2024
Topiramate treatment of pediatric metabolic dysfunction–associated steatotic liver disease: A descriptive cohort study
Kohut T, Tou A, Carr E, Xanthakos S, Arce‐Clachar A, Fawaz R, Valentino P, Panganiban J, Mouzaki M. Topiramate treatment of pediatric metabolic dysfunction–associated steatotic liver disease: A descriptive cohort study. Journal Of Parenteral And Enteral Nutrition 2024, 49: 308-313. PMID: 39720872, DOI: 10.1002/jpen.2722.Peer-Reviewed Original ResearchBody mass indexBody mass index z-scoreBaseline to 3Alanine aminotransferaseGlycated hemoglobinLifestyle modificationZ-scoreAlanine aminotransferase normalizationPatients aged <Weight loss medicationsAlanine aminotransferase levelsMild side effectsSerum alanine aminotransferaseObesity pharmacotherapyTopiramate treatmentPrimary treatmentLaboratory valuesOff-labelPediatric obesityMass indexTopiramateCohort studySingle agentPrimary outcomeLipid profileUsing Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia
Jones L, Rukhlenko O, Dias T, Carmody C, Wynne K, Kholodenko B, Bond J. Using Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia. Blood 2024, 144: 4161-4161. DOI: 10.1182/blood-2024-207308.Peer-Reviewed Original ResearchAcute myeloid leukemiaPatient-derived xenograftsCombination-treated miceInhibitor combinationsPeripheral bloodPhosphorylated ERKBone marrowRAS pathway activationSpleen weightMyeloid leukemiaAML patient-derived xenograftDrug combinationsVehicle controlSingle agentHuman CD45+ cellsPre-clinical mouse modelPediatric acute myeloid leukemiaAssociated with poor outcomesHigh-risk patient groupsMedian spleen weightSB-treated micePreclinical in vivo modelsCD45+ cellsLateral tail veinPathway activationFirst-in-human phase I trial of the oral first-in-class ubiquitin specific peptidase 1 (USP1) inhibitor KSQ-4279 (KSQi), given as single agent (SA) and in combination with olaparib (OLA) or carboplatin (CARBO) in patients (pts) with advanced solid tumors, enriched for deleterious homologous recombination repair (HRR) mutations.
Yap T, Lakhani N, Patnaik A, Lee E, Gutierrez M, Moore K, Carneiro B, Hays J, Huang M, LoRusso P, Wylie A, Cadzow L, Goulet M, Tobin E, Krieter O, Schmid D, Blake S, Dieterich M, Jamois C, Harris P. First-in-human phase I trial of the oral first-in-class ubiquitin specific peptidase 1 (USP1) inhibitor KSQ-4279 (KSQi), given as single agent (SA) and in combination with olaparib (OLA) or carboplatin (CARBO) in patients (pts) with advanced solid tumors, enriched for deleterious homologous recombination repair (HRR) mutations. Journal Of Clinical Oncology 2024, 42: 3005-3005. DOI: 10.1200/jco.2024.42.16_suppl.3005.Peer-Reviewed Original ResearchUbiquitin specific peptidase 1Treatment-emergent adverse eventsHomologous recombination repair mutationsSingle agentPARP inhibitorsHomologous recombination repairFirst-in-human phase I trialPreliminary anti-tumor activityPaired tumor biopsiesTNBC PDX modelsDisease control ratePhase I trialAUC 4Olaparib concentrationsRECIST PRDose escalationExpansion cohortCancer ptsDose proportionalityTumor biopsiesI trialMaculopapular rashPDX modelsDiscontinued treatmentDNA damage response pathway
2023
Abstract A137: Pharmacokinetics and pharmacodynamics of IGM-8444, a first-in-class engineered pentameric DR5-targeting agonist IgM monoclonal antibody, in patients with R/R and newly diagnosed cancers
Hernandez G, Bilic S, Guan Y, So J, Bhattacharya S, Wang B, Kotturi M, Oyasu M, Desbois M, Cao Y, Humke E, Ahern S, Sinclair A, Ulahannan S, Subbiah V, Pelster M, Lorusso P, Falchook G, Wang J, Barve M, Grewal J, Chow W, Henry J, Cecchini M, Takimoto C, Leabman M. Abstract A137: Pharmacokinetics and pharmacodynamics of IGM-8444, a first-in-class engineered pentameric DR5-targeting agonist IgM monoclonal antibody, in patients with R/R and newly diagnosed cancers. Molecular Cancer Therapeutics 2023, 22: a137-a137. DOI: 10.1158/1535-7163.targ-23-a137.Peer-Reviewed Original ResearchCleaved caspase-3Single agentNewly diagnosed cancerIgM monoclonal antibodyPreclinical mouse tumor modelsIgM antibodiesCASP-3Monoclonal antibodiesInduce tumor cell apoptosisPopulation PK modelPopulation PK analysisDose-dependent increaseMouse tumor modelsTumor cell apoptosisTerminal half-lifeTreatment-related increasesDose-dependent efficacyCleaved caspase-3 levelsEffects of ADAADA titersTwo-compartment modelPharmacodynamic changesTargeted therapyEfficacious dosePK analysisPredictors of Outcome for Allogeneic Stem Cell Transplantation with a Reduced Intensity Pentostatin/TBI Conditioning Regimen in T-Cell Lymphomas: A Single Center Experience
Hamouche R, Foss F, Mirza S, Di M, Isufi I, Bar N, Gowda L, Perreault S, Roberts K, Seropian S, Sethi T. Predictors of Outcome for Allogeneic Stem Cell Transplantation with a Reduced Intensity Pentostatin/TBI Conditioning Regimen in T-Cell Lymphomas: A Single Center Experience. Blood 2023, 142: 2172. DOI: 10.1182/blood-2023-189414.Peer-Reviewed Original ResearchT-cell lymphomaTotal body irradiationAggressive T-cell lymphomaReduced intensity conditioning regimenHematopoietic stem cell transplantationRefractory T-cell lymphomaNodal T-cell lymphomasIntensity conditioning regimenPotential curative optionStem cell transplantationConditioning regimenAdult patientsCurative optionRetrospective reviewBody irradiationCell transplantationSingle agentPatientsRegimenPentostatinAlloSCTTransplantationLymphomaNovel Causal Inference Method Estimates Treatment Effects of Contemporary Drugs in a Global Cohort of Patients with Relapsed and Refractory Mature T-Cell and NK-Cell Neoplasms
Koh M, Boussi L, Han J, Peng L, Sorial M, Eche-Ugwu I, Miranda E, Chiattone C, Stuver R, Horwitz S, Turizo M, McCabe S, Merrill M, Jacobsen E, Kim J, Kim Y, Cho J, Eipe T, Shet T, Jain H, Sengar M, Singh S, Gabler J, Koh M, Van Der Weyden C, Prince M, Hamouche R, Muradashvili T, Foss F, Gentilini M, Casadei B, Zinzani P, Okatani T, Yoshida N, Yoon S, Kim W, Panchoo G, Mohamed Z, Verburgh E, Alturas J, Al Mansour M, Ford J, Manni M, Federico M, O'Connor O, Cabrera M, Shen C, Marchi E, Shah D, Jain S. Novel Causal Inference Method Estimates Treatment Effects of Contemporary Drugs in a Global Cohort of Patients with Relapsed and Refractory Mature T-Cell and NK-Cell Neoplasms. Blood 2023, 142: 1703. DOI: 10.1182/blood-2023-185881.Peer-Reviewed Original ResearchSuperior overall survivalCytotoxic chemotherapyOverall survivalNK-cell neoplasmsBrentuximab vedotinPTCL-NOSMultivariate CoxSingle agentALK- ALCLSmall molecule inhibitorsComparable OSGlobal cohortLargest global cohortClinical trialsT cellsConcordance indexMultivariate Cox regression modelSecond-line therapyPrimary refractory patientsIndependent prognostic effectCox regression modelMolecule inhibitorsReal-world evidenceEpigenetic modifiersMature T cellsA phase 1a dose-escalation study of PY159, a monoclonal antibody targeting TREM1 (triggering receptor expressed on myeloid cells 1).
Winer I, Patnaik A, Barve M, Kummar S, Schenk E, LoRusso P, Yeku O, Fu S, Jahchan N, Myers M, Liang L, Deegan D, Jackson L, Li Y, Reyno L, Chamberlain M. A phase 1a dose-escalation study of PY159, a monoclonal antibody targeting TREM1 (triggering receptor expressed on myeloid cells 1). Journal Of Clinical Oncology 2023, 41: 2523-2523. DOI: 10.1200/jco.2023.41.16_suppl.2523.Peer-Reviewed Original ResearchSingle agentDose levelsNon-small cell lung cancerAdvanced refractory solid tumorsDose-escalation study designImmune-related adverse eventsTriple-negative breast cancerImmune checkpoint inhibitorsAcceptable safety profileDose-escalation studyRefractory solid tumorsCell lung cancerArchival tumor tissueEnrollment of subjectsImmune-related reactionsDose proportionalECOG PSRECIST 1.1Stable diseaseTREM1 expressionCheckpoint inhibitorsAdverse eventsPartial responseRadiographic responseGynecologic cancerWhat’s Next after Hypomethylating Agents Failure in Myeloid Neoplasms? A Rational Approach
Awada H, Gurnari C, Xie Z, Bewersdorf J, Zeidan A. What’s Next after Hypomethylating Agents Failure in Myeloid Neoplasms? A Rational Approach. Cancers 2023, 15: 2248. PMID: 37190176, PMCID: PMC10137017, DOI: 10.3390/cancers15082248.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsAcute myeloid leukemiaMDS/AML patientsEarly clinical trialsPotential therapeutic agentAML patientsMultidrug combinationsClinical trialsMyeloid leukemiaMyeloid neoplasmsRational approachSingle agentCurrent managementTherapeutic potentialStandardized guidelinesTherapeutic agentsMutational characteristicsPatientsNeoplasmsLatest findingsGenomic factorsCellular adaptationAgentsHMA resistanceFailureLeukemiaThe Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo
Han C, McNamara B, Bellone S, Harold J, Manara P, Hartwich T, Mutlu L, Yang-Hartwich Y, Zipponi M, Demirkiran C, Verzosa M, Altwerger G, Ratner E, Huang G, Clark M, Andikyan V, Azodi M, Dottino P, Schwartz P, Santin A. The Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo. Gynecologic Oncology 2023, 170: 172-178. PMID: 36706643, PMCID: PMC10023457, DOI: 10.1016/j.ygyno.2023.01.015.Peer-Reviewed Original ResearchConceptsCombination of olaparibOvarian cancerHER2 expressionSingle agentCell linesGynecologic cancer mortalityHER2-negative tumorsOvarian cancer cell linesOvarian cancer patientsEpithelial ovarian carcinomaNovel therapeutic optionsOC cell linesUnmet medical needPoly (ADP-ribose) polymerase (PARP) inhibitorsPan-ErbB inhibitorSingle-agent olaparibPolymerase inhibitor olaparibPoly (ADP-ribose) polymerase (PARP) inhibitor olaparibPrimary HER2Cancer cell linesNegative tumorsTherapeutic optionsCancer mortalityCancer patientsNeu expression
2022
Randomized Phase II Study to Assess the Role of Nivolumab As Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients after Chemotherapy (NCI9706 protocol; REMAIN Trial)
Liu H, Sharon E, Karrison T, Zha Y, Fulton N, Streicher H, Sweet K, Yaghmour G, Liu J, Jonas B, Schimmer A, Grant S, Zeidan A, Hildebrandt G, Hourigan C, Lowrey C, Mattison R, Palmisiano N, Salhotra A, Tzachanis D, Baer M, Lin T, Patel P, Chen H, Stadler W, Odenike O, Larson R, Gajewski T, Stock W. Randomized Phase II Study to Assess the Role of Nivolumab As Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients after Chemotherapy (NCI9706 protocol; REMAIN Trial). Blood 2022, 140: 1716-1719. DOI: 10.1182/blood-2022-157326.Peer-Reviewed Original ResearchComparative efficacy and tolerability of novel agents vs chemotherapy in relapsed and refractory T-cell lymphomas: a meta-analysis
Shafagati N, Koh M, Boussi L, Park H, Stuver R, Bain P, Foss FM, Shen C, Jain S. Comparative efficacy and tolerability of novel agents vs chemotherapy in relapsed and refractory T-cell lymphomas: a meta-analysis. Blood Advances 2022, 6: 4740-4762. PMID: 35816645, PMCID: PMC9631658, DOI: 10.1182/bloodadvances.2022007425.Peer-Reviewed Original ResearchConceptsPeripheral T-cell lymphomaOverall response rateR Peripheral T Cell LymphomaCombination chemotherapyT-cell lymphomaSingle agentComparative efficacyRefractory T-cell lymphomaPhase ISingle-agent strategyPhase II trialPlatinum-based regimensPhase III trialsPhase I trialOptimal treatment strategyNovel single agentsRandom-effects modelSignificant subgroup differencesII trialIII trialsI trialHistological subtypesTreatment paradigmClinical trialsDrug classesSynergistic activity of neratinib in combination with olaparib in uterine serous carcinoma overexpressing HER2/neu
Yadav G, Roque DM, Bellone S, Manavella DD, Hartwich TMP, Zipponi M, Harold J, Tymon-Rosario J, Mutlu L, Altwerger G, Menderes G, Ratner E, Buza N, Hui P, Huang GS, Andikyan V, Clark M, Azodi M, Schwartz PE, Alexandrov LB, Santin AD. Synergistic activity of neratinib in combination with olaparib in uterine serous carcinoma overexpressing HER2/neu. Gynecologic Oncology 2022, 166: 351-357. PMID: 35641325, DOI: 10.1016/j.ygyno.2022.05.021.Peer-Reviewed Original ResearchConceptsUterine serous carcinomaHER2/neu expressionHER2/neuCombination of olaparibUSC xenograftsUSC cell linesNeu expressionSerous carcinomaLow HER2/neu expressionHER2/neu 3Cell linesHER2/neu gene amplificationNovel therapeutic optionsPolymerase inhibitor olaparibNeu gene amplificationDurable growth inhibitionNeratinib treatmentUSC cellsUSC patientsEndometrial cancerAggressive variantTherapeutic optionsPoor prognosisHER2/Single agentLenvatinib Plus Pembrolizumab for Advanced Endometrial Cancer
Makker V, Colombo N, Herráez A, Santin A, Colomba E, Miller D, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Sakata J, Yonemori K, Kim Y, Guerra E, Sanli U, McCormack M, Smith A, Keefe S, Bird S, Dutta L, Orlowski R, Lorusso D. Lenvatinib Plus Pembrolizumab for Advanced Endometrial Cancer. Obstetrical & Gynecological Survey 2022, 77: 275-276. DOI: 10.1097/ogx.0000000000001032.Peer-Reviewed Original ResearchEndometrial cancerRecurrent endometrial cancerSecond-line treatmentAdvanced endometrial cancerPlatinum-based chemotherapyRecurrent endometrial carcinomaTyrosine kinase inhibitorsEndometrial carcinomaOptimal treatmentDisease progressionLimited efficacySingle agentKinase inhibitorsLenvatinibCancerTreatmentPembrolizumabLittle consensusChemotherapyCarcinomaProgression
2021
Novel Single Agents Are Equivalent to Conventional Chemotherapy Inpatients with Relapsed and Refractory Mature T-Cell Lymphomas: A Meta-Analysis
Shafagati N, Stuver R, Boussi L, Koh M, Park A, Bain P, Foss F, Shen C, Jain S. Novel Single Agents Are Equivalent to Conventional Chemotherapy Inpatients with Relapsed and Refractory Mature T-Cell Lymphomas: A Meta-Analysis. Blood 2021, 138: 1431. DOI: 10.1182/blood-2021-150315.Peer-Reviewed Original ResearchOverall response rateT-cell lymphomaHistological subtypesNovel single agentsSingle agentHistone deacetylase inhibitorsConventional chemotherapyResponse rateCentral RegisterPartial responsePTCL-NOSClinical trialsChemotherapy agentsComparable overall response ratesGeneric inverse variance methodCutaneous T-cell lymphomaPhase IParticular histological subtypeSpeakers bureauCochrane Central RegisterProgression-free survivalMature T-cell lymphomasPI3K/Akt/mTORDuration of responseInverse variance methodPredictive Biomarkers of Response to the Polo-like Kinase 1 (PLK1) Inhibitor, Onvansertib, in Combination with Decitabine in Relapsed or Refractory Acute Myeloid Leukemia (R/R AML)
Zeidan A, Ridinger M, Croucher P, Samuëlsz E, Erlander M, Ruffner K, Wang E. Predictive Biomarkers of Response to the Polo-like Kinase 1 (PLK1) Inhibitor, Onvansertib, in Combination with Decitabine in Relapsed or Refractory Acute Myeloid Leukemia (R/R AML). Blood 2021, 138: 3431. DOI: 10.1182/blood-2021-145129.Peer-Reviewed Original ResearchClinical Trials CommitteeCurrent equity holderR AML patientsClinical responseTrials CommitteeGene expression signaturesSpeakers bureauAML patientsSingle agentMulticenter phase 2 studyPhase 1b/2 clinical trialRefractory acute myeloid leukemiaData Safety Monitoring CommitteeAdvisory CommitteeDaiichi SankyoSF mutationsCR/CRiPhase 2 studySafety Monitoring CommitteeChronic myelomonocytic leukemiaCycles of treatmentExpression signaturesComplete hematologic recoveryAcute myeloid leukemiaBone marrow samplesBBIT20 inhibits homologous DNA repair with disruption of the BRCA1–BARD1 interaction in breast and ovarian cancer
Raimundo L, Paterna A, Calheiros J, Ribeiro J, Cardoso DSP, Piga I, Neto SJ, Hegan D, Glazer PM, Indraccolo S, Mulhovo S, Costa JL, Ferreira M, Saraiva L. BBIT20 inhibits homologous DNA repair with disruption of the BRCA1–BARD1 interaction in breast and ovarian cancer. British Journal Of Pharmacology 2021, 178: 3627-3647. PMID: 33899955, PMCID: PMC9124438, DOI: 10.1111/bph.15506.Peer-Reviewed Original ResearchConceptsTriple-negative breastOvarian cancerXenograft mouse modelMouse modelAntitumour activityAdvanced ovarian cancerCancer cellsPatient-derived cell linesHomologous DNA repairOvarian cancer cellsNon-malignant cellsPatient-derived cellsMarked synergistic effectAvailable therapiesCombination therapyCell cycle arrestReactive oxygen species generationSide effectsDNA repair-related genesSingle agentTherapeutic outcomesCancerOxygen species generationPersonalized treatmentResistant cancersLow‐dose pembrolizumab in the treatment of advanced non‐small cell lung cancer
Low J, Huang Y, Sooi K, Ang Y, Chan Z, Spencer K, Jeyasekharan A, Sundar R, Goh B, Soo R, Yong W. Low‐dose pembrolizumab in the treatment of advanced non‐small cell lung cancer. International Journal Of Cancer 2021, 149: 169-176. PMID: 33634869, PMCID: PMC9545741, DOI: 10.1002/ijc.33534.Peer-Reviewed Original ResearchConceptsAdvanced non-small cell lung cancerNon-small cell lung cancerProgression-free survivalCell lung cancerFood and Drug AdministrationOverall survivalTreatment of advanced non-small cell lung cancerLung cancerDose of pembrolizumabImmune-related toxicitiesEffectiveness of pembrolizumabWeight-based dosingRetrospective observational studyNational University HospitalDegrees of cost savingsCost-minimisation analysisFixed doseSurvival outcomesAsian patientsNo significant differencePembrolizumabOncogenic driversSingle agentLow dosesRandomised trials
2020
Gilteritinib Remains Clinically Active in Relapsed/Refractory FLT3 Mutated AML Previously Treated with FLT3 inhibitors
Numan Y, Rahman Z, Grenet J, Boisclair S, Bewersdorf J, Barth D, Zeidan A, Yilmaz M, Dinner S, Deutsch Y, Frankfurt O, Litzow M, Al-Kali A, Foran J, Sproat L, Jovanovic B, Daver N, Perl A, Altman J. Gilteritinib Remains Clinically Active in Relapsed/Refractory FLT3 Mutated AML Previously Treated with FLT3 inhibitors. Blood 2020, 136: 5-7. DOI: 10.1182/blood-2020-137251.Peer-Reviewed Original ResearchStem cell transplantMedian survivalFLT3 mutationsBristol-Myers SquibbDaiichi SankyoBoehringer IngelheimCRC ratesLymphoma SocietyCombination therapyPolymerase chain reactionFLT3-ITDSingle agentDrug resistanceAdvisory CommitteeBone marrow flow cytometryComposite complete remissionFLT3-D835 mutationsHigher CRCS ratesNon-transplanted patientsPoor median survivalKaplan-Meier curvesMulti-institutional analysisLog-rank testBayer HealthCare PharmaceuticalsMAPK pathwayOutcomes of Patients with Transformed Mycosis Fungoides: Analysis from a Prospective Multicenter US Cohort Study
Lansigan F, Horwitz SM, Pinter-Brown LC, Carson KR, Shustov AR, Rosen ST, Pro B, Hsi ED, Federico M, Gisselbrecht C, Schwartz M, Bellm LA, Acosta M, Foss FM. Outcomes of Patients with Transformed Mycosis Fungoides: Analysis from a Prospective Multicenter US Cohort Study. Clinical Lymphoma Myeloma & Leukemia 2020, 20: 744-748. PMID: 32532611, PMCID: PMC8447249, DOI: 10.1016/j.clml.2020.05.001.Peer-Reviewed Original ResearchConceptsLymph node involvementOutcomes of patientsMedian survivalNode involvementCohort studyMycosis fungoidesSingle agentPeripheral T-cell lymphoma patientsT-cell lymphoma patientsProspective cohort studyKaplan-Meier methodologyUS cohort studyNovel treatment approachesConcomitant radiotherapyMost patientsSystemic therapyMedian agePatient characteristicsMedian timeLymphoma patientsLiposomal doxorubicinPatientsTreatment approachesSurvival rateLactate dehydrogenase
2019
LAM-003, a new drug for treatment of tyrosine kinase inhibitor–resistant FLT3-ITD–positive AML
Beeharry N, Landrette S, Gayle S, Hernandez M, Grotzke JE, Young PR, Beckett P, Zhang X, Carter BZ, Andreeff M, Halene S, Xu T, Rothberg J, Lichenstein H. LAM-003, a new drug for treatment of tyrosine kinase inhibitor–resistant FLT3-ITD–positive AML. Blood Advances 2019, 3: 3661-3673. PMID: 31751472, PMCID: PMC6880894, DOI: 10.1182/bloodadvances.2019001068.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Line, TumorDisease Models, AnimalDose-Response Relationship, DrugDrug Resistance, NeoplasmDrug SynergismEpigenesis, Geneticfms-Like Tyrosine Kinase 3Gene DuplicationGene Expression Regulation, LeukemicHumansLeukemia, Myeloid, AcuteMiceMutationProtein Kinase InhibitorsConceptsAcute myeloid leukemiaAML cell linesFLT3 inhibitorsFLT3-ITDSingle agentPositive acute myeloid leukemiaFLT3 inhibitor therapyStromal-conditioned mediumInitial clinical responseInternal tandem duplication mutationsFLT3-ITD patientsPoor patient prognosisXenograft mouse modelCell linesFLT3 kinase inhibitorsTandem duplication mutationsDiscovery of synergyWide CRISPR screenClinical responseTyrosine kinase receptorsInhibitor therapyPreclinical findingsBcl-2 inhibitorsMechanisms of resistancePatient prognosis
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