2013
Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors
Schott AF, Landis MD, Dontu G, Griffith KA, Layman RM, Krop I, Paskett LA, Wong H, Dobrolecki LE, Lewis MT, Froehlich AM, Paranilam J, Hayes DF, Wicha MS, Chang JC. Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors. Clinical Cancer Research 2013, 19: 1512-1524. PMID: 23340294, PMCID: PMC3602220, DOI: 10.1158/1078-0432.ccr-11-3326.Peer-Reviewed Original ResearchConceptsBreast cancer stem cellsGamma-secretase inhibitorsAdvanced breast cancerClinical trialsBreast cancerSecretase inhibitorsMaximum-tolerated doseEfficacy of docetaxelSerial tumor biopsiesNotch pathwayTumors of patientsDoses of MKConcurrent clinical trialsHuman breast tumorsNotch pathway inhibitorsCancer stem cellsManageable toxicityTumorgraft modelsDocetaxel treatmentBCSC markersSerial biopsiesConventional therapyPreclinical dataClinical studiesExperimental therapies
2012
Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients With Advanced Solid Tumors
Krop I, Demuth T, Guthrie T, Wen PY, Mason WP, Chinnaiyan P, Butowski N, Groves MD, Kesari S, Freedman SJ, Blackman S, Watters J, Loboda A, Podtelezhnikov A, Lunceford J, Chen C, Giannotti M, Hing J, Beckman R, LoRusso P. Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients With Advanced Solid Tumors. Journal Of Clinical Oncology 2012, 30: 2307-2313. PMID: 22547604, DOI: 10.1200/jco.2011.39.1540.Peer-Reviewed Original ResearchConceptsAdvanced solid tumorsClinical benefitDose levelsSolid tumorsCommon drug-related toxicitiesGene signatureObjective complete responsePreliminary antitumor efficacyWeekly dose levelMaximum-tolerated doseDose-proportional mannerDrug-related toxicityHigh-grade gliomasHighest dose levelStable diseaseWeekly dosingAdult patientsComplete responseOral inhibitorNotch signalingCombination trialsNovel agentsPharmacodynamic studiesPatientsNotch pathway activation
2010
Phase II Study of the Antibody Drug Conjugate Trastuzumab-DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) –Positive Breast Cancer After Prior HER2-Directed Therapy
Burris HA, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O'Shaughnessy JA. Phase II Study of the Antibody Drug Conjugate Trastuzumab-DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) –Positive Breast Cancer After Prior HER2-Directed Therapy. Journal Of Clinical Oncology 2010, 29: 398-405. PMID: 21172893, DOI: 10.1200/jco.2010.29.5865.Peer-Reviewed Original ResearchMeSH KeywordsAdo-Trastuzumab EmtansineAdultAgedAged, 80 and overAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic AgentsBreast NeoplasmsDisease-Free SurvivalFemaleHumansImmunotoxinsKaplan-Meier EstimateMaytansineMiddle AgedReceptor, ErbB-2RNA, MessengerTime FactorsTrastuzumabTreatment OutcomeUnited StatesConceptsHER2-positive metastatic breast cancerMetastatic breast cancerPhase II studyTrastuzumab-DM1II studyAdverse eventsResponse rateBreast cancerHER2 levelsMedian progression-free survival timeSingle-arm phase II studyRobust single-agent activityProgression-free survival timeHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Human epidermal growth factor receptorHER2-directed therapiesMaximum-tolerated doseMost adverse eventsObjective response ratePhase II doseGrowth factor receptor 2Single-agent activityHER2-positive tumorsReverse transcriptase-polymerase chain reactionPhase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer
Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, Girish S, Tibbitts J, Yi JH, Sliwkowski MX, Jacobson F, Lutzker SG, Burris HA. Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer. Journal Of Clinical Oncology 2010, 28: 2698-2704. PMID: 20421541, DOI: 10.1200/jco.2009.26.2071.Peer-Reviewed Original ResearchMeSH KeywordsAdo-Trastuzumab EmtansineAdultAgedAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedBiopsy, NeedleBone NeoplasmsBreast NeoplasmsDose-Response Relationship, DrugDrug Administration ScheduleFemaleFollow-Up StudiesHalf-LifeHumansImmunoconjugatesImmunohistochemistryLiver NeoplasmsLung NeoplasmsMaximum Tolerated DoseMaytansineMiddle AgedNeoplasm StagingPatient SelectionReceptor, ErbB-2Risk AssessmentSurvival AnalysisThrombocytopeniaTrastuzumabTreatment OutcomeConceptsMaximum-tolerated doseAdvanced HER2-positive breast cancerHER2-positive breast cancerTrastuzumab-DM1Breast cancerAdverse eventsCommon drug-related adverse eventsHER2-positive metastatic breast cancerDrug-related adverse eventsHER2 antibody-drug conjugatesClinical benefit rateConfirmed response rateSubstantial clinical activityTrastuzumab-based therapyMetastatic breast cancerHER2-positive cellsAntibody-drug conjugatesMeasurable diseaseNeuropathy eventsElevated transaminasesCardiac effectsDose modificationMetastatic diseaseObjective responseReversible toxicity