2020
Phase 1 study of belinostat (PXD-101) and bortezomib (Velcade, PS-341) in patients with relapsed or refractory acute leukemia and myelodysplastic syndrome
Holkova B, Shafer D, Yazbeck V, Dave S, Bose P, Tombes MB, Shrader E, Wan W, Bandyopadhyay D, Weir C, Collins EB, Garnett A, Kmieciak M, Roberts JD, Garcia-Manero G, Grant S. Phase 1 study of belinostat (PXD-101) and bortezomib (Velcade, PS-341) in patients with relapsed or refractory acute leukemia and myelodysplastic syndrome. Leukemia & Lymphoma 2020, 62: 1187-1194. PMID: 33356689, PMCID: PMC8106643, DOI: 10.1080/10428194.2020.1861270.Peer-Reviewed Original ResearchConceptsStable diseaseAcute leukemiaDay 1Phase 1 dose-escalation studyRefractory acute leukemiaDose-escalation studyPhase 1 studyWhole-exome sequencingComplete pathologicKaryotypic responseAdult patientsQTc prolongationFirst patientMyelodysplastic syndromeTreatment strategiesBlast crisisPatientsExceptional responseKaryotypic aberrationsBelinostatGood responseBortezomibAMLLeukemiaFurther investigation
2018
A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma
Yazbeck V, Shafer D, Perkins EB, Coppola D, Sokol L, Richards KL, Shea T, Ruan J, Parekh S, Strair R, Flowers C, Morgan D, Kmieciak M, Bose P, Kimball A, Badros AZ, Baz R, Lin HY, Zhao X, Reich RR, Tombes MB, Shrader E, Sankala H, Roberts JD, Sullivan D, Grant S, Holkova B. A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma. Clinical Lymphoma Myeloma & Leukemia 2018, 18: 569-575.e1. PMID: 30122201, DOI: 10.1016/j.clml.2018.05.023.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBortezomibDrug Resistance, NeoplasmFemaleFollow-Up StudiesHumansLymphoma, Large B-Cell, DiffuseLymphoma, Mantle-CellMaleMiddle AgedNeoplasm Recurrence, LocalPrognosisProspective StudiesSalvage TherapySurvival RateVorinostatConceptsLarge B-cell lymphomaPhase II trialStable diseaseProgressive diseaseB-cell lymphomaPartial responseII trialCohort BCohort ADay 1Median progression-free survivalNonrandomized phase II trialDiffuse large B-cell lymphomaProgression-free survivalHistone deacetylase inhibitor vorinostatOverall response rateCombination of bortezomibMantle cell lymphomaNF-κB activationProteasome inhibitor bortezomibCell lymphoma cellsPresent multicenterRefractory MCLClinical responseCohort C
2017
A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma
Holkova B, Yazbeck V, Kmieciak M, Bose P, Ma S, Kimball A, Tombes MB, Shrader E, Wan W, Weir-Wiggins C, Singh A, Hogan KT, Conine S, Sankala H, Roberts JD, Shea TC, Grant S. A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma. Leukemia & Lymphoma 2017, 58: 1349-1357. PMID: 28103725, PMCID: PMC5817887, DOI: 10.1080/10428194.2016.1276287.Peer-Reviewed Original ResearchConceptsT-cell lymphomaMaximum-tolerated doseDose-limiting toxicityPhase 1 studyStable diseaseChronic lymphocytic leukemia/small lymphocytic lymphomaRefractory CLL/SLLPeripheral T-cell lymphomaCutaneous T-cell lymphomaIndolent B-cell lymphomaGrade 3 fatigueMedian treatment durationCLL/SLLSingle-agent bortezomibSmall lymphocytic lymphomaExpression of NFB-cell lymphomaRefractory CLLMedian durationPartial responseProgressive diseaseSafety profileLymphocytic lymphomaTreatment durationDay 1
2016
Phase I study of pemetrexed with sorafenib in advanced solid tumors
Poklepovic A, Gordon S, Shafer DA, Roberts JD, Bose P, Geyer CE, McGuire WP, Tombes MB, Shrader E, Strickler K, Quigley M, Wan W, Kmieciak M, Massey HD, Booth L, Moran RG, Dent P. Phase I study of pemetrexed with sorafenib in advanced solid tumors. Oncotarget 2016, 7: 42625-42638. PMID: 27213589, PMCID: PMC5173162, DOI: 10.18632/oncotarget.9434.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCohort StudiesFemaleHumansInflammationMaleMaximum Tolerated DoseMiddle AgedNeoplasmsNiacinamidePemetrexedPhenylurea CompoundsPTEN PhosphohydrolaseSorafenibTreatment OutcomeTriple Negative Breast NeoplasmsConceptsAdvanced solid tumorsDay 1Solid tumorsOral sorafenibDose scheduleBreast cancerTriple-negative breast cancerDose-escalation schemaPhase II dosePhase I trialSorafenib dosingSorafenib therapyStable diseaseCohort BComplete responseI trialPartial responseTolerable combinationRadiographic assessmentCumulative toxicityCombination treatmentPatientsSorafenibPhase IAntitumor activityA 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 criteriaA Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma
Holkova B, Zingone A, Kmieciak M, Bose P, Badros AZ, Voorhees PM, Baz R, Korde N, Lin HY, Chen JQ, Herrmann M, Xi L, Raffeld M, Zhao X, Wan W, Tombes MB, Shrader E, Weir-Wiggins C, Sankala H, Hogan KT, Doyle A, Annunziata CM, Wellons M, Roberts JD, Sullivan D, Landgren O, Grant S. A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma. Clinical Cancer Research 2016, 22: 1067-1075. PMID: 26446942, PMCID: PMC4775365, DOI: 10.1158/1078-0432.ccr-15-1076.Peer-Reviewed Original ResearchConceptsRefractory multiple myelomaPartial responseMultiple myelomaRelapsed/Refractory Multiple MyelomaMedian progression-free survival timeResponse rateProgression-free survival timeTwo-stage Simon designCommon grade 3Good partial responsePhase II studyPhase II trialMEK1/2 inhibitorSignificant preclinical activityMultiple myeloma cellsPrior therapyStable diseaseII trialClinical responseII studyProgressive diseaseMedian ageMean durationPreclinical activityDisease progression
2015
Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors
Wong SJ, Karrison T, Hayes DN, Kies MS, Cullen KJ, Tanvetyanon T, Argiris A, Takebe N, Lim D, Saba NF, Worden FP, Gilbert J, Lenz HJ, Razak AR, Roberts JD, Vokes EE, Cohen EE. Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors. Annals Of Oncology 2015, 27: 318-323. PMID: 26598548, PMCID: PMC4722891, DOI: 10.1093/annonc/mdv537.Peer-Reviewed Original ResearchConceptsMalignant salivary gland tumorsAdverse eventsStable diseaseObjective responseACC patientsCystic carcinomaECOG performance status 0Grade 3 adverse eventsMedian age 56 yearsGrade 4 adverse eventsMedian progression-free survivalFrequent adverse eventsMedian overall survivalNon-ACC patientsPerformance status 0Noncardiac chest painPhase II studyPhase II trialProgression-free survivalAge 56 yearsMalignant salivary tumorsAdenoid cystic carcinomaSalivary gland tumorsCycle 2Prior chemotherapy
2014
Phase I Trial of Bortezomib (PS-341; NSC 681239) and “Nonhybrid” (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms
Holkova B, Kmieciak M, Perkins EB, Bose P, Baz RC, Roodman GD, Stuart RK, Ramakrishnan V, Wan W, Peer CJ, Dawson J, Kang L, Honeycutt C, Tombes MB, Shrader E, Weir-Wiggins C, Wellons M, Sankala H, Hogan KT, Colevas AD, Doyle LA, Figg WD, Coppola D, Roberts JD, Sullivan D, Grant S. Phase I Trial of Bortezomib (PS-341; NSC 681239) and “Nonhybrid” (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms. Clinical Cancer Research 2014, 20: 5652-5662. PMID: 25248382, PMCID: PMC4233160, DOI: 10.1158/1078-0432.ccr-14-0805.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityCombination of bortezomibCommon hematologic toxicityCommon nonhematologic toxicitiesIndolent B-cell neoplasmsRefractory multiple myelomaDose-escalation designNon-Hodgkin lymphomaTotal response rateB-cell malignanciesB-cell neoplasmsPharmacodynamic study resultsNonhematologic toxicitySchedule regimenStable diseaseComplete remissionHematologic toxicityPartial remissionClinical responseInvestigator's discretionDosing regimenI trialPharmacokinetic findingsSensory neuropathyInfusion schedule
2013
A Phase I Trial of Vorinostat and Alvocidib in Patients with Relapsed, Refractory, or Poor Prognosis Acute Leukemia, or Refractory Anemia with Excess Blasts-2
Holkova B, Supko JG, Ames MM, Reid JM, Shapiro GI, Perkins EB, Ramakrishnan V, Tombes MB, Honeycutt C, McGovern RM, Kmieciak M, Shrader E, Wellons MD, Sankala H, Doyle A, Wright J, Roberts JD, Grant S. A Phase I Trial of Vorinostat and Alvocidib in Patients with Relapsed, Refractory, or Poor Prognosis Acute Leukemia, or Refractory Anemia with Excess Blasts-2. Clinical Cancer Research 2013, 19: 1873-1883. PMID: 23515411, PMCID: PMC3618599, DOI: 10.1158/1078-0432.ccr-12-2926.Peer-Reviewed Original ResearchMeSH KeywordsAcute DiseaseAdultAgedAnemia, Refractory, with Excess of BlastsAntineoplastic Combined Chemotherapy ProtocolsCell Line, TumorCyclin-Dependent Kinase Inhibitor p21FemaleFlavonoidsHumansHydroxamic AcidsLeukemiaMaleMaximum Tolerated DoseMiddle AgedMyeloid Cell Leukemia Sequence 1 ProteinPiperidinesPrognosisProto-Oncogene Proteins c-bcl-2RecurrenceRNA Polymerase IITreatment OutcomeVorinostatYoung AdultConceptsMaximum-tolerated dosePoor-prognosis acute leukemiaExcess blasts-2Objective responseQT prolongationAcute leukemiaBlasts-2Phase I trialBone marrow responseCardiac arrhythmia atrial fibrillationArrhythmia atrial fibrillationEvaluable patientsStable diseaseVorinostat pharmacokineticsDisease stabilizationMaintenance infusionI trialMarrow responsePharmacodynamic effectsRefractory anemiaIntravenous infusionLoading infusionPatientsVorinostatSecondary objective
2012
Phase I Trial of Belinostat and Bortezomib in Patients with Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia in Blast Crisis - One Year Update
Holkova B, Bose P, Tombes M, Shrader E, Wan W, Weir-Wiggins C, Stoddert E, Sankala H, Kmieciak M, Roberts J, Garcia-Manero G, Grant S. Phase I Trial of Belinostat and Bortezomib in Patients with Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia in Blast Crisis - One Year Update. Blood 2012, 120: 3588. DOI: 10.1182/blood.v120.21.3588.3588.Peer-Reviewed Original ResearchHematopoietic stem cell transplantationStem cell transplantationAcute myeloid leukemiaRefractory acute leukemiaDose level 5Myelodysplastic syndromeStable diseaseCycles of treatmentPartial responseComplete responseAcute leukemiaChronic myelogenous leukemiaCML-BCAdverse eventsI trialMyelogenous leukemiaDay 1Allogeneic hematopoietic stem cell transplantationIncomplete blood count recoveryTreatment-related adverse eventsPrimary acute myeloid leukemiaAcute leukemia refractoryBlood count recoveryDose level 4Second partial responsePhase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies
Bose P, Perkins EB, Honeycut C, Wellons MD, Stefan T, Jacobberger JW, Kontopodis E, Beumer JH, Egorin MJ, Imamura CK, Douglas Figg W, Karp JE, Koc ON, Cooper BW, Luger SM, Colevas AD, Roberts JD, Grant S. Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies. Cancer Chemotherapy And Pharmacology 2012, 69: 1657-1667. PMID: 22349810, PMCID: PMC3365614, DOI: 10.1007/s00280-012-1839-5.Peer-Reviewed Original ResearchConceptsTyrosine kinase inhibitorsCombination of flavopiridolStable diseasePhase I dose-escalation studyPhiladelphia chromosome-positive acute leukemiaSecond-generation BCR-ABL tyrosine kinase inhibitorBone marrow blast countI dose-escalation studyBCR-ABL tyrosine kinase inhibitorsKinase inhibitorsImatinib-resistant diseaseIntravenous infusion weeklyPhase II dosesDose-escalation studyMarrow blast countPhase I trialNovel combination regimenMajor pharmacokinetic interactionsBCR-ABL tyrosine kinaseChronic myelogenous leukemiaInfusion weeklyCyclin-dependent kinase inhibitorBlast countCombination regimenComplete response
2011
A Phase II Study of the MEK 1/2 Inhibitor AZD6244 (Selumetinib, ARRY-142866) in Relapsed or Refractory Multiple Myeloma
Holkova B, Badros A, Geller R, Voorhees P, Zingone A, Korde N, Lin H, Tombes M, Shrader E, Sankala H, Kmieciak M, Roberts J, Sullivan D, Landgren O, Grant S. A Phase II Study of the MEK 1/2 Inhibitor AZD6244 (Selumetinib, ARRY-142866) in Relapsed or Refractory Multiple Myeloma. Blood 2011, 118: 2931. DOI: 10.1182/blood.v118.21.2931.2931.Peer-Reviewed Original ResearchPhase II studyAspartate aminotransferaseRefractory MMII studyCommon treatment-related adverse eventsPresent phase II studyTreatment-related adverse eventsTwo-stage Simon designAcute kidney injuryCommon grade 3Objective partial responsePeripheral sensory neuropathyECOG performance scoreRefractory multiple myelomaFavorable clinical profilePre-clinical activityResponse/resistanceEffects of AZD6244Multiple myeloma cellsCompetitive small molecule inhibitorBone marrow microenvironmentPost-treatment expressionOrtho BiotechPrior regimensStable diseasePhase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory B-Cell Neoplasms
Holkova B, Perkins EB, Ramakrishnan V, Tombes MB, Shrader E, Talreja N, Wellons MD, Hogan KT, Roodman GD, Coppola D, Kang L, Dawson J, Stuart RK, Peer C, Figg WD, Kolla S, Doyle A, Wright J, Sullivan DM, Roberts JD, Grant S. Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory B-Cell Neoplasms. Clinical Cancer Research 2011, 17: 3388-3397. PMID: 21447728, PMCID: PMC3096752, DOI: 10.1158/1078-0432.ccr-10-2876.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityCombination of bortezomibFebrile neutropeniaPharmacodynamic studiesDay 1Refractory B-cell neoplasmsElevated aspartate aminotransferase levelsCommon hematologic toxicityCommon nonhematologic toxicitiesPhase II studyRefractory multiple myelomaPhase I studiesAspartate aminotransferase levelsB-cell malignanciesB-cell neoplasmsHematologic toxicityIntravenous pushNonhematologic toxicityStable diseaseAminotransferase levelsI trialII studyPartial responseComplete responseDose escalation
2010
A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors
Dickson MA, Rathkopf DE, Carvajal RD, Grant S, Roberts JD, Reid JM, Ames MM, McGovern RM, Lefkowitz RA, Gonen M, Cane LM, Dials HJ, Schwartz GK. A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors. Investigational New Drugs 2010, 29: 1004-1012. PMID: 20461440, PMCID: PMC3545439, DOI: 10.1007/s10637-010-9447-x.Peer-Reviewed Original ResearchConceptsSerum levelsPhase I pharmacokinetic studyIntermittent high doseResults 34 patientsD1-3I pharmacokinetic studyCyclin-dependent kinase inhibitor flavopiridolKinase inhibitor flavopiridolStable diseaseOral doseOral dosingHigh doseCombination treatmentPatientsSolid tumorsCmaxOne weekDosePharmacokinetic studyVorinostatMTDFlavopiridolNeutropeniaChemotherapyLevels
2008
Phase I Trial of Bortezomib (NSC 681239) and Flavopiridol (NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms.
Grant S, Sullivan D, Roodman D, Stuart R, Perkins E, Kolla S, Ramakrishnan V, Wright J, Colevas A, Tombes M, Roberts J. Phase I Trial of Bortezomib (NSC 681239) and Flavopiridol (NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms. Blood 2008, 112: 1573. DOI: 10.1182/blood.v112.11.1573.1573.Peer-Reviewed Original ResearchB-cell neoplasmsDose levelsBolus scheduleI trialMinor responseNF-kappaB nuclear localizationIndolent B-cell neoplasmsPhase II evaluationPhase I trialPhospho-JNKCorrelative laboratory studiesNF-kappaB DNA bindingChronic lymphocytic leukemiaB-cell malignanciesBone marrow CD138Mcl-1Evaluable patientsStable diseaseEligible patientsPostural hypotensionHerpes zosterPartial responseRefractory diseaseStandard therapySystemic therapy
2005
Phase I Trial of Bortezomib (NSC 681239) and Flavopiridol (NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms.
Grant S, Sullivan D, Roodman D, Stuart R, Perkins E, Ramakrishnan V, Wright J, Colevas A, Roberts J. Phase I Trial of Bortezomib (NSC 681239) and Flavopiridol (NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms. Blood 2005, 106: 3338. DOI: 10.1182/blood.v106.11.3338.3338.Peer-Reviewed Original ResearchI trialDose levelsPre-existing peripheral neuropathyIndolent B-cell lymphomaNF-kappaB nuclear localizationIndolent B-cell neoplasmsCase of exacerbationPhase I trialPhase II evaluationPhospho-JNKCorrelative laboratory studiesNF-kappaB DNA bindingB-cell lymphomaB-cell malignanciesBone marrow CD138B-cell neoplasmsMcl-1Eligible patientsStable diseaseHerpes zosterPartial responseRefractory diseaseStandard therapySystemic therapyComplete response
2000
Weekly lometrexol with daily oral folic acid is appropriate for phase II evaluation
Roberts J, Poplin E, Tombes M, Kyle B, Spicer D, Grant S, Synold T, Moran R. Weekly lometrexol with daily oral folic acid is appropriate for phase II evaluation. Cancer Chemotherapy And Pharmacology 2000, 45: 103-110. PMID: 10663624, DOI: 10.1007/s002800050017.Peer-Reviewed Original ResearchConceptsDaily oral folic acidOral folic acidDose omissionsFolic acidDose combinationWeekly scheduleEarlier Phase I trialPredose plasma samplesPhase II dosePhase II trialDose-limiting toxicityPhase I trialPhase II evaluationRed blood cell contentSevere toxic eventsRenal cell carcinomaDays of treatmentAppropriate dose combinationBlood cell contentInfusion weeklyStable diseaseII trialDose intensityPartial responseWeekly administration