2020
Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer
Fong L, Hotson A, Powderly JD, Sznol M, Heist RS, Choueiri TK, George S, Hughes BGM, Hellmann MD, Shepard DR, Rini BI, Kummar S, Weise AM, Riese MJ, Markman B, Emens LA, Mahadevan D, Luke JJ, Laport G, Brody JD, Hernandez-Aya L, Bonomi P, Goldman JW, Berim L, Renouf DJ, Goodwin RA, Munneke B, Ho PY, Hsieh J, McCaffery I, Kwei L, Willingham SB, Miller RA. Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer. Cancer Discovery 2020, 10: 40-53. PMID: 31732494, PMCID: PMC6954326, DOI: 10.1158/2159-8290.cd-19-0980.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Renal CellDrug Resistance, NeoplasmFemaleFollow-Up StudiesFuransHumansKidney NeoplasmsMaleMiddle AgedNeoplasm Recurrence, LocalPrognosisPyridinesPyrimidinesReceptor, Adenosine A2ASalvage TherapySurvival RateConceptsRenal cell cancerPretreatment tumor biopsiesClinical responseGene expression signaturesCell cancerTumor biopsiesPD-1/PD-L1 inhibitorsPD-1/PD-L1Refractory renal cell cancerPhase I clinical trialL1 combination therapyRecruitment of CD8Targetable immune checkpointsDurable clinical benefitPD-L1 inhibitorsT cell repertoireAdenosine 2A receptorAntitumor immunityReceptor blockadeImmune checkpointsPD-L1L1 antibodyClinical benefitCombination therapyImmune cells
2016
Phase I trial of daily triapine in combination with cisplatin chemotherapy for advanced-stage malignancies
Kunos CA, Chu E, Beumer JH, Sznol M, Ivy SP. Phase I trial of daily triapine in combination with cisplatin chemotherapy for advanced-stage malignancies. Cancer Chemotherapy And Pharmacology 2016, 79: 201-207. PMID: 27878356, PMCID: PMC5226891, DOI: 10.1007/s00280-016-3200-x.Peer-Reviewed Original ResearchConceptsPhase I trialSolid tumor malignanciesI trialObjective responseTumor malignancyDaily days 1Frequent grade 3Advanced-stage malignanciesDose-finding phase I trialResultsThe MTDStable diseasePrimary endpointSecondary endpointsVulvar cancerElectrolyte abnormalitiesAdverse eventsCisplatin chemotherapyUterine cervixGrade 3Day 1Day 2Day 3PatientsMalignancyDifferent schedules
2009
C-Raf Is Associated with Disease Progression and Cell Proliferation in a Subset of Melanomas
Jilaveanu LB, Zito CR, Aziz SA, Conrad PJ, Schmitz JC, Sznol M, Camp RL, Rimm DL, Kluger HM. C-Raf Is Associated with Disease Progression and Cell Proliferation in a Subset of Melanomas. Clinical Cancer Research 2009, 15: 5704-5713. PMID: 19737955, PMCID: PMC2763114, DOI: 10.1158/1078-0432.ccr-09-0198.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overBenzenesulfonatesCell Line, TumorCell ProliferationCell SurvivalCohort StudiesDisease ProgressionFemaleGene SilencingHumansIndolesMaleMelanomaMiddle AgedNevusNiacinamidePhenolsPhenylurea CompoundsProtein Kinase InhibitorsProto-Oncogene Proteins c-rafPyridinesRNA, Small InterferingSensitivity and SpecificitySkin NeoplasmsSorafenibYoung AdultConceptsExtracellular signal-regulated kinaseC-RafC-Raf expressionSubset of melanomasPhospho-c-RafSignal-regulated kinaseCell linesProtein kinase inhibitionMitogen-activated protein kinase inhibitionDecreased viabilityDecreased Bcl-2 expressionProtein kinaseCell signalingBcl-2 inhibitionRaf kinaseB-RafMelanoma cell linesPhospho-MEKSpecific siRNAsSitu protein expressionGW5074Major isoformsKinasePhospho-ERKBcl-2 expression
2007
A Phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders
Karp JE, Giles FJ, Gojo I, Morris L, Greer J, Johnson B, Thein M, Sznol M, Low J. A Phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders. Leukemia Research 2007, 32: 71-77. PMID: 17640728, PMCID: PMC2726775, DOI: 10.1016/j.leukres.2007.05.003.Peer-Reviewed Original ResearchConceptsAggressive myeloproliferative disorderDaily x 5Refractory acute leukemiaMyeloproliferative disordersAcute leukemiaRibonucleotide reductase inhibitorReductase inhibitorsDays of fludarabineRefractory myeloid malignanciesPhase I trialDrug-related toxicityNovel ribonucleotide reductase inhibitorNucleoside analog fludarabinePotent ribonucleotide reductase inhibitorPartial responseI trialMetabolic acidosisSchedule AFludarabineMyeloid malignanciesPatientsPhase ILeukemiaDisordersInhibitorsPhase I and pharmacokinetic study of Triapine®, a potent ribonucleotide reductase inhibitor, in adults with advanced hematologic malignancies
Gojo I, Tidwell ML, Greer J, Takebe N, Seiter K, Pochron MF, Johnson B, Sznol M, Karp JE. Phase I and pharmacokinetic study of Triapine®, a potent ribonucleotide reductase inhibitor, in adults with advanced hematologic malignancies. Leukemia Research 2007, 31: 1165-1173. PMID: 17324462, DOI: 10.1016/j.leukres.2007.01.004.Peer-Reviewed Original ResearchConceptsHematologic malignanciesDay 1White blood cell countPhase IAdvanced hematologic malignanciesBlood cell countPeak plasma concentrationPre-clinical modelsAnti-leukemia activityPotent ribonucleotide reductase inhibitorWarrants further investigationAdvanced leukemiaH infusionPlasma concentrationsDose levelsRibonucleotide reductase inhibitorCell countReductase inhibitorsPharmacokinetic studyMalignancyGrowth inhibitionFurther investigationPotent inhibitorAdultsDays
2006
Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome
Yee KW, Cortes J, Ferrajoli A, Garcia-Manero G, Verstovsek S, Wierda W, Thomas D, Faderl S, King I, O’Brien S, Jeha S, Andreeff M, Cahill A, Sznol M, Giles FJ. Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome. Leukemia Research 2006, 30: 813-822. PMID: 16478631, DOI: 10.1016/j.leukres.2005.12.013.Peer-Reviewed Original ResearchMeSH KeywordsAcute DiseaseAdolescentAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsCytarabineDose-Response Relationship, DrugDrug Administration ScheduleDrug CombinationsFemaleHumansInjections, IntravenousLeukemia, MyeloidMaleMaximum Tolerated DoseMiddle AgedMyelodysplastic SyndromesPyridinesRecurrenceRisk FactorsThiosemicarbazonesTreatment OutcomeConceptsAra-C dose levelsDose levelsM2/dayAcute leukemiaSignificant anti-leukemia activityConsecutive daysPhase II regimenRefractory acute leukemiaHigh-risk MDSAnti-leukemia activityEvaluable patientsMyelodysplastic syndromeActive combinationPatientsPhase IIron chelatorsLeukemiaAraPotent inhibitorDaysTriapineRegimenCytarabineInfusionSyndrome
2004
A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer
Yen Y, Margolin K, Doroshow J, Fishman M, Johnson B, Clairmont C, Sullivan D, Sznol M. A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. Cancer Chemotherapy And Pharmacology 2004, 54: 331-342. PMID: 15148626, DOI: 10.1007/s00280-004-0821-2.Peer-Reviewed Original ResearchConceptsPhase I trialI trialAdvanced cancerToxicity profileDiffuse coronary artery diseaseST-T wave changesGemcitabine plasma concentrationsLarge liver metastasesNon-specific ST-T wave changesPhase II trialCoronary artery diseaseAsymptomatic myocardial infarctionMild QT prolongationCytotoxicity of gemcitabineEvaluable patientsGemcitabine 1000Gemcitabine doseAcute hypotensionII trialPartial responseArtery diseaseCardiovascular reserveComplete responseLiver metastasesAcute symptomsPhase I and Pharmacokinetic Study of the Ribonucleotide Reductase Inhibitor, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, Administered by 96-Hour Intravenous Continuous Infusion
Wadler S, Makower D, Clairmont C, Lambert P, Fehn K, Sznol M. Phase I and Pharmacokinetic Study of the Ribonucleotide Reductase Inhibitor, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, Administered by 96-Hour Intravenous Continuous Infusion. Journal Of Clinical Oncology 2004, 22: 1553-1563. PMID: 15117978, DOI: 10.1200/jco.2004.07.158.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityIntravenous continuous infusionContinuous infusionPreclinical tumor model systemsPhase II dosesStabilization of diseaseHepatic adverse eventsMaximum-tolerated dosePhase II dosePhase II trialPhase I trialAccelerated titration designPharmacokinetic studySerum tumor markersSubstantial inter-patient variabilityAbnormal organ functionDetailed pharmacokinetic studiesTumor model systemsInter-patient variabilityStable diseaseII trialObjective responseAdverse eventsI trialAdvanced cancer
2003
Phase I and pharmacodynamic study of Triapine®, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia
Giles FJ, Fracasso PM, Kantarjian HM, Cortes JE, Brown RA, Verstovsek S, Alvarado Y, Thomas DA, Faderl S, Garcia-Manero G, Wright LP, Samson T, Cahill A, Lambert P, Plunkett W, Sznol M, DiPersio JF, Gandhi V. Phase I and pharmacodynamic study of Triapine®, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia. Leukemia Research 2003, 27: 1077-1083. PMID: 12921943, DOI: 10.1016/s0145-2126(03)00118-8.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overDeoxyadenine NucleotidesDeoxyguanine NucleotidesDNADNA, NeoplasmEnzyme InhibitorsFemaleHumansInfusions, IntravenousLeukemia, LymphoidLeukemia, Myelogenous, Chronic, BCR-ABL PositiveLeukocyte CountMaleMiddle AgedPyridinesRibonucleotide ReductasesSafetyThiosemicarbazonesConceptsDose-limiting toxicityNovel ribonucleotide reductase inhibitorDay 1Ribonucleotide reductase inhibitorReductase inhibitorsWhite blood cell countPhase IContinuous intravenous infusionBlood cell countWarrants further studyObjective responseRefractory leukemiaStarting doseAdvanced leukemiaIntravenous infusionH infusionSecond infusionHematologic malignanciesPlasma concentrationsPharmacodynamic studiesPharmacodynamic dataPatientsSecond courseDay 8H beginningPhase I and pharmacokinetic study of triapine, a potent ribonucleotide reductase inhibitor, administered daily for five days in patients with advanced solid tumors.
Murren J, Modiano M, Clairmont C, Lambert P, Savaraj N, Doyle T, Sznol M. Phase I and pharmacokinetic study of triapine, a potent ribonucleotide reductase inhibitor, administered daily for five days in patients with advanced solid tumors. Clinical Cancer Research 2003, 9: 4092-100. PMID: 14519631.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityAdverse eventsSafety profilePhase IGrade 3Week scheduleDrug-related adverse eventsGrade 2 adverse eventsGrade 1Common nonhematological toxicitiesGrade 4 leukopeniaSingle-patient cohortsAcceptable safety profileAdvanced solid tumorsDose-escalation phaseHepatic adverse eventsPhase II trialCohort of patientsCumulative urinary recoveryLinear pharmacokinetic behaviorPotent ribonucleotide reductase inhibitorNonhematological toxicitiesII trialMean eliminationStarting dose