2016
KDR Amplification Is Associated with VEGF-Induced Activation of the mTOR and Invasion Pathways but does not Predict Clinical Benefit to the VEGFR TKI Vandetanib
Nilsson MB, Giri U, Gudikote J, Tang X, Lu W, Tran H, Fan Y, Koo A, Diao L, Tong P, Wang J, Herbst R, Johnson BE, Ryan A, Webster A, Rowe P, Wistuba II, Heymach JV. KDR Amplification Is Associated with VEGF-Induced Activation of the mTOR and Invasion Pathways but does not Predict Clinical Benefit to the VEGFR TKI Vandetanib. Clinical Cancer Research 2016, 22: 1940-1950. PMID: 26578684, PMCID: PMC4834253, DOI: 10.1158/1078-0432.ccr-15-1994.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, Non-Small-Cell LungCell Line, TumorCell MovementCell ProliferationHumansHypoxia-Inducible Factor 1, alpha SubunitLung NeoplasmsP38 Mitogen-Activated Protein KinasesPiperidinesProtein Kinase InhibitorsProto-Oncogene Proteins c-metQuinazolinesSignal TransductionTOR Serine-Threonine KinasesTreatment OutcomeVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2ConceptsNon-small cell lung cancerTyrosine kinase inhibitorsVEGFR tyrosine kinase inhibitorsNSCLC cell linesZODIAC studyClinical benefitLung cancerPlatinum-refractory non-small cell lung cancerAdvanced non-small cell lung cancerImproved progression-free survivalDifferent lung cancersObjective response rateProgression-free survivalVEGF pathway inhibitorsCell lung cancerArchival tumor samplesCell linesActivation of mTORVandetanib armOverall survivalNSCLC modelsNSCLC cellsPreclinical studiesPatientsVEGFR inhibition
2015
A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies
Platt A, Morten J, Ji Q, Elvin P, Womack C, Su X, Donald E, Gray N, Read J, Bigley G, Blockley L, Cresswell C, Dale A, Davies A, Zhang T, Fan S, Fu H, Gladwin A, Harrod G, Stevens J, Williams V, Ye Q, Zheng L, de Boer R, Herbst RS, Lee JS, Vasselli J. A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies. BMC Cancer 2015, 15: 171. PMID: 25881079, PMCID: PMC4412099, DOI: 10.1186/s12885-015-1146-8.Peer-Reviewed Original ResearchConceptsGene copy number gainCopy number gainsRET rearrangementsTumor samplesComparator armVandetanib treatmentNumber gainRandomized phase III studyPhase III clinical trialsCell lung cancer trialsObjective response ratePhase III studyLung cancer trialsRET protein expressionNSCLC subpopulationVandetanib armRadiologic evidenceIII studyNSCLC patientsObjective responseTumor shrinkageComparator drugsCancer trialsClinical trialsRetrospective analysis
2014
EGFR biomarkers predict benefit from vandetanib in combination with docetaxel in a randomized phase III study of second-line treatment of patients with advanced non-small cell lung cancer
Heymach JV, Lockwood SJ, Herbst RS, Johnson BE, Ryan AJ. EGFR biomarkers predict benefit from vandetanib in combination with docetaxel in a randomized phase III study of second-line treatment of patients with advanced non-small cell lung cancer. Annals Of Oncology 2014, 25: 1941-1948. PMID: 25057173, PMCID: PMC4176452, DOI: 10.1093/annonc/mdu269.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerSecond-line treatmentProgression-free survivalAdvanced non-small cell lung cancerRandomized phase III studyPhase III studyCell lung cancerMutation-positive tumorsEGFR mutationsIII studyTumor samplesClinical benefitLung cancerSecond-line non-small cell lung cancerEGFR FISH-positive tumorsEGFR mutation-positive tumorsEpidermal growth factor receptor (EGFR) gene mutationsObjective response rateRelative clinical benefitFirst-line chemotherapyObjective tumor responseProtein expressionOverall study populationGene mutationsPretreatment tumor samplesVandetanib and Indwelling Pleural Catheter for Non–Small-Cell Lung Cancer With Recurrent Malignant Pleural Effusion
Massarelli E, Onn A, Marom EM, Alden CM, Liu DD, Tran HT, Mino B, Wistuba II, Faiz SA, Bashoura L, Eapen GA, Morice RC, Lee J, Hong WK, Herbst RS, Jimenez CA. Vandetanib and Indwelling Pleural Catheter for Non–Small-Cell Lung Cancer With Recurrent Malignant Pleural Effusion. Clinical Lung Cancer 2014, 15: 379-386. PMID: 24913066, PMCID: PMC4160385, DOI: 10.1016/j.cllc.2014.04.002.Peer-Reviewed Original ResearchConceptsRecurrent malignant pleural effusionCell lung cancer patientsMalignant pleural effusionLung cancer patientsCell lung cancerPleural effusionCancer patientsMedian timeCatheter placementLung cancerEastern Cooperative Oncology Group performance statusPoor overall median survivalEnd pointSingle-arm phase II clinical trialPhase II clinical trialIndwelling pleural catheterOverall median survivalPrimary end pointSecondary end pointsDaily oral doseWeeks of treatmentPleural fluid cytologyVEGF receptor inhibitorPleural fluid cytokinesEligible patients
2013
Clinical and Biomarker Outcomes of the Phase II Vandetanib Study from the BATTLE Trial
Tsao AS, Liu S, Lee JJ, Alden CM, Blumenschein GR, Herbst R, Davis SE, Kim E, Lippman S, Heymach J, Tran H, Tang X, Wistuba I, Hong WK. Clinical and Biomarker Outcomes of the Phase II Vandetanib Study from the BATTLE Trial. Journal Of Thoracic Oncology 2013, 8: 658-661. PMID: 23584298, PMCID: PMC5118909, DOI: 10.1097/jto.0b013e31828d08ae.Peer-Reviewed Original ResearchMeSH KeywordsAcute-Phase ProteinsAgedAntineoplastic AgentsBiomarkers, TumorCarcinoma, Non-Small-Cell LungDisease-Free SurvivalFemaleGene AmplificationGenes, erbB-1HumansInterleukin-9Kaplan-Meier EstimateLipocalin-2LipocalinsLung NeoplasmsMaleMiddle AgedMutationPiperidinesProportional Hazards ModelsProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)QuinazolinesRas ProteinsTNF-Related Apoptosis-Inducing LigandConceptsDisease control rateWorse OSShorter PFSControl rateMutation patientsDual epidermal growth factor receptorVascular endothelial growth factor receptor inhibitionLung Cancer Elimination (BATTLE) trialNeutrophil gelatinase-associated lipocalinCell lung cancer patientsGrowth factor receptor inhibitionPhase II trialGelatinase-associated lipocalinLung cancer patientsTumor core biopsiesSerum biomarker analysisEGFR mutation patientsEpidermal growth factor receptorEGFR gene amplificationApoptosis-inducing ligandGrowth factor receptorMedian PFSOS benefitEpidermal growth factor receptor tyrosine kinaseII trialPhase 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
Clinical Outcomes and Biomarker Profiles of Elderly Pretreated NSCLC Patients from the BATTLE Trial
Tsao AS, Liu S, Lee JJ, Alden C, Blumenschein G, Herbst R, Davis SE, Kim E, Lippman S, Stewart D, Tang XM, Wistuba I, Hong WK. Clinical Outcomes and Biomarker Profiles of Elderly Pretreated NSCLC Patients from the BATTLE Trial. Journal Of Thoracic Oncology 2012, 7: 1645-1652. PMID: 23059780, PMCID: PMC5161038, DOI: 10.1097/jto.0b013e31826910ff.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBexaroteneBiomarkers, TumorCarcinoma, Non-Small-Cell LungCarcinoma, Squamous CellDrug Resistance, NeoplasmErlotinib HydrochlorideFemaleFollow-Up StudiesHumansLung NeoplasmsMaleMiddle AgedNeoplasm StagingNiacinamidePhenylurea CompoundsPiperidinesPrognosisQuinazolinesRetrospective StudiesSalvage TherapySorafenibSurvival RateTetrahydronaphthalenesConceptsProgression-free survivalDisease control rateNSCLC patientsOverall survivalElderly menGrade 3Older womenOlder menBetter median progression-free survivalHigher disease control rateLung Cancer Elimination (BATTLE) trialMedian progression-free survivalAge groupsBetter progression-free survivalCell lung cancer patientsBiomarker-Integrated ApproachesBiopsy-related pneumothoraxElderly NSCLC patientsMore grade 3Treatment-related deathsTumor tissue biomarkersRetrospective subgroup analysisSubset of patientsHigher overall survivalLung cancer patients
2010
Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial
Herbst RS, Sun Y, Eberhardt W, Germonpré P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. The Lancet Oncology 2010, 11: 619-626. PMID: 20570559, PMCID: PMC3225192, DOI: 10.1016/s1470-2045(10)70132-7.Peer-Reviewed Original ResearchConceptsProgression-free survivalMedian progression-free survivalVascular endothelial growth factor receptorCell lung cancerEpidermal growth factor receptorVandetanib groupFebrile neutropeniaGrowth factor receptorPlacebo groupAdverse eventsLung cancerCommon serious adverse eventsDefinitive phase 3 trialLonger progression-free survivalComparison of PFSDaily oral inhibitorHigher adverse eventsSecond-line treatmentFirst-line chemotherapyFirst-line therapyPhase 2 studyPhase 3 trialSerious adverse eventsFactor receptorEndothelial growth factor receptor
2009
Baseline Vascular Endothelial Growth Factor Concentration as a Potential Predictive Marker of Benefit from Vandetanib in Non–Small Cell Lung Cancer
Hanrahan EO, Ryan AJ, Mann H, Kennedy SJ, Langmuir P, Natale RB, Herbst RS, Johnson BE, Heymach JV. Baseline Vascular Endothelial Growth Factor Concentration as a Potential Predictive Marker of Benefit from Vandetanib in Non–Small Cell Lung Cancer. Clinical Cancer Research 2009, 15: 3600-3609. PMID: 19447868, DOI: 10.1158/1078-0432.ccr-08-2568.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCarcinoma, Non-Small-Cell LungClinical Trials, Phase II as TopicEnzyme-Linked Immunosorbent AssayHumansKaplan-Meier EstimateLung NeoplasmsMeta-Analysis as TopicPiperidinesPredictive Value of TestsQuinazolinesRandomized Controlled Trials as TopicReceptors, Vascular Endothelial Growth FactorTreatment OutcomeVascular Endothelial Growth Factor AConceptsNon-small cell lung cancerProgression-free survivalCell lung cancerAdvanced non-small cell lung cancerVandetanib monotherapyLung cancerDisease progressionVEGF levelsVEGF valuesSimilar riskRandomized phase II studyVascular endothelial growth factor concentrationsExploratory retrospective analysisPhase II studyBaseline VEGF levelsPotential predictive markerLower VEGF levelsGrowth factor concentrationsBaseline VEGFCarboplatin-paclitaxelPFS advantageII studyPredictive markerRetrospective analysisHealthy subjects
2008
Randomized Phase II Study of Vandetanib Alone or With Paclitaxel and Carboplatin as First-Line Treatment for Advanced Non–Small-Cell Lung Cancer
Heymach JV, Paz-Ares L, De Braud F, Sebastian M, Stewart DJ, Eberhardt WE, Ranade AA, Cohen G, Trigo JM, Sandler AB, Bonomi PD, Herbst RS, Krebs AD, Vasselli J, Johnson BE. Randomized Phase II Study of Vandetanib Alone or With Paclitaxel and Carboplatin as First-Line Treatment for Advanced Non–Small-Cell Lung Cancer. Journal Of Clinical Oncology 2008, 26: 5407-5415. PMID: 18936474, DOI: 10.1200/jco.2008.17.3138.Peer-Reviewed Original ResearchConceptsProgression-free survivalPhase II studyRisk of progressionVandetanib monotherapyII studyOverall survivalLung cancerAdvanced non-small cell lung cancerNon-small cell lung cancerMedian progression-free survivalLonger progression-free survivalRandomized phase II studyShorter progression-free survivalEnd pointVascular endothelial growth factor receptorCommon adverse eventsPrimary end pointStudy end pointSquamous cell histologyEndothelial growth factor receptorCell lung cancerCNS metastasesGrowth factor receptorMonotherapy armNSCLC histology
2007
Targeted Therapy Against VEGFR and EGFR With ZD6474 Enhances the Therapeutic Efficacy of Irradiation in an Orthotopic Model of Human Non–Small-Cell Lung Cancer
Shibuya K, Komaki R, Shintani T, Itasaka S, Ryan A, Jürgensmeier JM, Milas L, Ang K, Herbst RS, O'Reilly MS. Targeted Therapy Against VEGFR and EGFR With ZD6474 Enhances the Therapeutic Efficacy of Irradiation in an Orthotopic Model of Human Non–Small-Cell Lung Cancer. International Journal Of Radiation Oncology • Biology • Physics 2007, 69: 1534-1543. PMID: 17889445, PMCID: PMC2151850, DOI: 10.1016/j.ijrobp.2007.07.2350.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell ProliferationCombined Modality TherapyDNA RepairEpidermal Growth FactorErbB ReceptorsFeasibility StudiesHumansLung NeoplasmsMaleMiceMice, NudeNeovascularization, PathologicPiperidinesPleural EffusionQuinazolinesRadiation ToleranceRadiation-Sensitizing AgentsReceptors, Vascular Endothelial Growth FactorVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor AssaysConceptsVascular endothelial growth factor receptor 2Epidermal growth factor receptorLung cancerHuman lung cancerOrthotopic modelRadiation therapyHuman lung adenocarcinoma cellsLung adenocarcinoma cellsConventional therapyAntitumor effectsOrthotopic human lung cancer modelNon-small cell lung cancerHuman non-small cell lung cancerHuman lung cancer modelAdenocarcinoma cellsGrowth factor receptor 2Lung tumor burdenLung cancer modelEndothelial growth factor receptor 2Pleural effusion formationFactor receptor 2Basic fibroblast growth factorMatrix metalloproteinase-2Human lung adenocarcinomaSublethal damage repairRandomized, 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 studyTargeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade
Wu W, Onn A, Isobe T, Itasaka S, Langley RR, Shitani T, Shibuya K, Komaki R, Ryan AJ, Fidler IJ, Herbst RS, O'Reilly MS. Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade. Molecular Cancer Therapeutics 2007, 6: 471-483. PMID: 17308046, DOI: 10.1158/1535-7163.mct-06-0416.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAngiogenesis InhibitorsAnimalsApoptosisBlotting, WesternCarcinoma, Squamous CellCell Line, TumorCell ProliferationEndothelium, VascularErbB ReceptorsFlow CytometryHumansLung NeoplasmsMaleMiceMice, Inbred BALB CMice, Inbred CBANeovascularization, PathologicPhosphorylationPiperidinesProto-Oncogene Proteins c-aktQuinazolinesSignal TransductionVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor AssaysConceptsVascular endothelial growth factorVEGF receptor 2EGF receptorEpidermal growth factorLung cancerHuman lung cancerEndothelial growth factorGrowth factorMitogen-activated protein kinaseNon-small cell lung cancerOrthotopic human lung cancerProtein tyrosine kinase inhibitorEndothelial cellsTumor-associated endothelial cellsHuman lung cancer specimensAdvanced lung cancerSelective protein tyrosine kinase inhibitorCell lung cancerLung cancer patientsOrthotopic mouse modelEndothelial cell tube formationLung cancer specimensHuman lung adenocarcinoma cellsTyrosine kinase inhibitorsSmall molecule inhibitorsVandetanib (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
Toxicities of Antiangiogenic Therapy in Non–Small-Cell Lung Cancer
Herbst RS. Toxicities of Antiangiogenic Therapy in Non–Small-Cell Lung Cancer. Clinical Lung Cancer 2006, 8: s23-s30. PMID: 17239287, DOI: 10.3816/clc.2006.s.010.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenesis InhibitorsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic AgentsBenzenesulfonatesBevacizumabCarcinoma, Non-Small-Cell LungCarcinoma, Squamous CellHumansIndolesLung NeoplasmsNiacinamidePhenylurea CompoundsPiperidinesPyridinesPyrrolesQuinazolinesSorafenibSunitinibVascular Endothelial Growth FactorsConceptsAnti-VEGF antibodyCell lung cancerVascular endothelial growth factorAntiangiogenic agentsOverall survivalLung cancerPhase III pivotal trialsClass-effect toxicitiesFirst-line chemotherapyAdverse event profileSquamous cell histologyChemotherapy-associated toxicityVEGFR tyrosine kinaseTyrosine kinase inhibitorsEndothelial growth factorMetastatic NSCLCThromboembolic eventsCell histologyPivotal trialsEvent profileRisk factorsVEGF receptor activityAntiangiogenic therapySmall molecule inhibitorsTumor types
2005
Angiogenesis and lung cancer: prognostic and therapeutic implications.
Herbst RS, Onn A, Sandler A. Angiogenesis and lung cancer: prognostic and therapeutic implications. Journal Of Clinical Oncology 2005, 23: 3243-56. PMID: 15886312, DOI: 10.1200/jco.2005.18.853.Peer-Reviewed Original ResearchConceptsVascular endothelial growth factorAntiangiogenic agentsLung cancerSurrogate markerProangiogenic vascular endothelial growth factorMajority of patientsReliable surrogate markerTumor vascular developmentDownstream receptor signalingKey therapeutic strategyEndothelial growth factorVEGF receptor bindingMetastatic diseaseMost patientsCancer deathConventional chemotherapyCommon causeTherapeutic strategiesTherapeutic implicationsTumor typesTumor vasculatureTarget inhibitionAnticancer effectsCytostatic effectReceptor signaling
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