2023
NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Cecchini M, Walther Z, Wei W, Hafez N, Pilat M, Boerner S, Durecki D, Eder J, Schalper K, Chen A, LoRusso P. NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors. Cancer Research Communications 2023, 3: 1113-1117. PMID: 37377610, PMCID: PMC10292219, DOI: 10.1158/2767-9764.crc-22-0485.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityHomologous recombination deficiencyPARP inhibitorsStable diseaseWeekly irinotecanObjective responseDay 1Day 3Solid tumorsPhase I dose-escalation studyTwice daily days 1I dose-escalation studyPhase I clinical trialDaily days 1Dose level 1Doses of veliparibGrade 3 neutropeniaMultiple-dose schedulesProgression-free survivalAdvanced solid tumorsDose-escalation studyEvaluable patientsNonoverlapping toxicitiesDose scheduleSystemic treatmentThe MDM2–p53 antagonist BI 907828 in patients with advanced or metastatic solid tumors: results of a phase Ia, first-in-human, dose-escalation study
LoRusso P, Yamamoto N, Patel M, Laurie S, Bauer T, Geng J, Davenport T, Teufel M, Li J, Lahmar M, Gounder M. The MDM2–p53 antagonist BI 907828 in patients with advanced or metastatic solid tumors: results of a phase Ia, first-in-human, dose-escalation study. Cancer Discovery 2023, 13: 1802-1813. PMID: 37269344, PMCID: PMC10401071, DOI: 10.1158/2159-8290.cd-23-0153.Peer-Reviewed Original ResearchConceptsTreatment-related adverse eventsSolid tumorsDay 1Common treatment-related adverse eventsGrowth differentiation factor-15 levelsMDM2-p53 antagonistsManageable safety profileAdvanced solid tumorsDose-escalation studyDose-limiting toxicityMetastatic solid tumorsDose-dependent increaseIA/IBAdverse eventsSafety profilePreliminary efficacyDedifferentiated liposarcomaClinical investigationCommon gradePatientsRelated commentaryIssue featureTarget engagementAntitumor activityTumorsA phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients (pts) with solid tumors: Safety and efficacy in patients with dedifferentiated liposarcoma (DDLPS).
LoRusso P, Gounder M, Yamamoto N, Patel M, Bauer T, Geng J, Sailer R, Tang Y, Jayadeva G, Schöffski P. A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients (pts) with solid tumors: Safety and efficacy in patients with dedifferentiated liposarcoma (DDLPS). Journal Of Clinical Oncology 2023, 41: 11554-11554. DOI: 10.1200/jco.2023.41.16_suppl.11554.Peer-Reviewed Original ResearchTreatment-related AEsProgression-free survivalManageable safety profileOverall response rateDedifferentiated liposarcomaSafety profileCohort 1Day 1Phase IbSolid tumorsMedian progression-free survivalDisease control rateECOG PS 0/1MDM2-p53 antagonistsPrior systemic therapySmall intestine obstructionSubgroups of ptsAdvanced solid tumorsFirst-line treatmentPreclinical antitumor activityFast track designationIA/IBPS 0/1Serious AEsPrimary endpoint
2022
A phase 1b, multicenter, dose-escalation study of subasumstat (TAK-981) in combination with pembrolizumab in patients (pts) with advanced solid tumors.
Goel S, Ulahannan S, Olszanski A, LoRusso P, Sanborn R, Sharma S, Emens L, Reilley M, Priego V, Li S, Wang B, Dong L, Sachsenmeier K, Gibbs J, Gharavi R, Martinez A, Proscurshim I, Fram R, Gomez-Pinillos A, Rasco D. A phase 1b, multicenter, dose-escalation study of subasumstat (TAK-981) in combination with pembrolizumab in patients (pts) with advanced solid tumors. Journal Of Clinical Oncology 2022, 40: 2506-2506. DOI: 10.1200/jco.2022.40.16_suppl.2506.Peer-Reviewed Original ResearchTreatment-emergent adverse eventsCheckpoint inhibitorsDay 1Anti-PD-1 checkpoint inhibitorsMicrosatellite stable colorectal cancerSynergistic tumor growth inhibitionDose-escalation partPhase 1b studyPhase 2 dosePre-treated NSCLCPromising anti-tumor activityRelapsed/refractoryT cell-dependent antitumor responseAdvanced solid tumorsDose-escalation studyActivation of CD8Dose-limiting toxicityNatural killer cellsCell lung cancerFavorable safety profilePhase 2 clinical developmentSyngeneic mouse modelDependent immune responsesType 1 interferonAnti-tumor activityA phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS).
Gounder M, Yamamoto N, Patel M, Bauer T, Schöffski P, Grempler R, Durland-Busbice S, Geng J, Maerten A, LoRusso P. A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS). Journal Of Clinical Oncology 2022, 40: 3004-3004. DOI: 10.1200/jco.2022.40.16_suppl.3004.Peer-Reviewed Original ResearchAdvanced liposarcomaDay 1Solid tumorsECOG PS 0/1Manageable safety profileObjective response rateOverall safety dataPrior systemic therapyTreatment-related AEsGDF-15 levelsAdvanced solid tumorsSubgroup of patientsNumber of patientsPatient-derived xenograftsHigher plasma exposureTarget engagement markerPart AEvaluable patientsIA/IBPS 0/1Dose expansionPrimary endpointMetastatic liposarcomaOverall survivalArm B
2021
A phase I dose-escalation study of the MDM2-p53 antagonist BI 907828 in patients (pts) with advanced solid tumors.
LoRusso P, Gounder M, Patel M, Yamamoto N, Bauer T, Laurie S, Grempler R, Davenport T, Geng J, Rohrbacher M, Lahmar M. A phase I dose-escalation study of the MDM2-p53 antagonist BI 907828 in patients (pts) with advanced solid tumors. Journal Of Clinical Oncology 2021, 39: 3016-3016. DOI: 10.1200/jco.2021.39.15_suppl.3016.Peer-Reviewed Original ResearchDose-limiting toxicityAdvanced solid tumorsArm AAdverse eventsArm BSolid tumorsDay 1Phase I dose-escalation studyExperienced dose-limiting toxicityNon-hematologic adverse eventsTreatment-related adverse eventsI dose-escalation studyAntitumor activityBiomarkers GDF-15Dose-escalation partGrade 3 nauseaManageable safety profileMDM2-p53 antagonistsPreliminary PK dataDose-escalation studyPatient-derived xenograftsClearance/FCycle 1Favorable PK propertiesLogistic regression modelsA phase 1 dose-escalation study of intravenously (IV) administered TAK-676, a novel STING agonist, alone and in combination with pembrolizumab in patients (pts) with advanced or metastatic solid tumors.
Falchook G, Luke J, Strauss J, Gao X, LoRusso P, VOON P, Li C, Shaw M, Gregory R, Horn K, Gibbs J, Lineberry N, Stumpo K, Malek K, Olszanski A. A phase 1 dose-escalation study of intravenously (IV) administered TAK-676, a novel STING agonist, alone and in combination with pembrolizumab in patients (pts) with advanced or metastatic solid tumors. Journal Of Clinical Oncology 2021, 39: tps2670-tps2670. DOI: 10.1200/jco.2021.39.15_suppl.tps2670.Peer-Reviewed Original ResearchMetastatic solid tumorsCombination armCheckpoint inhibitorsSTING agonistsNovel STING agonistSolid tumorsDose escalationEastern Cooperative Oncology Group performance status 0Anti-programmed death ligand 1 therapyDay 1Phase 1 dose-escalation studyAnti-programmed death-1Death ligand 1 therapyPerformance status 0Phase 2 doseProinflammatory tumor environmentSolid Tumors (RECIST) v.Immune checkpoint inhibitorsDose-escalation studyResponse Evaluation CriteriaInnate immune cellsPreliminary antitumor activityStandard therapeutic optionAntitumor immune mechanismsImmuno-oncology therapies
2019
466P Interim results from trial of SL-801, a novel XPO-1 inhibitor, in patients with advanced solid tumours
Wang J, Barve M, Chiorean E, LoRusso P, Courtney K, Qi D, Bullington J, Sardone M, Chen J, Brooks C, Shemesh S, Bauer T. 466P Interim results from trial of SL-801, a novel XPO-1 inhibitor, in patients with advanced solid tumours. Annals Of Oncology 2019, 30: v175. DOI: 10.1093/annonc/mdz244.028.Peer-Reviewed Original ResearchSchedule ADay 1Optimal dose/schedulePreliminary anti-tumor activityDose-escalation stageStudy dose levelsMetastatic solid tumorsDose/scheduleAggressive tumor behaviorAnti-tumor activityAssess pharmacokineticsStarting doseDose intensityStandard therapyPoor prognosisHematologic malignanciesTumor behaviorDose levelsSolid tumorsPatientsNuclear export proteinVivo activityDoseLonger recovery timeDaysPhase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors
Jung KH, LoRusso P, Burris H, Gordon M, Bang YJ, Hellmann MD, Cervantes A, de Olza M, Marabelle A, Hodi FS, Ahn MJ, Emens LA, Barlesi F, Hamid O, Calvo E, McDermott D, Soliman H, Rhee I, Lin R, Pourmohamad T, Suchomel J, Tsuhako A, Morrissey K, Mahrus S, Morley R, Pirzkall A, Davis SL. Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors. Clinical Cancer Research 2019, 25: 3220-3228. PMID: 30770348, PMCID: PMC7980952, DOI: 10.1158/1078-0432.ccr-18-2740.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsB7-H1 AntigenBiomarkers, TumorHumansImidazolesIndoleamine-Pyrrole 2,3,-DioxygenaseIndolesMagnetic Resonance ImagingMiddle AgedNeoplasm MetastasisNeoplasm StagingNeoplasmsTomography, X-Ray ComputedTreatment OutcomeConceptsPD-L1 inhibitorsT cellsPartial responseAdvanced cancerDay 1Dose levelsCommon treatment-related AEsDose-escalation stageTreatment-related AEsAdvanced solid tumorsEffector T cellsRegulatory T cellsLinear pharmacokinetic profileLocal tumor microenvironmentInvestigational small-molecule inhibitorExpansion patientsKynurenine accumulationComplete responseImmune suppressionIntravenous infusionAcceptable safetyTryptophan depletionNavoximodAtezolizumabPlasma KynPhase 1, first-in-human study of TRAIL receptor agonist fusion protein ABBV-621.
Ratain M, Doi T, De Jonge M, LoRusso P, Dunbar M, Chiney M, Motwani M, Glasgow J, Petrich A, Rasco D, Calvo E. Phase 1, first-in-human study of TRAIL receptor agonist fusion protein ABBV-621. Journal Of Clinical Oncology 2019, 37: 3013-3013. DOI: 10.1200/jco.2019.37.15_suppl.3013.Peer-Reviewed Original ResearchDose escalationDose-limiting toxicityBlood-based markersECOG 0Prior regimensStable diseaseAcceptable toxicityMedian durationRespiratory failureMedian agePartial responseColorectal cancerPancreatic cancerBlood bilirubinBayesian continual reassessment methodPD markersContinual reassessment methodHuman studiesDay 1Solid tumorsTumor typesPK studiesTumor modelAntitumor activityApoptotic cell death
2012
507 Phase I, Open-Label, Randomized, Crossover Study Evaluating the Effects of Linifanib on Qtc Intervals in Patients with Solid Tumors
Chiu Y, LoRusso P, Ricker J, Li X, Pradhan R, Carlson D. 507 Phase I, Open-Label, Randomized, Crossover Study Evaluating the Effects of Linifanib on Qtc Intervals in Patients with Solid Tumors. Annals Of Oncology 2012, 23: ix173. DOI: 10.1016/s0923-7534(20)33069-6.Peer-Reviewed Original ResearchAdvanced solid tumorsDay 1Solid tumorsCardiac repolarizationAdequate organ functionECOG PS 0Primary end pointExposure-response analysisEffects modelMeasurable diseaseMorning doseOpen labelCrossover fashionPS 0QTc prolongationStandard therapyCrossover studyQTc intervalBaseline QTcFQTcF intervalStudy completionMDV3100-08: A phase I open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of MDV3100 in women with incurable breast cancer.
Elias A, Richer J, LoRusso P, Peterson A, Steinberg J, Mordenti J, Lopez C, Hudis C, Traina T. MDV3100-08: A phase I open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of MDV3100 in women with incurable breast cancer. Journal Of Clinical Oncology 2012, 30: tps668-tps668. DOI: 10.1200/jco.2012.30.15_suppl.tps668.Peer-Reviewed Original ResearchPhase 2 doseIncurable breast cancerBreast cancerAndrogen receptorDay 1PK samplesDay 8Dose-escalation stageOverall survival benefitDose-escalation studyPhase 1 studyAR nuclear translocationInhibition of androgenPotential therapeutic strategyPK samplingAdverse eventsDaily dosingSurvival benefitAR expressionHistologic subtypeDiscontinuation criteriaPreclinical activityProstate cancerTumor assessmentMDV3100
2011
Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study
Leal T, Remick S, Takimoto C, Ramanathan R, Davies A, Egorin M, Hamilton A, LoRusso P, Shibata S, Lenz H, Mier J, Sarantopoulos J, Mani S, Wright J, Ivy S, Neuwirth R, von Moltke L, Venkatakrishnan K, Mulkerin D. Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study. Cancer Chemotherapy And Pharmacology 2011, 68: 1439-1447. PMID: 21479634, PMCID: PMC3481841, DOI: 10.1007/s00280-011-1637-5.Peer-Reviewed Original ResearchConceptsSevere renal dysfunctionNormal renal functionRenal dysfunctionAdult cancer patientsRenal functionDialysis patientsDose escalationCancer patientsPatient populationNational Cancer Institute Organ Dysfunction Working Group StudyDose of bortezomibImpaired renal functionGeneral patient populationIntravenous bortezomibRenal impairmentCreatinine clearanceModerate dysfunctionMild dysfunctionSevere dysfunctionDose reductionPharmacologic dataPatientsDay 1DysfunctionBortezomib
2010
Pharmacokinetics and Safety of Bortezomib In Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Results of the Phase 1 National Cancer Institute Organ Dysfunction Working Group Study NCI 6432
Venkatakrishnan K, Ramanathan R, Sarantopoulos J, Mulkerin D, Shibata S, Hamilton A, Dowlati A, Mani S, Rudek M, Ivy P, Takimoto C, Neuwirth R, Parasuraman S, LoRusso P. Pharmacokinetics and Safety of Bortezomib In Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Results of the Phase 1 National Cancer Institute Organ Dysfunction Working Group Study NCI 6432. Blood 2010, 116: 3975. DOI: 10.1182/blood.v116.21.3975.3975.Peer-Reviewed Original ResearchMild hepatic impairmentSevere hepatic impairmentNormal hepatic functionCancer Therapy Evaluation ProgramHepatic impairmentHepatic function× ULNAdverse eventsDay 1Advanced malignanciesDose escalationNational Cancer Institute Cancer Therapy Evaluation ProgramHI groupGeometric least square mean ratioDay 8Least square mean ratioPoor hepatic functionSevere HI groupsSubsequent dose escalationUS Prescribing InformationCommon adverse eventsECOG performance statusMost adverse eventsPhase 1 studySafety of bortezomib
2009
Phase I study of MGCD265 administered intermittently to patients with advanced malignancies (Study 265–102)
Hong D, LoRusso P, Kurzrock R, Maroun C, Mehran M, Drouin M, Martell R, Wheler J. Phase I study of MGCD265 administered intermittently to patients with advanced malignancies (Study 265–102). Journal Of Clinical Oncology 2009, 27: e14516-e14516. DOI: 10.1200/jco.2009.27.15_suppl.e14516.Peer-Reviewed Original ResearchDose levelsSolid tumorsGrade 3 nonhematologic toxicityPhase IDrug-related AEsGrade 4 neutropeniaGrade 4 thrombocytopeniaAdvanced solid tumorsDrug-related toxicityTreatment of patientsDose-dependent increaseVariety of cancersEfficacious exposureNonhematologic toxicitySustained hypertensionAdvanced malignanciesEscalation studyFirst doseIntermittent administrationDisease progressionAvailable small moleculesPD markersXenograft modelPatientsDay 1
2007
A phase I study of EC145 administered weeks 1 and 3 of a 4-week cycle in patients with refractory solid tumors
Sausville E, LoRusso P, Quinn M, Forman K, Leamon C, Morganstern D, Bever S, Messmann R. A phase I study of EC145 administered weeks 1 and 3 of a 4-week cycle in patients with refractory solid tumors. Journal Of Clinical Oncology 2007, 25: 2577-2577. DOI: 10.1200/jco.2007.25.18_suppl.2577.Peer-Reviewed Original ResearchBolus dosesDay 1Folate receptorPhase IRefractory solid tumorsCommon side effectsFolic acidPhase I trialTime of presentationIntravenous bolus doseEligible patientsDisease stabilizationFlat doseI trialIntravenous bolusBolus doseMinor responsePK analysisSide effectsPatientsWeek 1Dose levelsEscalation plansSolid tumorsPK model
2006
A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors
Heath E, Alousi A, Eder J, Valdivieso M, Vasist L, Appleman L, Bhargava P, Colevas A, Lorusso P, Shapiro G. A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors. Journal Of Clinical Oncology 2006, 24: 2026-2026. DOI: 10.1200/jco.2006.24.18_suppl.2026.Peer-Reviewed Original ResearchGrade 4 neutropeniaAdvanced solid tumorsDose levelsDay 1Phosphohistone 3Solid tumorsGrade 3 febrile neutropeniaMultiple murine tumor modelsGrade 1 fatigueGrade 3 neutropeniaToxicity of myelosuppressionGrade 3/4 toxicitiesSerial tumor biopsiesRenal cell carcinomaMurine tumor modelsKinesin spindle proteinPreliminary pharmacokinetic dataSignificant antitumor activityNovel cytotoxic agentsEvaluable patientsFebrile neutropeniaMTD cohortStable diseaseEscalation trialCell carcinomaPhase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors
Krop I, Kosh M, Fearen I, Savoie J, Dallob A, Matthews C, Stone J, Winer E, Freedman S, Lorusso P. Phase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors. Journal Of Clinical Oncology 2006, 24: 10574-10574. DOI: 10.1200/jco.2006.24.18_suppl.10574.Peer-Reviewed Original ResearchGrade 3 diarrheaAdvanced breast cancerBreast cancerPlasma AbetaDay 1Notch intracellular domainDose levelsSolid tumorsAccelerated dose escalationGamma-SecretaseGrade 2/3 fatigueMean PK parametersSubset of ptsElevated liver transaminasesAdvanced solid tumorsDaily oral dosingIntermittent dosing scheduleAnalysis of efficacyHuman breast cancerBC cell proliferationInhibition of NotchAbdominal crampingLiver transaminasesDosing schedulesPharmacodynamic trial