2005
Phase I Study of Cloretazine (VNP40101M), a Novel Sulfonylhydrazine Alkylating Agent, Combined with Cytarabine in Patients with Refractory Leukemia
Giles F, Verstovsek S, Thomas D, Gerson S, Cortes J, Faderl S, Ferrajoli A, Ravandi F, Kornblau S, Garcia-Manero G, Jabbour E, O'Brien S, Karsten V, Cahill A, Yee K, Albitar M, Sznol M, Kantarjian H. Phase I Study of Cloretazine (VNP40101M), a Novel Sulfonylhydrazine Alkylating Agent, Combined with Cytarabine in Patients with Refractory Leukemia. Clinical Cancer Research 2005, 11: 7817-7824. PMID: 16278404, DOI: 10.1158/1078-0432.ccr-05-1070.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAlkylating AgentsAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsBase Pair MismatchCohort StudiesCytarabineDisease ProgressionDNADNA RepairFemaleHumansHydrazinesLeukemiaLeukocytes, MononuclearMaleMiddle AgedModels, ChemicalO(6)-Methylguanine-DNA MethyltransferaseSulfonamidesTime FactorsConceptsContinuous infusionAGT activityAra-C regimenSignificant antileukemia activityPredictors of responseAcute myeloid leukemiaCourse of treatmentGm/Significant antileukemic activityEvaluable patientsNovel sulfonylhydrazineRefractory diseaseRefractory leukemiaStarting doseComplete responseDose schedulePatient subsetsMyeloid leukemiaPatientsAlkylguanine-DNA alkyltransferaseDose levelsDay 2Antileukemia activityAntileukemic activityCloretazineA phase I and pharmacokinetic study of VNP40101M, a new alkylating agent, in patients with advanced or metastatic cancer
Murren J, Modiano M, Kummar S, Clairmont C, Egorin M, Chu E, Sznol M. A phase I and pharmacokinetic study of VNP40101M, a new alkylating agent, in patients with advanced or metastatic cancer. Investigational New Drugs 2005, 23: 123-135. PMID: 15744588, DOI: 10.1007/s10637-005-5857-6.Peer-Reviewed Original ResearchConceptsPhase II trialDose levelsII trialVNP40101MGrade 2 adverse eventsIntra-patient dose escalationPre-treated patient populationBroad anti-tumor activityGrade 3 thrombocytopeniaPhase I trialPeak plasma concentrationDose-related toxicityMurine tumor modelsAnti-tumor activityModerate granulocytopeniaAcute headacheStarting doseAdverse eventsI trialMajor toxicityDose escalationFacial flushingPatient populationPlasma concentrationsMetastatic cancer
2004
A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia
Giles F, Thomas D, Garcia-Manero G, Faderl S, Cortes J, Verstovsek S, Ferrajoli A, Jeha S, Beran M, Koller C, Andreeff M, Cahill A, Clairmont C, Sznol M, Kantarjian H. A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia. Clinical Cancer Research 2004, 10: 2908-2917. PMID: 15131024, DOI: 10.1158/1078-0432.ccr-03-0738.Peer-Reviewed Original ResearchConceptsMaximum-tolerated doseAcute myeloid leukemiaMyelodysplastic syndromeVNP40101MExtramedullary toxicityMyeloid leukemiaDay 1Poor‐risk myelodysplastic syndromesAntileukemic activityPhase IMinimal extramedullary toxicitySignificant extramedullary toxicityFrequent adverse eventsPhase II doseInfusion-related toxicityPharmacokinetic studyCourse of treatmentSignificant antileukemic activityBroad antitumor activityNovel sulfonylhydrazineComplete remissionStarting doseAdverse eventsRefractory diseaseRefractory leukemia
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