2021
Clinical pharmacokinetics of bdtx-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies in MasterKey-01 study.
Waters N, Patel M, Schram A, Ahnert J, Jauhari S, Sachdev J, Zhu V, LoRusso P, Nguyen D, Hong D, Tarilonte L, Humphrey R, Janne P, Hamilton E, Witt K. Clinical pharmacokinetics of bdtx-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies in MasterKey-01 study. Journal Of Clinical Oncology 2021, 39: 3097-3097. DOI: 10.1200/jco.2021.39.15_suppl.3097.Peer-Reviewed Original ResearchHigh-fat mealFasted stateEGFR WTRapid absorptionPK/PD profilesDose-escalation cohortsNon-fasting statePhase 2 doseAdvanced solid malignanciesHigh-fat breakfastSubset of patientsElimination t 1/2Serial blood samplesNon-compartmental methodsDose-dependent increaseSustained pharmacodynamic effectsMedian tmaxEscalation cohortsCrossover fashionDose escalationFat mealPharmacodynamic effectsSystemic exposureMultiple dosesClinical Pharmacokinetics
2020
Pharmacodynamic effects in blood and tumor tissue of eftozanermin alfa, a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist.
Motwani M, Modi D, Penugonda S, Zhang C, Palma J, Cunningham A, Calvo E, de Jonge M, LoRusso P. Pharmacodynamic effects in blood and tumor tissue of eftozanermin alfa, a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist. Journal Of Clinical Oncology 2020, 38: e15668-e15668. DOI: 10.1200/jco.2020.38.15_suppl.e15668.Peer-Reviewed Original ResearchPharmacodynamic effectsReceptor agonistMultiplex immunohistochemistryKRAS-mutant colorectal cancerTumor tissueDose-expansion cohortsSimilar time pointsMutant allele fractionM65 levelsH postdoseColorectal cancerPost-TxDownstream pathway activationPancreatic cancerHematologic malignanciesLiver enzymesScreening periodReverse phase protein arrayBiopsy coresTumor biopsiesMutant allele frequencyBiopsy samplesDose levelsBiopsyTumor typesMasterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies.
Hamilton E, Patel M, Rodon J, Hong D, Schram A, Janne P, LoRusso P, Sachdev J, Ou S, Buck E, O'Connor M, Waters N, Witt K, Cook C. Masterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies. Journal Of Clinical Oncology 2020, 38: tps3665-tps3665. DOI: 10.1200/jco.2020.38.15_suppl.tps3665.Peer-Reviewed Original ResearchAntitumor activityStandard therapyPreliminary efficacyERBB mutationsOpen-label multicenter studySignificant unmet need existsPhase I/IIHER2 tyrosine kinase inhibitorPhase 2 doseAdvanced solid malignanciesAdequate drug exposureMetastatic solid tumorsPreliminary antitumor activityExon 20 insertionsOncogenic driver mutationsTyrosine kinase inhibitorsUnmet need existsAssessment of safetyCurrent eGFRExpansion cohortMulticenter studyPharmacodynamic effectsSolid malignanciesDrug exposureCohort 1A First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors
Varga A, Soria JC, Hollebecque A, LoRusso P, Bendell J, Huang SA, Wagle MC, Okrah K, Liu L, Murray E, Sanabria-Bohorquez SM, Tagen M, Dokainish H, Mueller L, Burris H. A First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors. Clinical Cancer Research 2020, 26: 1229-1236. PMID: 31848189, DOI: 10.1158/1078-0432.ccr-19-2574.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedDose-Response Relationship, DrugFatigueFemaleHumansMaleMAP Kinase Signaling SystemMaximum Tolerated DoseMiddle AgedMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3NauseaNeoplasmsPatient SafetyProtein Kinase InhibitorsPyridonesPyrimidinesTissue DistributionVomitingConceptsBRAF-mutant colorectal cancerColorectal cancerAdverse eventsFDG-PETCommon drug-related adverse eventsSolid tumorsDrug-related adverse eventsPhase IPartial metabolic responseAcceptable safety profileAdvanced solid tumorsDose-proportional increaseGrade 3 rashMetastatic solid tumorsSerial tumor biopsiesSingle-agent activityBest overall responseHuman phase IMAPK pathway inhibitionMultiple tumor typesStable diseaseEscalation studyPartial responseOral inhibitorPharmacodynamic effects
2018
A phase I dose-escalation and dose-expansion study of brontictuzumab in subjects with selected solid tumors
Ferrarotto R, Eckhardt G, Patnaik A, LoRusso P, Faoro L, Heymach J, Kapoun A, Xu L, Munster P. A phase I dose-escalation and dose-expansion study of brontictuzumab in subjects with selected solid tumors. Annals Of Oncology 2018, 29: 1561-1568. PMID: 29726923, DOI: 10.1093/annonc/mdy171.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, MonoclonalAntineoplastic Agents, ImmunologicalCohort StudiesDose-Response Relationship, DrugDrug Resistance, NeoplasmFemaleFollow-Up StudiesHumansMaleMaximum Tolerated DoseMiddle AgedNeoplasm Recurrence, LocalNeoplasmsPrognosisReceptor, Notch1Salvage TherapySurvival RateTissue DistributionConceptsNotch1 pathway activationPartial responseSolid tumorsPathway activationAdverse eventsCommon drug-related adverse eventsDrug-related adverse eventsDose-expansion studyGrade 3 diarrheaGrade 3 fatigueUnconfirmed partial responseRefractory solid tumorsProlonged SDsDisease stabilizationExpansion cohortMain toxicityRECIST 1.1Dose escalationEfficacy signalsClinical benefitPharmacodynamic effectsPreliminary efficacyAssessable subjectsImmunohistochemistry assaysNonlinear pharmacokinetics
2002
Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition.
Albanell J, Rojo F, Averbuch S, Feyereislova A, Mascaro J, Herbst R, LoRusso P, Rischin D, Sauleda S, Gee J, Nicholson R, Baselga J. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. Journal Of Clinical Oncology 2002, 20: 110-24. PMID: 11773160, DOI: 10.1200/jco.2002.20.1.110.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAntineoplastic AgentsApoptosisBiomarkersCell Cycle ProteinsCyclin-Dependent Kinase Inhibitor p27Dose-Response Relationship, DrugErbB ReceptorsFemaleGefitinibHumansKeratinocytesMaleMAP Kinase Signaling SystemMiddle AgedNeoplasmsQuinazolinesSkinStatistics, NonparametricTumor Suppressor ProteinsConceptsCancer patientsEpidermal growth factor receptor tyrosine kinase inhibitor ZD1839Tyrosine kinase inhibitor ZD1839Phase I clinical trialMaximum-tolerated doseDose-limiting toxicityEGFR activationReceptor-dependent processUnacceptable toxicityDefinitive efficacyPharmacodynamic assessmentSafety trialPharmacodynamic effectsClinical trialsKeratin plugsReceptor inhibitionMaturation markersSkin biopsiesPharmacodynamic studiesProliferation indexDose levelsOral ZD1839PatientsOptimal dosesZD1839