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
2006
Development and Validation of a Drug Activity Biomarker that Shows Target Inhibition in Cancer Patients Receiving Enzastaurin, a Novel Protein Kinase C-β Inhibitor
Green LJ, Marder P, Ray C, Cook CA, Jaken S, Musib LC, Herbst RS, Carducci M, Britten CD, Basche M, Eckhardt SG, Thornton D. Development and Validation of a Drug Activity Biomarker that Shows Target Inhibition in Cancer Patients Receiving Enzastaurin, a Novel Protein Kinase C-β Inhibitor. Clinical Cancer Research 2006, 12: 3408-3415. PMID: 16740765, DOI: 10.1158/1078-0432.ccr-05-2231.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBiomarkersCapecitabineCell Line, TumorClinical Trials, Phase I as TopicDeoxycytidineEnzyme ActivatorsEnzyme InhibitorsFlow CytometryFluorouracilFollow-Up StudiesHumansIndolesLeukocytes, MononuclearMonocytesNeoplasmsProtein Kinase CProtein Kinase C betaReproducibility of ResultsSensitivity and SpecificitySignal TransductionStructure-Activity RelationshipTreatment OutcomeConceptsPeripheral blood mononuclear cellsDaily oral dosesBlood mononuclear cellsCancer patientsOral dosesMononuclear cellsFlow cytometryDrug activity biomarkerPKC activityTarget cellsActivity biomarkersPhorbol esterNormal donorsPatientsActivity of PKCU937 cell lineTarget inhibitionEnzastaurinKinase inhibitorsΒ inhibitorSignificant decreaseCell linesU937 cellsIntracellular phosphoproteinsProtein kinase C
2004
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Does Not Improve Paclitaxel Effect in an Orthotopic Mouse Model of Lung Cancer
Onn A, Isobe T, Wu W, Itasaka S, Shintani T, Shibuya K, Kenji Y, O’Reilly M, Fidler IJ, Herbst RS. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Does Not Improve Paclitaxel Effect in an Orthotopic Mouse Model of Lung Cancer. Clinical Cancer Research 2004, 10: 8613-8619. PMID: 15623645, DOI: 10.1158/1078-0432.ccr-04-1241.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinoma, Bronchiolo-AlveolarAnimalsAntineoplastic Agents, PhytogenicCarcinoma, Non-Small-Cell LungDrug Therapy, CombinationEnzyme ActivationEnzyme InhibitorsErbB ReceptorsFibroblast Growth Factor 2HumansLung NeoplasmsMaleMiceMice, NudeMitogen-Activated Protein KinasesModels, AnimalPaclitaxelPhosphorylationPyrimidinesPyrrolesSurvival RateConceptsEGFR tyrosine kinase inhibitorsTumor implantationLung cancerKinase inhibitorsEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsReceptor tyrosine kinase inhibitorsBasic fibroblast growth factor expressionCombination of paclitaxelFibroblast growth factor expressionGroups of miceLungs of miceOrthotopic mouse modelHuman lung cancerTyrosine kinase inhibitorsGrowth factor expressionMaximal therapeutic effectHuman lung adenocarcinoma cellsLung adenocarcinoma cellsPaclitaxel 100Phosphorylation of EGFRConcurrent administrationEGFR-TKITherapeutic effectEpidermal growth factor receptor (EGFR) activationPotential role of molecularly targeted therapy in the management of advanced nonsmall cell lung carcinoma in the elderly
Gridelli C, Massarelli E, Maione P, Rossi A, Herbst RS, Onn A, Ciardiello F. Potential role of molecularly targeted therapy in the management of advanced nonsmall cell lung carcinoma in the elderly. Cancer 2004, 101: 1733-1744. PMID: 15386339, DOI: 10.1002/cncr.20572.Peer-Reviewed Original ResearchConceptsAdvanced nonsmall cell lung carcinomaNonsmall cell lung carcinomaNovel biologic agentsElderly patientsCell lung carcinomaConventional chemotherapyPatient ageBiologic agentsLung carcinomaClinical developmentSuch elderly patientsVascular endothelial growth factorLung carcinoma casesQuality of lifeEndothelial growth factorEpidermal growth factor receptorGrowth factor receptorAggressive chemotherapyImproved tolerabilityYounger patientsOrgan failureTherapy regimensComorbid conditionsMalignant diseaseCarcinoma cases
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 survivalDose-comparative monotherapy trials of ZD1839 in previously treated non–small cell lung cancer patients
Herbst RS. Dose-comparative monotherapy trials of ZD1839 in previously treated non–small cell lung cancer patients. Seminars In Oncology 2003, 30: 30-38. PMID: 12644982, DOI: 10.1053/sonc.2003.50030.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerAdvanced non-small cell lung cancerSymptom improvement rateTumor response rateDay groupSolid tumorsChemotherapy regimensIDEAL-2Ideal 1Lung cancerClinical trialsStage IIIResponse rateNon-small cell lung cancer patientsEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsAdvanced unresectable stage IIIMedian progression-free survivalObjective tumor response rateCell lung cancer patientsImprovement rateSelective epidermal growth factor receptor tyrosine kinase inhibitorReceptor tyrosine kinase inhibitorsPhase I clinical trialIressa Dose Evaluation
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 rashThe role of the epidermal growth factor receptor in the treatment of colorectal carcinoma
Waxman ES, Herbst RS. The role of the epidermal growth factor receptor in the treatment of colorectal carcinoma. Seminars In Oncology Nursing 2002, 18: 20-29. PMID: 12053861, DOI: 10.1053/sonu.2002.33072.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorColorectal carcinomaGrowth factor receptorClinical experienceAnti-EGFR monoclonal antibodiesTraditional cytotoxic approachesFactor receptorExtensive clinical testingTyrosine kinase inhibitorsEarly clinical experienceVariety of tumorsSignificant antitumor activityBiological agentsTreatment of cancerCytotoxic approachesEGFR resultsClinical testingNursing practiceCarcinomaMonoclonal antibodiesEGFR pathwayKinase inhibitorsAntitumor activityVariety of mechanismsReceptorsAngiogenesis inhibitors in clinical development for lung cancer
Herbst RS, Hidalgo M, Pierson AS, Holden SN, Bergen M, Eckhardt SG. Angiogenesis inhibitors in clinical development for lung cancer. Seminars In Oncology 2002, 29: 66-77. PMID: 11894016, DOI: 10.1053/sonc.2002.31527.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenesis InhibitorsAntineoplastic Combined Chemotherapy ProtocolsClinical Trials as TopicDisease ProgressionEndothelial Growth FactorsEndpoint DeterminationEnzyme InhibitorsHumansLung NeoplasmsLymphokinesMatrix Metalloproteinase InhibitorsMatrix MetalloproteinasesNeovascularization, PathologicTreatment OutcomeVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsConceptsAngiogenesis inhibitorsLung cancerClinical trialsClinical developmentPhase II trialLong-term administrationPlatinum-based therapyEarly clinical trialsReceptor-targeted agentsPrimary endpointAdvanced diseaseII trialMetastatic diseaseAdjunctive therapyProcess of angiogenesisCancer patientsField of angiogenesisEfficacious dosesClinical evaluationTumor regressionNovel agentsAntiangiogenic agentsTherapeutic targetDependence of tumorsTumor angiogenesis