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 criteria
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
2013
Phase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma
Poklepovic A, Youseffian L, Winning M, Birdsell CA, Crosby NA, Ramakrishnan V, Ernstoff MS, Roberts JD. Phase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma. Investigational New Drugs 2013, 31: 937-942. PMID: 23315028, PMCID: PMC3844155, DOI: 10.1007/s10637-012-9913-8.Peer-Reviewed Original ResearchConceptsSoft tissue sarcomasPhase I trialTissue sarcomasPartial responseI trialPhase II dosesDurable complete responseAmine precursor uptakeTwenty-eight patientsProteasome inhibitor bortezomibHuman melanoma cell linesMurine xenograft tumor modelXenograft tumor modelCKIT mutationsDecarboxylation (APUD) tumorsProphylactic antiemeticsRECIST v1.0Eight patientsComplete responseMelanoma cell linesWeekly dosesDose escalationAgent dacarbazinePreclinical studiesDose levels
2011
Phase II Trials Powered to Detect Tumor Subtypes
Roberts JD, Ramakrishnan V. Phase II Trials Powered to Detect Tumor Subtypes. Clinical Cancer Research 2011, 17: 5538-5545. PMID: 21737510, DOI: 10.1158/1078-0432.ccr-10-2466.Peer-Reviewed Original ResearchConceptsTumor subtypesResponse ratePhase II trial designPhase II trialPhase III trialsOverall response ratePhase II designStage 1Characterization of tumorsII trialIII trialsMetastatic diseaseSimilar patientsProspective characterizationSample sizeTrial designSubtypesTumorsTotal sample sizePhase IIII designTrialsTreatmentVariables of interestDifferent treatments
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
2009
Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors
Pavlick AC, Wu J, Roberts J, Rosenthal MA, Hamilton A, Wadler S, Farrell K, Carr M, Fry D, Murgo AJ, Oratz R, Hochster H, Liebes L, Muggia F. Phase I study of bryostatin 1, a protein kinase C modulator, preceding cisplatin in patients with refractory non-hematologic tumors. Cancer Chemotherapy And Pharmacology 2009, 64: 803. PMID: 19221754, PMCID: PMC3901370, DOI: 10.1007/s00280-009-0931-y.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic AgentsBryostatinsCisplatinFemaleHumansMaleMaximum Tolerated DoseMiddle AgedNeoplasmsProtein Kinase CConceptsPeripheral blood mononuclear cellsPhase INon-hematologic tumorsPhase II dosesPhase II doseDose-limiting toxicityResultsFifty-three patientsBlood mononuclear cellsNon-hematologic malignanciesBryostatin 1Cytotoxicity of cisplatinCisplatin 50PurposePreclinical dataObjective responseContinuous infusionMononuclear cellsTolerable dosesProtein kinase C modulatorsCisplatin effectComputerized tomographyPatientsConsistent inhibitionCisplatin cytotoxicityCisplatinMinimal toxicity
2007
Extrinsic pathway- and cathepsin-dependent induction of mitochondrial dysfunction are essential for synergistic flavopiridol and vorinostat lethality in breast cancer cells
Mitchell C, Park MA, Zhang G, Yacoub A, Curiel DT, Fisher PB, Roberts JD, Grant S, Dent P. Extrinsic pathway- and cathepsin-dependent induction of mitochondrial dysfunction are essential for synergistic flavopiridol and vorinostat lethality in breast cancer cells. Molecular Cancer Therapeutics 2007, 6: 3101-3112. PMID: 18065490, DOI: 10.1158/1535-7163.mct-07-0561.Peer-Reviewed Original ResearchConceptsBcl-xLC-FLIPBreast cancer cellsMitogen-activated protein/ERK kinase 1X-chromosome-linked inhibitorCancer cellsExtracellular signal-regulated kinase 1/2Apoptosis protein levelsSignal-regulated kinase 1/2ERK kinase 1CDK inhibitor roscovitineIntrinsic apoptosis pathwayHistone deacetylase inhibitor suberoylanilide hydroxamic acidForm of AktProtease-dependent pathwayInhibition of AktTreatment of cellsBak functionBcl-xL expressionCell killingCyclin-dependent kinase inhibitor flavopiridolInhibitor suberoylanilide hydroxamic acidKinase inhibitor flavopiridolERK1/2 functionAkt activityLow-Dose BBR3610 Toxicity in Colon Cancer Cells Is p53-Independent and Enhanced by Inhibition of Epidermal Growth Factor Receptor (ERBB1)-Phosphatidyl Inositol 3 Kinase Signaling
Mitchell C, Kabolizadeh P, Ryan J, Roberts JD, Yacoub A, Curiel DT, Fisher PB, Hagan MP, Farrell NP, Grant S, Dent P. Low-Dose BBR3610 Toxicity in Colon Cancer Cells Is p53-Independent and Enhanced by Inhibition of Epidermal Growth Factor Receptor (ERBB1)-Phosphatidyl Inositol 3 Kinase Signaling. Molecular Pharmacology 2007, 72: 704-714. PMID: 17578896, DOI: 10.1124/mol.107.038406.Peer-Reviewed Original ResearchConceptsColon cancer cellsEpidermal growth factor receptorGrowth factor receptorActive AktC-FLIPMolecular inhibitionCaspase-8 functionsPhosphatidyl inositol 3 kinaseActivation of BaxDominant-negative AktErbB1 inhibitorsFactor receptorHuman colon cancer cellsOverexpression of XIAPCancer cellsSmall moleculesKinase signalingPI3K inhibitorsAkt activityCaspase-9Bcl-xLNull cellsMcl-1SW480 cellsK-RAS
2003
Phase I studies of weekly administration of cytotoxic agents: Implications of a mathematical model
McClish DK, Roberts JD. Phase I studies of weekly administration of cytotoxic agents: Implications of a mathematical model. Investigational New Drugs 2003, 21: 299-308. PMID: 14578680, DOI: 10.1023/a:1025464510639.Peer-Reviewed Original ResearchThe use of cyclin-dependent kinase inhibitors alone or in combination with established cytotoxic drugs in cancer chemotherapy
Grant S, Roberts JD. The use of cyclin-dependent kinase inhibitors alone or in combination with established cytotoxic drugs in cancer chemotherapy. Drug Resistance Updates 2003, 6: 15-26. PMID: 12654284, DOI: 10.1016/s1368-7646(02)00141-3.Peer-Reviewed Original ResearchConceptsCyclin-dependent kinase inhibitorCytotoxic agentsKinase inhibitorsSingle-agent activityCDK inhibitorsConventional cytotoxic agentsAnti-tumor effectsApoptotic regulatory moleculesCell cycle dysregulationNeoplastic cell proliferationAbundant preclinical evidencePreclinical evidenceTumor cell typesCritical molecular targetsClinical studiesSpecific tumor cell typesPreclinical studiesClinical developmentSmall molecule inhibitorsCell cycle traverseCytotoxic drugsAntitumor efficacyClinical arenaCancer chemotherapyMolecular targets
2002
Phase I Study of Bryostatin-1 and Fludarabine in Patients with Chronic Lymphocytic Leukemia and Indolent Non-Hodgkin's Lymphoma
Roberts JD, Smith MR, Feldman EJ, Cragg L, Grant S. Phase I Study of Bryostatin-1 and Fludarabine in Patients with Chronic Lymphocytic Leukemia and Indolent Non-Hodgkin's Lymphoma. Clinical Lymphoma Myeloma & Leukemia 2002, 3: 184-188. PMID: 12521398, DOI: 10.3816/clm.2002.n.025.Peer-Reviewed Original ResearchHigher doses of mitoxantrone among men with hormone‐refractory prostate carcinoma
Levine EG, Halabi S, Roberts JD, Kaplan EB, Rago R, Atkins JN, Vogelzang NJ. Higher doses of mitoxantrone among men with hormone‐refractory prostate carcinoma. Cancer 2002, 94: 665-672. PMID: 11857298, DOI: 10.1002/cncr.10217.Peer-Reviewed Original ResearchConceptsHormone-refractory prostate carcinomaHigh dosesPelvic irradiationProstate carcinomaArm IFrequency of thrombocytopeniaLow-dose glucocorticoidsArm IIPhase II trialPhase III trialsPhase III testingMedian survival timeGranulocyte-macrophage colony-stimulating factorColony-stimulating factorAssessable patientsEstramustine combinationsII trialIII trialsMedian survivalPartial responsePSA valuesFavorable outcomeSurvival timePatientsSame schedule
2001
Novel Approaches to Polynuclear Platinum Pro-Drugs. Selective Release of Cytotoxic Platinum−Spermidine Species through Hydrolytic Cleavage of Carbamates
Hegmans A, Qu Y, Kelland L, Roberts J, Farrell N. Novel Approaches to Polynuclear Platinum Pro-Drugs. Selective Release of Cytotoxic Platinum−Spermidine Species through Hydrolytic Cleavage of Carbamates. Inorganic Chemistry 2001, 40: 6108-6114. PMID: 11703107, DOI: 10.1021/ic010509a.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCarbamatesCatalysisChromatography, High Pressure LiquidFemaleHumansHydrogen-Ion ConcentrationHydrolysisInhibitory Concentration 50Leukemia L1210MiceMolecular StructureNuclear Magnetic Resonance, BiomolecularOrganoplatinum CompoundsOvarian NeoplasmsPolyaminesProdrugsSpermidineSpermineStereoisomerismStructure-Activity RelationshipTemperatureTumor Cells, CulturedConceptsDinuclear platinum compoundsPt–Cl bondsPreliminary biological assaysN-butyl side chainsMagnitude less cytotoxicPolynuclear platinumSecond generation analogsNMR spectroscopyPolyamine linkersQuaternary nitrogenFMOC derivativesConformational isomersDerivatives 4Electrostatic contributionSide chainsHydrolytic cleavageSpermidine moietyGreater selectivityOral deliveryTherapeutic indexPlatinum drugsRate constantsCellular uptakeN-propylBiological assays
2000
Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG2034.
McLeod HL, Cassidy J, Powrie RH, Priest DG, Zorbas MA, Synold TW, Shibata S, Spicer D, Bissett D, Pithavala YK, Collier MA, Paradiso LJ, Roberts JD. Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG2034. Clinical Cancer Research 2000, 6: 2677-84. PMID: 10914709.Peer-Reviewed Original ResearchConceptsGlycinamide ribonucleotide formyltransferaseCourse 1Systemic clearanceGrade III/IV toxicityGrade II toxicityMin/m2Rapid systemic clearanceVolume of distributionEvaluable patientsSystemic exposurePharmacodynamic evaluationClinical centersBolus injectionPharmacokinetic approachBlood samplesPatient toxicityPatientsElimination patternReproducible ELISAAG2034Course 3Phase IAnticancer agentsPurine synthesis pathwayDe novo purine synthesis pathwayPhase I study of AG2034, a targeted GARFT inhibitor, administered once every 3 weeks
Roberts J, Shibata S, Spicer D, McLeod H, Tombes M, Kyle B, Carroll M, Sheedy B, Collier M, Pithavala Y, Paradiso L, Clendeninn N. Phase I study of AG2034, a targeted GARFT inhibitor, administered once every 3 weeks. Cancer Chemotherapy And Pharmacology 2000, 45: 423-427. PMID: 10803927, DOI: 10.1007/s002800051012.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityPhase II doseCumulative toxicityAdvanced malignanciesIntravenous bolusAUC0-24Pharmacodynamic factorsFolate supplementationPlasma concentrationsIntermediate dosePharmacokinetic analysisDose levelsELISA assaysDosePhase IAG2034Progressive increaseGARFT inhibitorToxicityWeeksInhibitorsMucositisThrombocytopeniaDiarrheaHyperbilirubinemia
1999
Comparison of cytotoxicity and cellular accumulation of polynuclear platinum complexes in L1210 murine leukemia cell lines
Roberts J, Peroutka J, Beggiolin G, Manzotti C, Piazzoni L, Farrell N. Comparison of cytotoxicity and cellular accumulation of polynuclear platinum complexes in L1210 murine leukemia cell lines. Journal Of Inorganic Biochemistry 1999, 77: 47-50. PMID: 10626353, DOI: 10.1016/s0162-0134(99)00137-3.Peer-Reviewed Original ResearchConceptsPolynuclear platinum complexesPlatinum complexesDiamine linkerL1210 cell lineDinuclear platinum complexesTrinuclear platinum complexL1210 murine leukemia cell lineL1210/DDPDinuclear complexesAnticancer profileChemical featuresCytotoxicity profileCellular uptakeBBR3464LinkerMurine leukemia cell lineComplexesTransCharge contributesClinical agentsCytotoxicityUptake pathwayCellular accumulationAntitumor activityPlatinumCellular pharmacology of polynuclear platinum anti-cancer agents
Roberts J, Peroutka J, Farrell N. Cellular pharmacology of polynuclear platinum anti-cancer agents. Journal Of Inorganic Biochemistry 1999, 77: 51-57. PMID: 10626354, DOI: 10.1016/s0162-0134(99)00147-6.Peer-Reviewed Original ResearchConceptsCisplatin-resistant cell linesCell linesCross-linking adductsWild-type cell linesDNA repair mechanismsL1210 murine leukemia cell lineCellular pharmacologyType cell linesGenomic accessMurine leukemia cell lineWild typeCytotoxic effectsLeukemia cell linesRepair mechanismsDNA interstrandAnti-cancer agentsDiminished accumulationDinuclear platinum complexesTrinuclear platinum complexBBR3464Enhanced activityPotential anticancer agentsPotent cytotoxic agentComplexesVivo activity
1998
Phase Ib trial of bryostatin 1 in patients with refractory malignancies.
Grant S, Roberts J, Poplin E, Tombes MB, Kyle B, Welch D, Carr M, Bear HD. Phase Ib trial of bryostatin 1 in patients with refractory malignancies. Clinical Cancer Research 1998, 4: 611-8. PMID: 9533528.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic AgentsBryostatinsCohort StudiesCytotoxicity, ImmunologicDrug Administration ScheduleFemaleHumansImmunophenotypingInfusions, IntravenousInterleukin-2LactonesLymphocyte ActivationLymphocytesLymphomaMacrolidesMaleMetabolic Clearance RateMiddle AgedNeoplasmsPatient SelectionPlatelet AggregationProtein Kinase CConceptsPhase Ib trialIb trialCohort 3Lymphokine-activated killer cell activityBryostatin 1Bryostatin-1 administrationObjective clinical responsesKiller cell activityLiver function testsSubset of patientsBryostatin 1 treatmentSignificant posttreatment increasePKC activitySplit courseClinical responseFirst doseLiver metastasesNonhematological malignanciesRefractory malignanciesFunction testsPatient cohortCohort 1Interleukin-2Immunophenotypic profileTransient elevation
1996
Bryostatin 1 activates splenic lymphocytes and induces sustained depletion of splenocyte protein kinase C activity in vivo after a single intravenous administration
Bear H, McFadden A, Kostuchenko P, Lipshy K, Hamad G, Turner A, Roberts J, Carr M, Carr S, Grant S. Bryostatin 1 activates splenic lymphocytes and induces sustained depletion of splenocyte protein kinase C activity in vivo after a single intravenous administration. Anti-Cancer Drugs 1996, 7: 299-306. PMID: 8792004, DOI: 10.1097/00001813-199605000-00010.Peer-Reviewed Original ResearchConceptsBryostatin 1Normal murine spleen cellsT-cell activation marker CD69PKC activityActivation marker CD69Single bolus injectionEarly lymphocyte activationSingle intravenous administrationAnti-tumor effectsNormal host tissuesCell surface phenotypeProtein kinase CMurine spleen cellsPlasma levels resultsRegulate protein kinase CAnti-cancer agentsControl miceMarked splenomegalyBolus injectionIntravenous administrationC57BI/6 miceSpleen cellsSplenocyte proliferationSplenic lymphocytesSurface phenotype