2021
A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer
Balch SM, Vaz-Luis I, Li T, Tayob N, Jain E, Helvie K, Buendia-Buendia JE, Shannon E, Isakoff SJ, Tung NM, Krop IE, Lin NU, Wagle N, Freedman RA. A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer. Breast Cancer Research And Treatment 2021, 189: 411-423. PMID: 34302589, DOI: 10.1007/s10549-021-06329-x.Peer-Reviewed Original ResearchConceptsHuman epidermal growth factor receptor 2Objective response ratePhase II studyWhole-exome sequencingEribulin 1.4II studyTreatment landscapeCohort AEribulin mesylateDay 1Genomic alterationsMetastatic breast cancer settingEpidermal growth factor receptor 2More frequent alterationsBreast cancer settingModest clinical activityGrowth factor receptor 2Metastatic breast cancerResponse/resistanceFactor receptor 2Manageable toxicityPertuzumab exposurePrimary endpointSix patientsCohort BPharmacokinetic (PK) analyses in CSF and plasma from TBCRC049, an ongoing trial to assess the safety and efficacy of the combination of tucatinib, trastuzumab and capecitabine for the treatment of leptomeningeal metastasis (LM) in HER2 positive breast cancer.
Stringer-Reasor E, O'Brien B, Topletz-Erickson A, White J, Lobbous M, Riley K, Childress J, LaMaster K, Melisko M, Morikawa A, De Groot J, Krop I, Valero V, Rimawi M, Wolff A, Tripathy D, Lin N, Murthy R. Pharmacokinetic (PK) analyses in CSF and plasma from TBCRC049, an ongoing trial to assess the safety and efficacy of the combination of tucatinib, trastuzumab and capecitabine for the treatment of leptomeningeal metastasis (LM) in HER2 positive breast cancer. Journal Of Clinical Oncology 2021, 39: 1044-1044. DOI: 10.1200/jco.2021.39.15_suppl.1044.Peer-Reviewed Original ResearchLeptomeningeal metastasesBrain metastasesBreast cancerPharmacokinetic analysisPhase 2 single-arm studyHER2-positive breast cancerCombination of tucatinibNew brain metastasesSingle-arm studyPositive breast cancerTyrosine kinase inhibitorsHigh interindividual variabilityMetastatic HER2Accrual goalEligible patientsMetastatic settingPrimary endpointOverall survivalOmmaya reservoirOngoing trialsPlasma concentrationsCapecitabinePatientsDay 1PK samples
2020
Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases
Leone JP, Emblem KE, Weitz M, Gelman RS, Schneider BP, Freedman RA, Younger J, Pinho MC, Sorensen AG, Gerstner ER, Harris G, Krop IE, Morganstern D, Sohl J, Hu J, Kasparian E, Winer EP, Lin NU. Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases. Breast Cancer Research 2020, 22: 131. PMID: 33256829, PMCID: PMC7706261, DOI: 10.1186/s13058-020-01372-w.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntineoplastic Combined Chemotherapy ProtocolsBevacizumabBrainBrain NeoplasmsBreastBreast NeoplasmsCarboplatinFemaleGenotyping TechniquesHumansKaplan-Meier EstimateMagnetic Resonance ImagingMiddle AgedPolymorphism, Single NucleotideProgression-Free SurvivalTrastuzumabVascular Endothelial Growth Factor AConceptsProgression-free survivalBreast cancer brain metastasesEarly MRI changesCancer brain metastasesBrain metastasesOverall survivalMRI changesBreast cancerEastern Cooperative Oncology Group performance statusDay 1Cycle 1 day 1Cycle 1 day 8Median progression-free survivalWorse progression-free survivalRegimen warrants further investigationDurable objective responsesECOG PS 1Efficacy of bevacizumabHER2-positive diseaseProgressive brain metastasesResultsThirty-eight patientsMedian overall survivalObjective response ratePhase II trialContrast-enhanced brain MRIEffect of Eribulin With or Without Pembrolizumab on Progression-Free Survival for Patients With Hormone Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer
Tolaney SM, Barroso-Sousa R, Keenan T, Li T, Trippa L, Vaz-Luis I, Wulf G, Spring L, Sinclair NF, Andrews C, Pittenger J, Richardson ET, Dillon D, Lin NU, Overmoyer B, Partridge AH, Van Allen E, Mittendorf EA, Winer EP, Krop IE. Effect of Eribulin With or Without Pembrolizumab on Progression-Free Survival for Patients With Hormone Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer. JAMA Oncology 2020, 6: 1598-1605. PMID: 32880602, PMCID: PMC7489368, DOI: 10.1001/jamaoncol.2020.3524.Peer-Reviewed Original ResearchConceptsProgression-free survivalObjective response rateTumor-infiltrating lymphocytesTumor mutational burdenPD-L1 statusOverall survivalHormonal therapyPrior linesPD-L1Clinical trialsMedian numberDay 1Cell death ligand 1 (PD-L1) inhibitorsERBB2-negative metastatic breast cancerMedian progression-free survivalDeath ligand 1 (PD-L1) inhibitorsEnd pointCause adverse eventsEfficacy of eribulinHormone receptor positiveMulticenter phase 2PD-L1 22C3Treatment-related deathsLines of chemotherapyPrimary end point
2016
Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial
Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, Yardley DA, Melichar B, Forero-Torres A, Lee SC, de Boer R, Petrakova K, Vallentin S, Perez EA, Piccart M, Ellis M, Winer E, Gendreau S, Derynck M, Lackner M, Levy G, Qiu J, He J, Schmid P. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Oncology 2016, 17: 811-821. PMID: 27155741, PMCID: PMC5524539, DOI: 10.1016/s1470-2045(16)00106-6.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBiomarkers, TumorBreast NeoplasmsDouble-Blind MethodDrug Resistance, NeoplasmEstradiolEstrogen Receptor AntagonistsFemaleFollow-Up StudiesFulvestrantHumansMiddle AgedNeoplasm Recurrence, LocalNeoplasm StagingPrognosisReceptor, ErbB-2Receptors, EstrogenSalvage TherapySurvival RateConceptsProgression-free survivalSerious adverse eventsTreatment-related serious adverse eventsWorse adverse eventsPlacebo groupAdverse eventsNon-measurable diseaseAromatase inhibitor treatmentPIK3CA mutationsBreast cancerDay 1Grade 3Inhibitor treatmentDay 15Cycle 1Median progression-free survivalHER2-negative breast cancerEndocrine-resistant breast cancerPIK3CA-mutated tumorsPhase 2 studyPhase 2 trialMetastatic breast cancerWeeks of treatmentAromatase inhibitor resistanceF Hoffmann-La Roche
2015
SU2C 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
2014
NI-23BRAIN BREAST METASTASES RESPOND TO ANTI-ANGIOGENIC THERAPY BY MODES OF VASCULAR NORMALIZATION
Emblem K, Pinho M, Chandra V, Gerstner E, Stufflebeam S, Sorenson G, Harris G, Freedman R, Sohl J, Younger J, Krop I, Winer E, Lin N. NI-23BRAIN BREAST METASTASES RESPOND TO ANTI-ANGIOGENIC THERAPY BY MODES OF VASCULAR NORMALIZATION. Neuro-Oncology 2014, 16: v143-v143. PMCID: PMC4218348, DOI: 10.1093/neuonc/nou264.22.Peer-Reviewed Original ResearchAnti-angiogenic therapyBreast cancerBrain metastasesVascular normalizationTumor perfusionBrain tumorsDay 1Largest contrast-enhancing lesionPerfusion MRIParenchymal brain metastasesMonths of therapyPhase II studyHormone receptor statusMetastatic breast cancerSubset of patientsContrast-enhancing lesionsPrimary brain tumorsAnti-angiogenic effectsOxygen saturation levelsPrior therapyBreast metastasisII studySystemic therapyImproved survivalReceptor status
2013
Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM).
Lin N, Gelman R, Younger W, Sohl J, Freedman R, Sorensen A, Bullitt E, Harris G, Morganstern D, Schneider B, Krop I, Winer E. Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM). Journal Of Clinical Oncology 2013, 31: 513-513. DOI: 10.1200/jco.2013.31.15_suppl.513.Peer-Reviewed Original ResearchBreast cancer brain metastasesCNS responseDay 1CNS objective response rateNon-target lesionsObjective response rateAnti-edema effectCancer brain metastasesPhase II trialProgressive neurologic signsStandard brain MRINon-CNS diseasesMultiple tumor typesPrior lapatinibPrior trastuzumabRECIST 1.0Steroid dosePrimary endpointProtocol therapyBrain metastasesFirst doseII trialCNS lesionsOverall survivalPartial responseA phase II study of ixabepilone and trastuzumab for metastatic HER2-positive breast cancer
Tolaney SM, Najita J, Sperinde J, Huang W, Chen WY, Savoie J, Fornier M, Winer EP, Bunnell C, Krop IE. A phase II study of ixabepilone and trastuzumab for metastatic HER2-positive breast cancer. Annals Of Oncology 2013, 24: 1841-1847. PMID: 23559151, PMCID: PMC3690910, DOI: 10.1093/annonc/mdt121.Peer-Reviewed Original ResearchConceptsMetastatic HER2-positive breast cancerHER2-positive breast cancerCombination of ixabepilonePhase II studyBreast cancerII studyMetastatic diseaseCohort 2Cohort 1Treatment-related toxic effectsClinical benefit rateSubsequent-line therapyTrastuzumab-containing regimensMetastatic breast cancerPrior chemotherapyLine therapyBenefit rateOverall RRDay 1PatientsTrastuzumabIxabepiloneCancerTumor biomarkersCohort
2011
PD09-04: A Phase Ib, Open-Label, Dose-Escalation Study of the Safety and Pharmacology of the PI3-Kinase Inhibitor GDC-0941 in Combination with Paclitaxel and Bevacizumab in Patients with Locally Recurrent or Metastatic Breast Cancer.
Schöffski P, De Benedictis E, Gendreau S, Gianni L, Krop I, Levy G, Ware J, Wildiers H, Winer E. PD09-04: A Phase Ib, Open-Label, Dose-Escalation Study of the Safety and Pharmacology of the PI3-Kinase Inhibitor GDC-0941 in Combination with Paclitaxel and Bevacizumab in Patients with Locally Recurrent or Metastatic Breast Cancer. Cancer Research 2011, 71: pd09-04-pd09-04. DOI: 10.1158/0008-5472.sabcs11-pd09-04.Peer-Reviewed Original ResearchMetastatic BCDay 1Prior treatmentPhase Ib studyDose-escalation studySubclavian vein thrombosisMetastatic breast cancerSingle-agent activityDose-escalation designCycle 1Breast cancer cell linesClass I PI3K isoformsAnti-cancer therapyPI3K pathwayPhosphorylation of AktAdditional DLTsCancer cell linesDrug holidayOpen labelVein thrombosisEscalation designPI3K isoformsLocally RecurrentChemotherapy treatmentCohort 2
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