2024
Phase Ib dose-escalation trial of taselisib (GDC-0032) in combination with HER2-directed therapies in patients with advanced HER2+ breast cancer
Grinshpun A, Ren S, Graham N, DeMeo M, Wrabel E, Carter J, Tayob N, Pereslete A, Hamilton E, Juric D, Mayer E, Tolaney S, Krop I, Metzger O. Phase Ib dose-escalation trial of taselisib (GDC-0032) in combination with HER2-directed therapies in patients with advanced HER2+ breast cancer. ESMO Open 2024, 9: 103465. PMID: 38833970, PMCID: PMC11179085, DOI: 10.1016/j.esmoop.2024.103465.Peer-Reviewed Original ResearchProgression-free survivalMaximal tolerated doseHER2+ breast cancerAdverse eventsBreast cancerT-DM1Cohort AHuman epidermal growth factor receptor 2-positiveEpidermal growth factor receptor 2-positiveHER2+) breast cancerMedian progression-free survivalAll-grade adverse eventsAssociated with significant toxicityCirculating tumor DNA analysisDevelopment of acquired resistanceHER2-directed regimensHER2-directed therapyAnti-HER2 therapyHER2-Targeted TherapyPhase Ib studyTumor DNA analysisPI3KDose escalationImprove disease controlOral inhibitorFruquintinib plus paclitaxel versus paclitaxel as second-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma (FRUTIGA): A randomized, multicenter, double-blind, placebo-controlled, phase 3 study.
Xu R, Wang F, Shen L, Guo W, Liu T, Li J, Qin S, Bai Y, Chen Z, Wang J, Pan Y, Shu Y, Zhao F, Cheng Y, Ye F, Gu K, Zhang T, Pan H, Zhong H, Su W. Fruquintinib plus paclitaxel versus paclitaxel as second-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma (FRUTIGA): A randomized, multicenter, double-blind, placebo-controlled, phase 3 study. Journal Of Clinical Oncology 2024, 42: 438780-438780. DOI: 10.1200/jco.2024.42.36_suppl.438780.Peer-Reviewed Original ResearchPhase 3 studyAntitumor therapyMedian OSDouble-blindPrimary endpointInhibitor of VEGFR-1Dose of study drugSecond-line treatment optionDual primary endpointsPlacebo (PBO)-controlledFirst-line chemotherapyGastroesophageal junction adenocarcinomaMetastatic colorectal cancerSecond-line therapyLymph node metastasisTreatment of paclitaxelStatistical significanceCox proportional hazards modelsPost Hoc AnalysisOral inhibitorJunction adenocarcinomaEligible ptsPlacebo-ControlledStudy drugStatistically significant improvement
2020
Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia
DiNardo CD, Stein AS, Stein EM, Fathi AT, Frankfurt O, Schuh AC, Döhner H, Martinelli G, Patel PA, Raffoux E, Tan P, Zeidan AM, de Botton S, Kantarjian HM, Stone RM, Frattini MG, Lersch F, Gong J, Gianolio DA, Zhang V, Franovic A, Fan B, Goldwasser M, Daigle S, Choe S, Wu B, Winkler T, Vyas P. Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia. Journal Of Clinical Oncology 2020, 39: 57-65. PMID: 33119479, PMCID: PMC7771719, DOI: 10.1200/jco.20.01632.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaAdverse eventsQT prolongationMyeloid leukemiaMutant acute myeloid leukemiaBone marrow mononuclear cellsExpected safety profileIDH differentiation syndromeIntensive induction chemotherapyTreatment-related gradeMedian treatment durationPhase Ib trialComplete remission rateOverall response rateMarrow mononuclear cellsDifferentiation syndromeIb trialInduction chemotherapyOral ivosidenibSubcutaneous azacitidineComplete remissionComplete respondersRemission rateMedian durationOral inhibitorGlasdegib in combination with azacitidine (AZA) in patients (pts) with untreated higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML): Effects on marrow recovery and transfusion independence.
Zeidan A, Schuster M, Joris M, Krauter J, Maertens J, Gyan E, Kovacsovics T, Verma A, Vyas P, Wang E, Ma W, Zeremski M, Kudla A, Chan G, Sekeres M. Glasdegib in combination with azacitidine (AZA) in patients (pts) with untreated higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML): Effects on marrow recovery and transfusion independence. Journal Of Clinical Oncology 2020, 38: 7526-7526. DOI: 10.1200/jco.2020.38.15_suppl.7526.Peer-Reviewed Original ResearchChronic myelomonocytic leukemiaAcute myeloid leukemiaAbsolute neutrophil countMyelodysplastic syndromeEarly hematopoietic recoveryIntensive chemotherapyMedian durationTransfusion independenceMarrow recoveryHematopoietic recoveryPlatelet recoveryHigh-risk myelodysplastic syndromeEarly marrow recoveryEarly platelet recoveryManageable safety profilePhase Ib studyUp-front treatmentLow-dose cytarabineDose delaysPartial remissionRemission rateNeutrophil countOverall survivalOral inhibitorSafety profileA 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
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 doseMulticenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas.
Omuro A, Beal K, McNeill K, Young RJ, Thomas A, Lin X, Terziev R, Kaley TJ, DeAngelis LM, Daras M, Gavrilovic IT, Mellinghoff I, Diamond EL, McKeown A, Manne M, Caterfino A, Patel K, Bavisotto L, Gorman G, Lamson M, Gutin P, Tabar V, Chakravarty D, Chan TA, Brennan CW, Garrett-Mayer E, Karmali RA, Pentsova E. Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas. Journal Of Clinical Oncology 2018, 36: 1702-1709. PMID: 29683790, PMCID: PMC5993168, DOI: 10.1200/jco.2017.76.9992.Peer-Reviewed Original ResearchConceptsAnaplastic gliomasCohort 2Cohort 1Median progression-free survivalFavorable brain penetrationMedian overall survivalPhase Ib studyPhase Ib trialPhase II doseProgression-free survivalRecurrent anaplastic gliomasDependent calcium channelsNovel oral inhibitorSignal of activityMismatch repair genesIb trialTreat populationMethylguanine-DNA methyltransferaseOverall survivalComplete responseFlat doseOral inhibitorBrain penetrationResults FortyTherapeutic concentrations
2016
A phase I study of indoximod in patients with advanced malignancies
Soliman HH, Minton SE, Han HS, Ismail-Khan R, Neuger A, Khambati F, Noyes D, Lush R, Chiappori AA, Roberts JD, Link C, Vahanian NN, Mautino M, Streicher H, Sullivan DM, Antonia SJ. A phase I study of indoximod in patients with advanced malignancies. Oncotarget 2016, 7: 22928-22938. PMID: 27008709, PMCID: PMC5008412, DOI: 10.18632/oncotarget.8216.Peer-Reviewed Original ResearchConceptsStable diseaseDose levelsC-reactive protein levelsReactive protein levelsAdvanced solid tumorsTumor-mediated immunosuppressionPhase I trialUntreated brain metastasesMetastatic solid malignanciesMultiple dose levelsAntigen autoantibodiesBrain metastasesCheckpoint inhibitorsImmune correlatesPrimary endpointSecondary endpointsAdvanced malignanciesCRP levelsI trialOral inhibitorAutoimmune diseasesMarrow functionSolid malignanciesInclusion criteriaExclusion criteria
2014
NI-57DYNAMIC CONTRAST-ENHANCED MAGNETIC RESONANCE PERFUSION WEIGHTED IMAGING (DCE-MRI) AND DIFFUSION WEIGHTED IMAGING (DWI) FOR PHARMACODYNAMIC EVALUATION OF CARBOXYAMIDOTRIAZOLE OROTATE (CTO) AND TEMOZOLOMIDE IN MALIGNANT GLIOMA
Magge R, Perez J, Young R, Kaley T, Pentsova E, DeAngelis L, Diamond E, Mellinghoff I, Peck K, Anderson B, Gorman G, Mclean S, Karmali R, Omuro A. NI-57DYNAMIC CONTRAST-ENHANCED MAGNETIC RESONANCE PERFUSION WEIGHTED IMAGING (DCE-MRI) AND DIFFUSION WEIGHTED IMAGING (DWI) FOR PHARMACODYNAMIC EVALUATION OF CARBOXYAMIDOTRIAZOLE OROTATE (CTO) AND TEMOZOLOMIDE IN MALIGNANT GLIOMA. Neuro-Oncology 2014, 16: v150-v151. PMCID: PMC4218384, DOI: 10.1093/neuonc/nou264.55.Peer-Reviewed Original ResearchBlood perfusionMalignant gliomasVascular permeabilityDCE-MRIProgressive malignant gliomaPhase I trialSubset of patientsContrast-enhanced magnetic resonanceWnt/b-cateninMann-Whitney U testEarly pharmacodynamic effectsVolumetric histogram analysisMechanism of actionBiological effectsAdvanced imaging techniquesI trialOral inhibitorEarly drug developmentPharmacodynamic effectsVascular permeability parametersDrug exposurePharmacodynamic evaluationVEGF blockadeAdvanced neuroimagingBrain tumorsFirst-in-human study of AMG 337, a highly selective oral inhibitor of MET, in adult patients (pts) with advanced solid tumors.
Hong D, LoRusso P, Hamid O, Beaupre D, Janku F, Khan R, Kittaneh M, Loberg R, Amore B, Caudillo I, Hwang Y, Tang R, Ngarmchamnanrith G, Kwak E. First-in-human study of AMG 337, a highly selective oral inhibitor of MET, in adult patients (pts) with advanced solid tumors. Journal Of Clinical Oncology 2014, 32: 2508-2508. DOI: 10.1200/jco.2014.32.15_suppl.2508.Peer-Reviewed Original Research
2013
A phase I study of neoadjuvant chemotherapy (NCT) with the gamma secretase (GS) inhibitor RO4929097 in combination with paclitaxel (P) and carboplatin (C) in women with triple-negative breast cancer (TNBC).
Mrozek E, Wesolowski R, Lustberg M, Layman R, Ling Y, Schaaf L, Phelps M, Ivy S, Grever M, Shapiro C. A phase I study of neoadjuvant chemotherapy (NCT) with the gamma secretase (GS) inhibitor RO4929097 in combination with paclitaxel (P) and carboplatin (C) in women with triple-negative breast cancer (TNBC). Journal Of Clinical Oncology 2013, 31: 1043-1043. DOI: 10.1200/jco.2013.31.15_suppl.1043.Peer-Reviewed Original ResearchTriple-negative breast cancerMaximum-tolerated doseNon-hematologic toxicitiesNeoadjuvant chemotherapyAUC 5G4 neutropeniaDay 1Gamma secretase inhibitor RO4929097Cycles of NACGrade 4 thrombocytopeniaComplete pathologic responseTreatment-related toxicityMinimal residual cancerMinimal residual diseaseLC-MS/MS assaysAUC 6G3 anemiaG3 fatigueG3 neutropeniaG3 thrombocytopeniaG4 thrombocytopeniaStarting dosePathologic responseResidual cancerOral inhibitorPharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial.
Patnaik A, LoRusso P, Ball H, Bahceci E, Yuen G, Papadopoulos K, Kittaneh M, Tolcher A. Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial. Journal Of Clinical Oncology 2013, 31: 2602-2602. DOI: 10.1200/jco.2013.31.15_suppl.2602.Peer-Reviewed Original ResearchAdvanced malignanciesDay 28Phase 1 dose-escalation trialALT/AST increasesCohort expansion phaseDose-escalating cohortsDose-escalation partECOG PS 2Grade 2 nauseaOral ALK inhibitorPre-dose valuesDose-escalation trialGrade 3 rashALK fusion geneALK receptor tyrosine kinaseAbdominal painCommon AEsEscalation trialMedian tmaxDaily dosingOral inhibitorNon-linear PKClinical activityALK inhibitorsPromising safety
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
2009
Phase I evaluation of lapatinib and everolimus in patients with advanced malignancies: Southwest Oncology Group trial S0528
Hoban C, Hoering A, Synold T, Chung V, Gandara D, Schott A, Kingsbury L, Lew D, LoRusso P, Gadgeel S. Phase I evaluation of lapatinib and everolimus in patients with advanced malignancies: Southwest Oncology Group trial S0528. Journal Of Clinical Oncology 2009, 27: 3553-3553. DOI: 10.1200/jco.2009.27.15_suppl.3553.Peer-Reviewed Original ResearchLapatinib 1250Oral inhibitorCombination of lapatinibMedian age 63Phase I evaluationPre-clinical studiesPI3/Akt pathwayAnti-tumor activityEligible ptsStable diseaseAdvanced malignanciesAdvanced tumorsLung cancerCommon tumorsEffective therapyPharmacokinetic analysisI evaluationEverolimusAge 63Drug pharmacokineticsPharmacokineticsMTDPhase ILapatinibAkt pathwayCediranib, a VEGF receptor 1, 2, and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC)
Gadgeel S, Wozniak A, Edelman M, Valdivieso M, Heilbrun L, Venkatramanamoorthy R, Shields A, LoRusso P, Hackstock D, Ruckdeschel J. Cediranib, a VEGF receptor 1, 2, and 3 inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC). Journal Of Clinical Oncology 2009, 27: e19007-e19007. DOI: 10.1200/jco.2009.27.15_suppl.e19007.Peer-Reviewed Original ResearchNon-small cell lung cancerRecurrent non-small cell lung cancerFLT-PET scansNSCLC ptsDose reductionPET scansMeasurable non-small cell lung cancerConfirmed response rateDisease control ratePhase II trialMedian age 60Cell lung cancerStandard uptake valueVEGF receptor 1Males 56Pemetrexed combinationsPrior regimensBrain metastasesGrade 3/4II trialVEGF therapyMajor hemorrhageOral inhibitorControl rateLung cancer
2007
A phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991
O’Dwyer P, LoRusso P, DeMichele A, Gupta V, Barbi A, Dials H, Chen I, Courtney R, Wilner K, Schwartz G. A phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991. Journal Of Clinical Oncology 2007, 25: 3550-3550. DOI: 10.1200/jco.2007.25.18_suppl.3550.Peer-Reviewed Original ResearchMTD/RP2DSchedule 2/1Stable diseasePD-0332991Escalation trialPhase IPositive solid tumorsRb-positive tumorsCommon tumor typesDose-dependent increaseNovel oral inhibitorEffect of foodPhospho-Rb proteinsCommon AEsPharmacodynamic modulationMedian ageAdvanced cancerOral inhibitorPositive tumorsTumor specimensPatientsSingle agentSolid tumorsTumor typesSuccessive dose
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