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non–Small-Cell Lung Cancer
Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA. TRIBUTE: A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non–Small-Cell Lung Cancer. Journal Of Clinical Oncology 2005, 23: 5892-5899. PMID: 16043829, DOI: 10.1200/jco.2005.02.840.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsCarboplatinCarcinoma, Non-Small-Cell LungDisease ProgressionErbB ReceptorsErlotinib HydrochlorideFemaleHumansLung NeoplasmsMaleMiddle AgedPaclitaxelPlacebosProtein Kinase InhibitorsQuinazolinesSurvival AnalysisConceptsUntreated advanced NSCLCOverall survivalAdvanced NSCLCObjective responseLung cancerAdvanced non-small cell lung cancerEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsNon-small cell lung cancerEnd pointReceptor tyrosine kinase inhibitorsCycles of carboplatinGood performance statusImproved overall survivalOutcomes of patientsPrimary end pointSecondary end pointsPhase III trialsSingle-agent activityCell lung cancerDuration of responseTyrosine kinase inhibitorsAssessable patientsConcurrent carboplatinErlotinib armPhase 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 responseDynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study
Liu G, Rugo HS, Wilding G, McShane TM, Evelhoch JL, Ng C, Jackson E, Kelcz F, Yeh BM, Lee FT, Charnsangavej C, Park JW, Ashton EA, Steinfeldt HM, Pithavala YK, Reich SD, Herbst RS. Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study. Journal Of Clinical Oncology 2005, 23: 5464-5473. PMID: 16027440, DOI: 10.1200/jco.2005.04.143.Peer-Reviewed Original ResearchConceptsAdvanced solid tumorsAG-013736Vascular responsesMagnetic resonance imagingAcute dosingDay 2Solid tumorsAngiogenesis inhibitorsResonance imagingContrast-enhanced magnetic resonance imagingOral angiogenesis inhibitorSchedule of therapyTumor vascular functionDynamic contrast-enhanced magnetic resonance imagingObjective disease responsePhase II testingDCE-MRI scansEffect of treatmentTumor vascular parametersVolume transfer constantMorning doseSuitable markerPharmacodynamic measuresVascular functionPharmacodynamic responseClinically Meaningful Improvement in Symptoms and Quality of Life for Patients With Non-Small-Cell Lung Cancer Receiving Gefitinib in a Randomized Controlled Trial
Cella D, Herbst RS, Lynch TJ, Prager D, Belani CP, Schiller JH, Heyes A, Ochs JS, Wolf MK, Kay AC, Kris MG, Natale RB. Clinically Meaningful Improvement in Symptoms and Quality of Life for Patients With Non-Small-Cell Lung Cancer Receiving Gefitinib in a Randomized Controlled Trial. Journal Of Clinical Oncology 2005, 23: 2946-2954. PMID: 15699477, DOI: 10.1200/jco.2005.05.153.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAged, 80 and overAntineoplastic AgentsCarcinoma, Non-Small-Cell LungDose-Response Relationship, DrugDouble-Blind MethodEndpoint DeterminationFemaleGefitinibHealth StatusHumansLung NeoplasmsMaleMiddle AgedQuality of LifeQuinazolinesSensitivity and SpecificitySurvival AnalysisConceptsLung Cancer SubscaleSymptom improvementTumor responseQuality of lifeCancer Therapy-Lung (FACT-L) questionnairePivotal phase II trialMedian overall survival timeCoprimary end pointsPrior chemotherapy regimensProtocol-specified analysisSymptom improvement ratePhase II trialBetter overall survivalCell lung cancerOverall survival timeGefitinib 250Radiographic regressionChemotherapy regimensStable diseaseII trialMost patientsOverall survivalRadiographic responseSymptomatic patientsNSCLC patients
2003
Efficacy of Gefitinib, an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Symptomatic Patients With Non–Small Cell Lung Cancer: A Randomized Trial
Kris MG, Natale RB, Herbst RS, Lynch TJ, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC. Efficacy of Gefitinib, an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Symptomatic Patients With Non–Small Cell Lung Cancer: A Randomized Trial. JAMA 2003, 290: 2149-2158. PMID: 14570950, DOI: 10.1001/jama.290.16.2149.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerRadiographic tumor regressionPartial radiographic responseCell lung cancerRadiographic responseTumor regressionEpidermal growth factor receptorOral gefitinibLung cancerOral EGFR tyrosine kinase inhibitorRandomized phase 2 trialEGFR tyrosine kinase inhibitorsAcne-like rashCommunity oncology centersPhase 2 trialLung cancer symptomsPhase 1 trialEfficacy of gefitinibDisease-related symptomsFraction of patientsGrowth factor receptorNSCLC symptomsChemotherapy regimensEpidermal growth factor receptor tyrosine kinaseOverall survivalImprovements in quality of life and disease-related symptoms in phase I trials of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in non-small cell lung cancer and other solid tumors.
LoRusso PM, Herbst RS, Rischin D, Ranson M, Calvert H, Raymond E, Kieback D, Kaye S, Gianni L, Harris A, Bjork T, Maddox AM, Rothenberg ML, Small EJ, Rubin EH, Feyereislova A, Heyes A, Averbuch SD, Ochs J, Baselga J. Improvements in quality of life and disease-related symptoms in phase I trials of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in non-small cell lung cancer and other solid tumors. Clinical Cancer Research 2003, 9: 2040-8. PMID: 12796366.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerPhase I clinical trialCell lung cancerDisease-related symptomsQuality of lifeAdvanced cancerLung cancerClinical changesClinical trialsOvarian cancerEpidermal growth factor receptor tyrosine kinase inhibitor ZD1839Tumor typesEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsTyrosine kinase inhibitor ZD1839Receptor tyrosine kinase inhibitorsCancer Therapy questionnaireLung Cancer SubscaleMultiple-dose safetyPhase I trialUnited States trialsTyrosine kinase inhibitorsFact QuestionnairePrior therapyTOI scores
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
2001
Phase II study of the antiangiogenesis agent thalidomide in recurrent or metastatic squamous cell carcinoma of the head and neck
Tseng J, Glisson B, Khuri F, Shin D, Myers J, El‐Naggar A, Roach J, Ginsberg L, Thall P, Wang X, Teddy S, Lawhorn K, Zentgraf R, Steinhaus G, Pluda J, Abbruzzese J, Hong W, Herbst R. Phase II study of the antiangiogenesis agent thalidomide in recurrent or metastatic squamous cell carcinoma of the head and neck. Cancer 2001, 92: 2364-2373. PMID: 11745292, DOI: 10.1002/1097-0142(20011101)92:9<2364::aid-cncr1584>3.0.co;2-p.Peer-Reviewed Original ResearchConceptsMetastatic squamous cell carcinomaSquamous cell carcinomaPhase II studyCell carcinomaProgressive diseaseII studySurvival timeAntiangiogenic effectsAdvanced squamous cell carcinomaBasic fibroblast growth factor levelsMedian overall survival timeFibroblast growth factor levelsSingle-agent thalidomideSingle-agent antitumor activityEarly-stage diseasePopulation of patientsOverall survival timeGrowth factor levelsVascular endothelial growth factorMinimal residual diseaseSignificant antitumor effectEndothelial growth factorMechanism of actionStage diseaseUnacceptable toxicity