2024
rBMA: A robust Bayesian Model Averaging Method for phase II basket trials based on informative mixture priors
Wang X, Wei W. rBMA: A robust Bayesian Model Averaging Method for phase II basket trials based on informative mixture priors. Contemporary Clinical Trials 2024, 140: 107505. PMID: 38521384, DOI: 10.1016/j.cct.2024.107505.Peer-Reviewed Original ResearchConceptsPhase II basket trialRobust Bayesian modelBasket trial designBiomarker-defined subgroupsMixture priorsBinary endpointsModel averaging methodPosterior distributionBayesian modelBasket trialsSimulation studyEra of targeted therapyDevelopment of targeted agentsPriorsAverage methodGenomic alterationsPatient populationNovel treatmentAntitumor activityPosterior weightsEarly phase oncology trialsStatistical powerOncology trialsTrial designTrials
2023
A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents
Bewersdorf J, Shallis R, Sharon E, Park S, Ramaswamy R, Roe C, Irish J, Caldwell A, Wei W, Yacoub A, Madanat Y, Zeidner J, Altman J, Odenike O, Yerrabothala S, Kovacsovics T, Podoltsev N, Halene S, Little R, Piekarz R, Gore S, Kim T, Zeidan A. A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents. Annals Of Hematology 2023, 103: 105-116. PMID: 38036712, DOI: 10.1007/s00277-023-05552-4.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityAcute myeloid leukemiaMarrow complete remissionPhase Ib trialAdverse eventsIb trialDose escalationNCI Cancer Therapy Evaluation ProgramAcute myeloid leukemia refractoryHematologic adverse eventsProtocol-defined responseDose level 1Anti-PD1 therapyAnti-PD1 antibodyDose-escalation designLimited clinical efficacySystems immunology approachHistone deacetylase inhibitor entinostatLeukemia refractoryMCR patientsComplete remissionRespiratory failureSuppressor cellsEscalation designClinical efficacyA bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better
Djureinovic D, Weiss S, Krykbaeva I, Qu R, Vathiotis I, Moutafi M, Zhang L, Perdigoto A, Wei W, Anderson G, Damsky W, Hurwitz M, Johnson B, Schoenfeld D, Mahajan A, Hsu F, Miller-Jensen K, Kluger Y, Sznol M, Kaech S, Bosenberg M, Jilaveanu L, Kluger H. A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better. Molecular Cancer 2023, 22: 182. PMID: 37964379, PMCID: PMC10644655, DOI: 10.1186/s12943-023-01884-x.Peer-Reviewed Original ResearchConceptsStable diseasePartial responseMacrophage populationsThree-drug regimenUnconfirmed partial responsePhase I trialLimited treatment optionsMonocyte/macrophage populationNon-classical monocytesMurine melanoma modelTreatment-related changesResultsThirteen patientsWorse survivalI trialInflammatory tumorPatient populationTreatment optionsImmune cellsDisease progressionMurine studiesPreclinical modelsResistant melanomaAntigen presentationMurine modelCyTOF analysisImmune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases
Schoenfeld D, Moutafi M, Martinez S, Djureinovic D, Merkin R, Adeniran A, Braun D, Signoretti S, Choueiri T, Parisi F, Hurwitz M, Rimm D, Wei W, Jilaveanu L, Kluger H. Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases. Journal For ImmunoTherapy Of Cancer 2023, 11: e007240. PMID: 37586773, PMCID: PMC10432651, DOI: 10.1136/jitc-2023-007240.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaBrain metastasesPrimary tumorTumor microenvironmentDigital spatial profilingCell carcinomaActivation protein expressionInflammatory macrophage markersRCC brain metastasesInnate immune activatorsNormal kidney samplesProgressive stagesExtracranial metastasesTim-3Immune checkpointsImmune dysfunctionImmune activationRCC metastasisLonger survivalImmune activatorsMacrophage markersTreatment responseSeparate cohortTissue microarrayMetastatic samplesA Phase II Trial of the CD40 Agonist Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Disease Progression on Anti-PD-1
Weiss S, Sznol M, Shaheen M, Berciano-Guerrero M, Couselo E, Rodríguez-Abreu D, Boni V, Schuchter L, Gonzalez-Cao M, Arance A, Wei W, Ganti A, Hauke R, Berrocal A, Iannotti N, Hsu F, Kluger H. A Phase II Trial of the CD40 Agonist Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Disease Progression on Anti-PD-1. Clinical Cancer Research 2023, 30: 74-81. PMID: 37535056, PMCID: PMC10767304, DOI: 10.1158/1078-0432.ccr-23-0475.Peer-Reviewed Original ResearchConceptsObjective response ratePhase II trialAdverse eventsPartial responseDisease progressionII trialGrade 3 adverse eventsAnti PD-1CD40 agonist antibodyElevated liver functionTreatment-related SAEsCommon adverse eventsActivation of CD40Subset of patientsFavorable safety profileAntigen presenting cellsStable diseaseMedian durationAdvanced melanomaAdditional patientsLiver functionSafety profileMetastatic melanomaPreclinical dataPresenting cellsQuantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer
Cecchini M, Zhang J, Wei W, Sklar J, Lacy J, Zhong M, Kong Y, Zhao H, DiPalermo J, Devine L, Stein S, Kortmansky J, Johung K, Bindra R, LoRusso P, Schalper K. Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer. Cancer Research Communications 2023, 3: 1132-1139. PMID: 37387791, PMCID: PMC10305782, DOI: 10.1158/2767-9764.crc-23-0045.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingMGMT protein expressionColorectal cancerStable diseaseQuantitative immunofluorescenceT cellsProtein expressionPromoter hypermethylationLow MGMT protein expressionPARP inhibitorsRadiographic tumor regressionMetastatic colorectal cancerAdvanced colorectal cancerPretreatment tumor biopsiesEffector T cellsTumor-infiltrating lymphocytesMGMT proteinDNA repair biomarkersBaseline CD8Eligible patientsIncreased CD8Methylguanine-DNA methyltransferaseObjective responseProgressive diseaseImmune markersNCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Cecchini M, Walther Z, Wei W, Hafez N, Pilat M, Boerner S, Durecki D, Eder J, Schalper K, Chen A, LoRusso P. NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors. Cancer Research Communications 2023, 3: 1113-1117. PMID: 37377610, PMCID: PMC10292219, DOI: 10.1158/2767-9764.crc-22-0485.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityHomologous recombination deficiencyPARP inhibitorsStable diseaseWeekly irinotecanObjective responseDay 1Day 3Solid tumorsPhase I dose-escalation studyTwice daily days 1I dose-escalation studyPhase I clinical trialDaily days 1Dose level 1Doses of veliparibGrade 3 neutropeniaMultiple-dose schedulesProgression-free survivalAdvanced solid tumorsDose-escalation studyEvaluable patientsNonoverlapping toxicitiesDose scheduleSystemic treatmentSubsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma.
Horowitch B, Lee D, Ding M, Martinez-Morilla S, Aung T, Ouerghi F, Wang X, Wei W, Damsky W, Sznol M, Kluger H, Rimm D, Ishizuka J. Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma. Clinical Cancer Research 2023, 29: 2908-2918. PMID: 37233452, PMCID: PMC10524955, DOI: 10.1158/1078-0432.ccr-23-0215.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsHuman melanoma cell linesMelanoma cell linesPD-L1Validation cohortYale-New Haven HospitalCombination of ipilimumabPD-L1 markersImmune checkpoint blockadePD-L1 biomarkerNew Haven HospitalSTAT1 levelsCell linesWestern blot analysisCheckpoint inhibitorsCheckpoint blockadeClinical responseOverall survivalImproved survivalResistance of cancersMetastatic melanomaMelanoma responsePredict responseTreatment responseDistinct patterns
2022
Bayesian local exchangeability design for phase II basket trials
Liu Y, Kane M, Esserman D, Blaha O, Zelterman D, Wei W. Bayesian local exchangeability design for phase II basket trials. Statistics In Medicine 2022, 41: 4367-4384. PMID: 35777367, PMCID: PMC10279458, DOI: 10.1002/sim.9514.Peer-Reviewed Original Research
2021
Programmed Death-Ligand 1 Tumor Proportion Score and Overall Survival From First-Line Pembrolizumab in Patients With Nonsquamous Versus Squamous NSCLC
Doroshow DB, Wei W, Gupta S, Zugazagoitia J, Robbins C, Adamson B, Rimm DL. Programmed Death-Ligand 1 Tumor Proportion Score and Overall Survival From First-Line Pembrolizumab in Patients With Nonsquamous Versus Squamous NSCLC. Journal Of Thoracic Oncology 2021, 16: 2139-2143. PMID: 34455068, PMCID: PMC8612948, DOI: 10.1016/j.jtho.2021.07.032.Peer-Reviewed Original ResearchConceptsPD-L1 tumor proportion scoreTumor proportion scoreHigh PD-L1 tumor proportion scoreOverall survivalNonsquamous histologySquamous NSCLCNonsquamous NSCLCPredictive biomarkersProportion scoreDeath ligand 1 (PD-L1) tumor proportion scoreElectronic health record-derived databaseFirst-line pembrolizumab therapyPD-1 expression levelsPD-L1 expression levelsCommunity oncology clinicsMedian OS differenceSingle-agent pembrolizumabImmune checkpoint inhibitorsImproved overall survivalMedian overall survivalPrimary end pointFirst-line pembrolizumabFirst-line therapyPD-L1 expressionPD-L1 testingA Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1
Weiss SA, Djureinovic D, Jessel S, Krykbaeva I, Zhang L, Jilaveanu L, Ralabate A, Johnson B, Levit NS, Anderson G, Zelterman D, Wei W, Mahajan A, Trifan O, Bosenberg M, Kaech SM, Perry CJ, Damsky W, Gettinger S, Sznol M, Hurwitz M, Kluger HM. A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1. Clinical Cancer Research 2021, 27: 4757-4767. PMID: 34140403, PMCID: PMC9236708, DOI: 10.1158/1078-0432.ccr-21-0903.Peer-Reviewed Original ResearchConceptsAnti-PD-1/PD-L1Non-small cell lung cancerCell lung cancerRenal cell carcinomaPD-L1Lung cancerDisease progressionCommon treatment-related adverse eventsPD-1/PD-L1 inhibitorsTreatment-related adverse eventsPhase 2 doseSubstantial clinical challengeUnconfirmed partial responseDose-limiting toxicityPD-L1 inhibitorsPhase I trialDose-escalation designPro-inflammatory cytokinesMultiple tumor typesAsymptomatic elevationStable diseaseIntolerable toxicityAdverse eventsMedian durationPartial responseComparison of programmed death-ligand 1 protein expression between primary and metastatic lesions in patients with lung cancer
Moutafi MK, Tao W, Huang R, Haberberger J, Alexander B, Ramkissoon S, Ross JS, Syrigos K, Wei W, Pusztai L, Rimm DL, Vathiotis IA. Comparison of programmed death-ligand 1 protein expression between primary and metastatic lesions in patients with lung cancer. Journal For ImmunoTherapy Of Cancer 2021, 9: e002230. PMID: 33833050, PMCID: PMC8039214, DOI: 10.1136/jitc-2020-002230.Peer-Reviewed Original ResearchConceptsPD-L1 expressionMetastatic lesionsLung cancer casesLung cancerCancer casesAdvanced stage non-small cell lung cancerNon-small cell lung cancerNon-squamous histologyCell lung cancerFuture patient managementDefinite diagnostic testSquamous histologyFoundation MedicineLymph nodesRoutine careHistologic subtypeMetastatic sitesPrimary lesionRetrospective studyAdrenal glandPrimary tumorPleural fluidPatient managementTrial designDrug AdministrationPublication Bias in Gastrointestinal Oncology Trials Performed over the Past Decade
Peters GW, Tao W, Wei W, Miccio JA, Jethwa KR, Cecchini M, Johung KL. Publication Bias in Gastrointestinal Oncology Trials Performed over the Past Decade. The Oncologist 2021, 26: 660-667. PMID: 33728733, PMCID: PMC8342580, DOI: 10.1002/onco.13759.Peer-Reviewed Original ResearchConceptsGI oncologyPublication biasImpact of RCTsFuture trial designMultivariable logistic regressionSignificant publication biasPast trialsAccrual completionCancer RCTsEvidence-based practiceGastrointestinal cancerClinical managementTrial completionTrial designOncology trialsClinical practicePublication statusRCTsTrial questionModern RCTsLogistic regressionHalf of trialsTrialsPhase IIIGold standardChallenges in the Evaluation and Management of Toxicities Arising From Immune Checkpoint Inhibitor Therapy for Patients With Myeloid Malignancies
Shallis RM, Bewersdorf JP, Swoboda DM, Wei W, Gowda L, Prebet T, Halene S, Pillai MM, Parker T, Neparidze N, Podoltsev NA, Seropian S, Sallman DA, Gore SD, Zeidan AM. Challenges in the Evaluation and Management of Toxicities Arising From Immune Checkpoint Inhibitor Therapy for Patients With Myeloid Malignancies. Clinical Lymphoma Myeloma & Leukemia 2021, 21: e483-e487. PMID: 33551344, DOI: 10.1016/j.clml.2021.01.003.Peer-Reviewed Original Research
2020
A phase 1b expansion study of TAS‐102 with oxaliplatin for refractory metastatic colorectal cancer
Cecchini M, Kortmansky JS, Cui C, Wei W, Thumar JR, Uboha NV, Hafez N, Lacy J, Fischbach NA, Sabbath KD, Gomez CM, Sporn JR, Stein S, Hochster HS. A phase 1b expansion study of TAS‐102 with oxaliplatin for refractory metastatic colorectal cancer. Cancer 2020, 127: 1417-1424. PMID: 33351187, PMCID: PMC8085021, DOI: 10.1002/cncr.33379.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsColorectal NeoplasmsDrug Administration ScheduleDrug CombinationsDrug Resistance, NeoplasmFemaleFluorouracilHumansIrinotecanLeucovorinMaleMiddle AgedOrganoplatinum CompoundsOxaliplatinProgression-Free SurvivalPyrrolidinesResponse Evaluation Criteria in Solid TumorsThymineTrifluridineConceptsMetastatic colorectal cancerOverall response rateRefractory metastatic colorectal cancerProgression-free survivalTAS-102Colorectal cancerDay 1Primary endpointOverall survivalDose escalationDay 5Median progression-free survivalPhase 1b studyMedian overall survivalResponse Evaluation CriteriaTreat populationDose expansionPartial responseStandard dosesUnexpected side effectsStudy treatmentTumor shrinkageUnexpected toxicitiesSide effectsNovel antimetaboliteClinical outcomes and characteristics of patients with TP53-mutated acute myeloid leukemia or myelodysplastic syndromes: a single center experience*
Bewersdorf JP, Shallis RM, Gowda L, Wei W, Hager K, Isufi I, Kim TK, Pillai MM, Seropian S, Podoltsev NA, Gore SD, Siddon AJ, Zeidan AM. Clinical outcomes and characteristics of patients with TP53-mutated acute myeloid leukemia or myelodysplastic syndromes: a single center experience*. Leukemia & Lymphoma 2020, 61: 2180-2190. PMID: 32362171, PMCID: PMC7603787, DOI: 10.1080/10428194.2020.1759051.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaMedian overall survivalTherapy-related malignanciesOverall survivalMyelodysplastic syndromeMyeloid leukemiaAllogeneic hematopoietic stem cell transplantLonger median overall survivalSingle-center retrospective studyComplex karyotypeHematopoietic stem cell transplantIntensive chemotherapy approachesYale Cancer CenterCharacteristics of patientsSingle-center experienceMinority of patientsStem cell transplantLong-term survivalLow response rateIntensive chemotherapyCenter experienceClinicopathologic characteristicsAdverse prognosisAML patientsCell transplantPembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial
Goldberg SB, Schalper KA, Gettinger SN, Mahajan A, Herbst RS, Chiang AC, Lilenbaum R, Wilson FH, Omay SB, Yu JB, Jilaveanu L, Tran T, Pavlik K, Rowen E, Gerrish H, Komlo A, Gupta R, Wyatt H, Ribeiro M, Kluger Y, Zhou G, Wei W, Chiang VL, Kluger HM. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. The Lancet Oncology 2020, 21: 655-663. PMID: 32251621, PMCID: PMC7380514, DOI: 10.1016/s1470-2045(20)30111-x.Peer-Reviewed Original ResearchConceptsBrain metastasis responseYale Cancer CenterPD-L1 expressionPhase 2 trialUntreated brain metastasesBrain metastasesAdrenal insufficiencyAdverse eventsMetastasis responseCNS diseaseCancer CenterCohort 2Cohort 1Eastern Cooperative Oncology Group performance statusTreatment-related serious adverse eventsModified Response Evaluation CriteriaStage IV NSCLCTreatment-related deathsAcute kidney injuryPD-1 blockadeSerious adverse eventsSolid Tumors criteriaPhase 2 studyProportion of patientsResponse Evaluation CriteriaManagement of hyperleukocytosis and impact of leukapheresis among patients with acute myeloid leukemia (AML) on short- and long-term clinical outcomes: a large, retrospective, multicenter, international study
Stahl M, Shallis RM, Wei W, Montesinos P, Lengline E, Neukirchen J, Bhatt VR, Sekeres MA, Fathi AT, Konig H, Luger S, Khan I, Roboz GJ, Cluzeau T, Martínez-Cuadron D, Raffoux E, Germing U, Umakanthan JM, Mukherjee S, Brunner AM, Miller A, McMahon CM, Ritchie EK, Rodríguez-Veiga R, Itzykson R, Boluda B, Rabian F, Tormo M, Acuña-Cruz E, Rabinovich E, Yoo B, Cano I, Podoltsev NA, Bewersdorf JP, Gore S, Zeidan AM. Management of hyperleukocytosis and impact of leukapheresis among patients with acute myeloid leukemia (AML) on short- and long-term clinical outcomes: a large, retrospective, multicenter, international study. Leukemia 2020, 34: 3149-3160. PMID: 32132655, PMCID: PMC8155811, DOI: 10.1038/s41375-020-0783-3.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaOverall survivalMyeloid leukemiaMultivariate analysisLong-term clinical outcomesComposite complete remissionImpact of leukapheresisManagement of hyperleukocytosisMedian overall survivalThirty-day mortalityHigh-quality evidenceWhite cell countProportional hazards modelUse of leukapheresisLogistic regression modelsSignificant resource useIntensive chemotherapyComplete remissionHazard ratioClinical outcomesInferior outcomesUnadjusted analysesQuality evidencePotential complicationsOdds ratioPatterns of care and clinical outcomes of patients with newly diagnosed acute myeloid leukemia presenting with hyperleukocytosis who do not receive intensive chemotherapy
Shallis RM, Stahl M, Wei W, Montesinos P, Lengline E, Neukirchen J, Bhatt VR, Sekeres MA, Fathi AT, Konig H, Luger S, Khan I, Roboz GJ, Cluzeau T, Martínez-Cuadron D, Raffoux E, Germing U, Umakanthan JM, Mukhereje S, Brunner AM, Miller A, McMahon CM, Ritchie EK, Rodríguez-Veiga R, Itzykson R, Boluda B, Rabian F, Tormo M, Acuña-Cruz E, Rabinovich E, Yoo B, Cano I, Podoltsev NA, Bewersdorf JP, Gore S, Zeidan AM. Patterns of care and clinical outcomes of patients with newly diagnosed acute myeloid leukemia presenting with hyperleukocytosis who do not receive intensive chemotherapy. Leukemia & Lymphoma 2020, 61: 1220-1225. PMID: 32100599, PMCID: PMC8273667, DOI: 10.1080/10428194.2020.1728753.Peer-Reviewed Original ResearchType 3 Inositol 1,4,5‐Trisphosphate Receptor Is Increased and Enhances Malignant Properties in Cholangiocarcinoma
Ueasilamongkol P, Khamphaya T, Guerra MT, Rodrigues M, Gomes DA, Kong Y, Wei W, Jain D, Trampert DC, Ananthanarayanan M, Banales JM, Roberts LR, Farshidfar F, Nathanson MH, Weerachayaphorn J. Type 3 Inositol 1,4,5‐Trisphosphate Receptor Is Increased and Enhances Malignant Properties in Cholangiocarcinoma. Hepatology 2020, 71: 583-599. PMID: 31251815, PMCID: PMC6934938, DOI: 10.1002/hep.30839.Peer-Reviewed Original ResearchConceptsType 3 inositolCCA cellsIntracellular calcium ionsPathogenesis of malignanciesCCA cell linesCommon malignancyPoor prognosisTrisphosphate receptorMalignant featuresMitochondrial CaITPR3 expressionCholangiocarcinomaRegions of ERMalignant propertiesCCA samplesCell proliferationCholangiocytesEndoplasmic reticulumType of tissueMalignancyCell linesITPR3PathogenesisCell deathCell migration