2020
Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors
Tsurutani J, Iwata H, Krop I, Jänne PA, Doi T, Takahashi S, Park H, Redfern C, Tamura K, Wise-Draper TM, Saito K, Sugihara M, Singh J, Jikoh T, Gallant G, Li BT. Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. Cancer Discovery 2020, 10: 688-701. PMID: 32213540, PMCID: PMC8292921, DOI: 10.1158/2159-8290.cd-19-1014.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerMutant non-small cell lung cancerTreatment-emergent adverse eventsMutant solid tumorsObjective response rateProgression-free survivalMedian progression-free survivalT-DXdSolid tumorsTrastuzumab deruxtecanDrug-related treatment-emergent adverse eventsCommon treatment-emergent adverse eventsConfirmed objective response rateSafety/tolerabilityAdvanced solid tumorsBiliary tract cancerPhase I trialHER2-positive breastInterstitial lung diseaseCell lung cancerSalivary gland cancerHeterogeneous patient populationUnmet medical needConfirmed responsesDose expansion
2019
Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study
Tamura K, Tsurutani J, Takahashi S, Iwata H, Krop IE, Redfern C, Sagara Y, Doi T, Park H, Murthy RK, Redman RA, Jikoh T, Lee C, Sugihara M, Shahidi J, Yver A, Modi S. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. The Lancet Oncology 2019, 20: 816-826. PMID: 31047803, DOI: 10.1016/s1470-2045(19)30097-x.Peer-Reviewed Original ResearchMeSH KeywordsAdo-Trastuzumab EmtansineAgedAntibodies, Monoclonal, HumanizedAntineoplastic Agents, ImmunologicalBreast NeoplasmsCamptothecinFemaleFollow-Up StudiesHumansImmunoconjugatesMaximum Tolerated DoseMiddle AgedPrognosisReceptor, ErbB-2Salvage TherapySurvival RateTissue DistributionTrastuzumabConceptsHER2-positive breast cancerTreatment-emergent adverse eventsAdvanced-stage breast cancerTrastuzumab emtansine treatmentTrastuzumab deruxtecanPhase 1 trialBreast cancerAdverse eventsProgressive diseaseSerious treatment-emergent adverse eventsWorse treatment-emergent adverse eventsAdvanced HER2-positive breast cancerSolid tumorsTopoisomerase I inhibitor payloadFrequent grade 3Grade 3 eventsTreatment-related deathsManageable safety profileAdvanced solid tumorsMultiple-dose studyPhase 1 studyInterstitial lung diseaseWithdrawal of consentWhite blood cellsYears of ageFirst‐in‐human, phase I study of PF‐06647263, an anti‐EFNA4 calicheamicin antibody–drug conjugate, in patients with advanced solid tumors
Garrido‐Laguna I, Krop I, Burris HA, Hamilton E, Braiteh F, Weise AM, Abu‐Khalaf M, Werner TL, Pirie‐Shepherd S, Zopf CJ, Lakshminarayanan M, Holland JS, Baffa R, Hong DS. First‐in‐human, phase I study of PF‐06647263, an anti‐EFNA4 calicheamicin antibody–drug conjugate, in patients with advanced solid tumors. International Journal Of Cancer 2019, 145: 1798-1808. PMID: 30680712, PMCID: PMC6875752, DOI: 10.1002/ijc.32154.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerAdvanced solid tumorsTumor responseSolid tumorsMetastatic triple-negative breast cancerPhase IPhase 2 doseAntitumor activityHuman xenograft tumor modelsAvailable standard therapiesDose-related mannerLimited antitumor activityXenograft tumor modelCommon AEsStable diseaseManageable safetyPartial responsePotent antitumor activityStandard therapyToxicity probability interval methodOvarian cancerBreast cancerPatientsRP2DTumor model
2018
Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer
Rodon J, Pérez-Fidalgo A, Krop IE, Burris H, Guerrero-Zotano A, Britten CD, Becerra C, Schellens J, Richards DA, Schuler M, Abu-Khalaf M, Johnson FM, Ranson M, Edenfield J, Silva AP, Hackl W, Quadt C, Demanse D, Duval V, Baselga J. Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer. Cancer Chemotherapy And Pharmacology 2018, 82: 285-298. PMID: 29882016, PMCID: PMC6286256, DOI: 10.1007/s00280-018-3610-z.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsDose-Response Relationship, DrugDrug CompoundingFemaleHumansImidazolesMaleMiddle AgedNeoplasmsPhosphoinositide-3 Kinase InhibitorsQuinolinesTOR Serine-Threonine KinasesTrastuzumabConceptsAdvanced breast cancerSingle agentBreast cancerSolid tumorsHigh dosesPhase I/IbEnd pointDual PI3K/mTOR inhibitorContinuous daily scheduleDose-escalation partMost frequent AEsOpen-label studyPrimary end pointSecondary end pointsAdvanced solid tumorsPI3K/mTOR inhibitorCombination cohortConclusionsThe MTDGastrointestinal AEsPartial responseDose escalationFrequent AEsOral inhibitorResultsOne hundredLow doseIncidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis
Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, Tolaney SM. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA Oncology 2018, 4: 173-182. PMID: 28973656, PMCID: PMC5838579, DOI: 10.1001/jamaoncol.2017.3064.Peer-Reviewed Original ResearchConceptsPD-1 inhibitorsCTLA-4 inhibitorsPD-L1 inhibitorsPrimary adrenal insufficiencyInsulin-deficient diabetesAdverse eventsCombination therapyEndocrine dysfunctionSystematic reviewAdrenal insufficiencyPD-1Clinical trialsDifferent immune checkpoint inhibitorsIncidence of AEsImmune checkpoint inhibitorsAdvanced solid tumorsEndocrine adverse eventsRisk of hyperthyroidismSuch adverse eventsPreferred Reporting ItemsRandom-effects modelGrade hypothyroidismInhibitor regimensMDX-010Checkpoint inhibitors
2015
First-in-human dose escalation, safety, and PK study of a novel EFNA4-ADC in patients with advanced solid tumors.
Hong D, Garrido-Laguna I, Krop I, Subbiah V, Werner T, Cotter C, Hamilton E, Velastegui K, Xuan D, Bugarini R, Gollerkeri A, Burris H. First-in-human dose escalation, safety, and PK study of a novel EFNA4-ADC in patients with advanced solid tumors. Journal Of Clinical Oncology 2015, 33: 2520-2520. DOI: 10.1200/jco.2015.33.15_suppl.2520.Peer-Reviewed Original ResearchSU2C Phase Ib Study of Paclitaxel and MK-2206 in Advanced Solid Tumors and Metastatic Breast Cancer
Gonzalez-Angulo AM, Krop I, Akcakanat A, Chen H, Liu S, Li Y, Culotta KS, Tarco E, Piha-Paul S, Moulder-Thompson S, Velez-Bravo V, Sahin AA, Doyle LA, Do KA, Winer EP, Mills GB, Kurzrock R, Meric-Bernstam F. SU2C Phase Ib Study of Paclitaxel and MK-2206 in Advanced Solid Tumors and Metastatic Breast Cancer. Journal Of The National Cancer Institute 2015, 107: dju493. PMID: 25688104, PMCID: PMC4342675, DOI: 10.1093/jnci/dju493.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorBreast NeoplasmsDrug Administration ScheduleDrug EruptionsFatigueFemaleHeterocyclic Compounds, 3-RingHumansHyperglycemiaMaleMaximum Tolerated DoseMiddle AgedNeoplasmsNeutropeniaPaclitaxelSeverity of Illness IndexTreatment OutcomeConceptsDose escalationDay 1Day 2Higher adverse eventsPhase Ib studyWeeks of therapyAdvanced solid tumorsCTCAE grade 3Metastatic breast cancerPrevious phase IPreliminary antitumor activityDose expansionStable diseaseObjective responseUnacceptable toxicityAdverse eventsMedian ageWeekly dosesClinical benefitPharmacodynamic markersSystemic exposureExcessive toxicityTumor responseGrade 3Median number
2012
A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer.
Krop I, Saura C, Rodon Ahnert J, Becerra C, Britten C, Isakoff S, Demanse D, Hackl W, Quadt C, Silva A, Burris H, Abu-Khalaf M, Baselga J. A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer. Journal Of Clinical Oncology 2012, 30: 508-508. DOI: 10.1200/jco.2012.30.15_suppl.508.Peer-Reviewed Original ResearchMetastatic breast cancerPI3K pathway alterationsBreast cancerG3 nauseaResistant HER2Disease stabilizationPathway alterationsPI3K/AKT/mTOR pathwayAcceptable safety profileDose-escalation studyAdvanced solid tumorsAKT/mTOR pathwayBreast cancer modelLogistic regression modelsPI3K pathwayG3 fatigueObserved DLTsBrain metastasesPartial responseSkin rashAdverse eventsLiver metastasesDose escalationSafety profileDose levelsPhase 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 activationPhase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors
Markman B, Tabernero J, Krop I, Shapiro G, Siu L, Chen L, Mita M, Cuero M, Stutvoet S, Birle D, Anak Ö, Hackl W, Baselga J. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Annals Of Oncology 2012, 23: 2399-2408. PMID: 22357447, DOI: 10.1093/annonc/mds011.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic AgentsBreast NeoplasmsColonic NeoplasmsDiarrheaFemaleFluorodeoxyglucose F18HumansImidazolesMaleMaximum Tolerated DoseMiddle AgedNauseaPhosphoinositide-3 Kinase InhibitorsProstatic NeoplasmsQuinolinesRadionuclide ImagingRadiopharmaceuticalsTOR Serine-Threonine KinasesTreatment OutcomeYoung AdultConceptsAdvanced solid tumorsPreliminary antitumor activityStable diseaseSystemic exposureAdaptive Bayesian logistic regression modelSolid tumorsPhase I dose-escalation studyI dose-escalation studyFluorodeoxyglucose positron emission tomographyStable metabolic diseaseVariable systemic exposureAntitumor activityDose-escalation studyLow systemic exposurePI3K pathway inhibitionDay three timesLogistic regression modelsAdverse eventsDose escalationFluorodeoxyglucose uptakeRapamycin inhibitorsTumor shrinkagePharmacodynamic studiesComputed tomographyMTOR inhibitors
2006
Phase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors
Krop I, Kosh M, Fearen I, Savoie J, Dallob A, Matthews C, Stone J, Winer E, Freedman S, Lorusso P. Phase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors. Journal Of Clinical Oncology 2006, 24: 10574-10574. DOI: 10.1200/jco.2006.24.18_suppl.10574.Peer-Reviewed Original ResearchGrade 3 diarrheaAdvanced breast cancerBreast cancerPlasma AbetaDay 1Notch intracellular domainDose levelsSolid tumorsAccelerated dose escalationGamma-SecretaseGrade 2/3 fatigueMean PK parametersSubset of ptsElevated liver transaminasesAdvanced solid tumorsDaily oral dosingIntermittent dosing scheduleAnalysis of efficacyHuman breast cancerBC cell proliferationInhibition of NotchAbdominal crampingLiver transaminasesDosing schedulesPharmacodynamic trial