2024
Results from phase 1a/1b analyses of TTX-080, a first in class HLA-G antagonist, in combination with cetuximab in patients (pts) with metastatic colorectal cancer and head and neck squamous cell carcinoma.
Ulahannan S, Marron T, Park H, Kaczmar J, Stephenson R, Lakhani N, Durm G, Grewal J, El-Khoueiry A, Luke J, Beers C, Murugappan S, LoRusso P, Adkins D, Hecht J. Results from phase 1a/1b analyses of TTX-080, a first in class HLA-G antagonist, in combination with cetuximab in patients (pts) with metastatic colorectal cancer and head and neck squamous cell carcinoma. Journal Of Clinical Oncology 2024, 42: 2524-2524. DOI: 10.1200/jco.2024.42.16_suppl.2524.Peer-Reviewed Original ResearchHead and neck squamous cell carcinomaMetastatic colorectal cancerNeck squamous cell carcinomaSquamous cell carcinomaPreliminary efficacy dataCell carcinomaColorectal cancerEfficacy dataSolid tumor cohortTreatment-related AEsImmune cell changesAnti-tumor activityStandard of careRandomized controlled studyDose escalationEscalating dosesHLA-G.Peripheral bloodTumor cohortsSolid tumorsDecreased appetiteAST increaseBlood samplesCell changesQ3W
2023
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial
Desai J, Alonso G, Kim S, Cervantes A, Karasic T, Medina L, Shacham-Shmueli E, Cosman R, Falcon A, Gort E, Guren T, Massarelli E, Miller W, Paz-Ares L, Prenen H, Amatu A, Cremolini C, Kim T, Moreno V, Ou S, Passardi A, Sacher A, Santoro A, Stec R, Ulahannan S, Arbour K, Lorusso P, Luo J, Patel M, Choi Y, Shi Z, Mandlekar S, Lin M, Royer-Joo S, Chang J, Jun T, Dharia N, Schutzman J, Han S. Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. Nature Medicine 2023, 30: 271-278. PMID: 38052910, PMCID: PMC10803265, DOI: 10.1038/s41591-023-02696-8.Peer-Reviewed Original ResearchPhase 1b trialColorectal cancerSafety profileMedian progression-free survivalTreatment-related adverse eventsInhibitor-naive patientsKRAS G12C inhibitionAntitumor activityManageable safety profileObjective response rateProgression-free survivalPreliminary antitumor activityKRAS G12C mutationKRAS G12C inhibitorsEpidermal growth factor receptorVariant allele frequencyGrowth factor receptorAdverse eventsMedian durationTreatment withdrawalPoor prognosisDisease progressionArm CDose reductionG12C inhibitorsSingle-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation
Sacher A, LoRusso P, Patel M, Miller W, Garralda E, Forster M, Santoro A, Falcon A, Kim T, Paz-Ares L, Bowyer S, de Miguel M, Han S, Krebs M, Lee J, Cheng M, Arbour K, Massarelli E, Choi Y, Shi Z, Mandlekar S, Lin M, Royer-Joo S, Chang J, Dharia N, Schutzman J, Desai J. Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. New England Journal Of Medicine 2023, 389: 710-721. PMID: 37611121, DOI: 10.1056/nejmoa2303810.Peer-Reviewed Original ResearchConceptsMedian progression-free survivalTreatment-related adverse eventsProgression-free survivalAdverse eventsSolid tumorsG12C mutationLow-grade adverse eventsGrade 3 eventsGrade 4 eventsTreatment-related deathsDiscontinuation of treatmentMetastatic solid tumorsPhase 1 studyDurable clinical responsesBiomarkers of responseKRAS G12C mutationAssessment of safetyVariant allele frequencyClinical responseColorectal cancerSerial assessmentDose reductionG12C inhibitorsPatientsTumor DNAQuantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer
Cecchini M, Zhang J, Wei W, Sklar J, Lacy J, Zhong M, Kong Y, Zhao H, DiPalermo J, Devine L, Stein S, Kortmansky J, Johung K, Bindra R, LoRusso P, Schalper K. Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer. Cancer Research Communications 2023, 3: 1132-1139. PMID: 37387791, PMCID: PMC10305782, DOI: 10.1158/2767-9764.crc-23-0045.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingMGMT protein expressionColorectal cancerStable diseaseQuantitative immunofluorescenceT cellsProtein expressionPromoter hypermethylationLow MGMT protein expressionPARP inhibitorsRadiographic tumor regressionMetastatic colorectal cancerAdvanced colorectal cancerPretreatment tumor biopsiesEffector T cellsTumor-infiltrating lymphocytesMGMT proteinDNA repair biomarkersBaseline CD8Eligible patientsIncreased CD8Methylguanine-DNA methyltransferaseObjective responseProgressive diseaseImmune markersFirst-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors
Bendell J, LoRusso P, Overman M, Noonan A, Kim D, Strickler J, Kim S, Clarke S, George T, Grimison P, Barve M, Amin M, Desai J, Wise-Draper T, Eck S, Jiang Y, Khan A, Wu Y, Martin P, Cooper Z, Elgeioushi N, Mueller N, Kumar R, Patel S. First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors. Cancer Immunology, Immunotherapy 2023, 72: 2443-2458. PMID: 37016126, PMCID: PMC10264501, DOI: 10.1007/s00262-023-03430-6.Peer-Reviewed Original ResearchConceptsTreatment-related adverse eventsPancreatic ductal adenocarcinomaColorectal cancerExpansion cohortHuman studiesResponse rateAnti-CD73 monoclonal antibodyProgression-free survival ratesTumor cellsMonoclonal antibodiesCommon being fatigueManageable safety profileObjective response rateAdvanced colorectal cancerAdvanced solid tumorsCell lung cancerPeripheral T cellsDate of registrationCD73 enzymatic activityAdverse eventsEscalation cohortsLocal immunosuppressionCD73 expressionSafety profileLung cancer
2022
362P Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation
Desai J, Han S, Forster M, Kim T, Casal G, Shmueli E, Bowyer S, De Miguel M, Gonzalez A, Jones R, Krebs M, Miller W, Paz-Ares L, Lorusso P, Sacher A, Dharia N, Lin M, Schutzman J, Shi Z, Patel M. 362P Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation. Annals Of Oncology 2022, 33: s701-s702. DOI: 10.1016/j.annonc.2022.07.500.Peer-Reviewed Original ResearchNCI 9938: Phase I clinical trial of ATR inhibitor berzosertib (M6620, VX-970) in combination with irinotecan in patients with advanced solid tumors.
Villaruz L, Kelly K, Waqar S, Davis E, Shapiro G, LoRusso P, Dees E, Normolle D, Rhee J, Chu E, Gore S, Beumer J. NCI 9938: Phase I clinical trial of ATR inhibitor berzosertib (M6620, VX-970) in combination with irinotecan in patients with advanced solid tumors. Journal Of Clinical Oncology 2022, 40: 3012-3012. DOI: 10.1200/jco.2022.40.16_suppl.3012.Peer-Reviewed Original ResearchDose-limiting toxicityExperienced dose-limiting toxicityCell lung cancerColorectal cancerPancreatic cancerLung cancerDose levelsSolid tumorsNon-small cell lung cancerCommon treatment-related gradeGrade 3 lung infectionStage IISmall cell lung cancerPhase I clinical trialDose-expansion cohortsGrade 3 diarrheaMutant solid tumorsPhase II doseTreatment-related gradeGrade 2 diarrheaAdvanced solid tumorsManageable side effectsDose-escalation designMutant colorectal cancerEfficacy of irinotecan
2021
Safety and efficacy of the anti-CD73 monoclonal antibody (mAb) oleclumab ± durvalumab in patients (pts) with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or EGFR-mutant non-small cell lung cancer (EGFRm NSCLC).
Bendell J, LoRusso P, Overman M, Noonan A, Kim D, Strickler J, Kim S, Clarke S, George T, Grimison P, Barve M, Amin M, Desai J, Wise-Draper T, Cooper Z, Elgeioushi N, Mueller N, Kumar R, Wu K, Patel S. Safety and efficacy of the anti-CD73 monoclonal antibody (mAb) oleclumab ± durvalumab in patients (pts) with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or EGFR-mutant non-small cell lung cancer (EGFRm NSCLC). Journal Of Clinical Oncology 2021, 39: 9047-9047. DOI: 10.1200/jco.2021.39.15_suppl.9047.Peer-Reviewed Original ResearchTreatment-related adverse eventsPancreatic ductal adenocarcinomaCommon treatment-related adverse eventsAdvanced colorectal cancerObjective responseCombination therapyColorectal cancerEGFRm NSCLCEscalation phaseNSCLC ptsEGFR-mutant non-small cell lung cancerNon-small cell lung cancerMicrosatellite stable colorectal cancerTolerable safety profileUpregulation of CD73Cell lung cancerDuration of responseStable colorectal cancerRECIST v1.1Expansion cohortPrevious interim analysisClinical responseData cutoffLocal immunosuppressionManageable safety
2020
Pharmacodynamic effects in blood and tumor tissue of eftozanermin alfa, a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist.
Motwani M, Modi D, Penugonda S, Zhang C, Palma J, Cunningham A, Calvo E, de Jonge M, LoRusso P. Pharmacodynamic effects in blood and tumor tissue of eftozanermin alfa, a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist. Journal Of Clinical Oncology 2020, 38: e15668-e15668. DOI: 10.1200/jco.2020.38.15_suppl.e15668.Peer-Reviewed Original ResearchPharmacodynamic effectsReceptor agonistMultiplex immunohistochemistryKRAS-mutant colorectal cancerTumor tissueDose-expansion cohortsSimilar time pointsMutant allele fractionM65 levelsH postdoseColorectal cancerPost-TxDownstream pathway activationPancreatic cancerHematologic malignanciesLiver enzymesScreening periodReverse phase protein arrayBiopsy coresTumor biopsiesMutant allele frequencyBiopsy samplesDose levelsBiopsyTumor typesA First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors
Varga A, Soria JC, Hollebecque A, LoRusso P, Bendell J, Huang SA, Wagle MC, Okrah K, Liu L, Murray E, Sanabria-Bohorquez SM, Tagen M, Dokainish H, Mueller L, Burris H. A First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors. Clinical Cancer Research 2020, 26: 1229-1236. PMID: 31848189, DOI: 10.1158/1078-0432.ccr-19-2574.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedDose-Response Relationship, DrugFatigueFemaleHumansMaleMAP Kinase Signaling SystemMaximum Tolerated DoseMiddle AgedMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3NauseaNeoplasmsPatient SafetyProtein Kinase InhibitorsPyridonesPyrimidinesTissue DistributionVomitingConceptsBRAF-mutant colorectal cancerColorectal cancerAdverse eventsFDG-PETCommon drug-related adverse eventsSolid tumorsDrug-related adverse eventsPhase IPartial metabolic responseAcceptable safety profileAdvanced solid tumorsDose-proportional increaseGrade 3 rashMetastatic solid tumorsSerial tumor biopsiesSingle-agent activityBest overall responseHuman phase IMAPK pathway inhibitionMultiple tumor typesStable diseaseEscalation studyPartial responseOral inhibitorPharmacodynamic effects
2019
Phase 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
2018
Safety, efficacy and pharmacodynamics (PD) of MEDI9447 (oleclumab) alone or in combination with durvalumab in advanced colorectal cancer (CRC) or pancreatic cancer (panc).
Overman M, LoRusso P, Strickler J, Patel S, Clarke S, Noonan A, Prasanna T, Amin M, Nemunaitis J, Desai J, O'Byrne K, George T, Englert J, She D, Cooper Z, Wu Y, Khan A, Kumar R, Bendell J. Safety, efficacy and pharmacodynamics (PD) of MEDI9447 (oleclumab) alone or in combination with durvalumab in advanced colorectal cancer (CRC) or pancreatic cancer (panc). Journal Of Clinical Oncology 2018, 36: 4123-4123. DOI: 10.1200/jco.2018.36.15_suppl.4123.Peer-Reviewed Original Research
2014
Phase I and IIa studies of simtuzumab alone and in combination with FOLFIRI in patients with advanced solid tumors.
LoRusso P, Hecht J, Thai D, Hawkins M, Dong H, Tolcher A. Phase I and IIa studies of simtuzumab alone and in combination with FOLFIRI in patients with advanced solid tumors. Journal Of Clinical Oncology 2014, 32: 554-554. DOI: 10.1200/jco.2014.32.3_suppl.554.Peer-Reviewed Original ResearchTreatment-emergent AEsAdvanced solid tumorsColorectal cancerDose expansionIIa studyPhase ISolid tumorsCommon treatment-emergent AEsKRAS-mutant colorectal cancerDrug-related SAEsPhase II studyPhase IIa trialPhase IIa studyMutant colorectal cancerExtracellular matrix enzymesMedian PFSIIa trialUnacceptable toxicityEscalation studyII studyDose escalationFourth dosesTumor sizePancreatic neuroendocrinePromising efficacy
2013
Phase II clinical activity and tolerability of the SMAC-mimetic birinapant (TL32711) plus irinotecan in irinotecan-relapsed/refractory metastatic colorectal cancer.
Senzer N, LoRusso P, Martin L, Schilder R, Amaravadi R, Papadopoulos K, Segota Z, Weng D, Graham M, Adjei A. Phase II clinical activity and tolerability of the SMAC-mimetic birinapant (TL32711) plus irinotecan in irinotecan-relapsed/refractory metastatic colorectal cancer. Journal Of Clinical Oncology 2013, 31: 3621-3621. DOI: 10.1200/jco.2013.31.15_suppl.3621.Peer-Reviewed Original ResearchMedian progression-free survivalProgression-free survivalClinical activityRefractory/BP riskOverall clinical benefit rateRefractory metastatic colorectal cancerKRAS-MTBest supportive careClinical benefit rateMetastatic colorectal cancerReversible side effectsPhase 1 studySMAC mimetic birinapantAnti-tumor synergyPrior regimensSupportive careClinical benefitColorectal cancerKRAS WTOngoing treatmentSmac mimeticsBenefit rateMedian numberTherapeutic synergy
2011
Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy
Garrett C, Siu L, El-Khoueiry A, Buter J, Rocha-Lima C, Marshall J, LoRusso P, Major P, Chemidlin J, Mokliatchouk O, Velasquez L, Hayes W, Feltquate D, Syed S, Ford S, Kollia G, Galbraith S, Nuyten D. Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. British Journal Of Cancer 2011, 105: 44-52. PMID: 21629245, PMCID: PMC3137402, DOI: 10.1038/bjc.2011.182.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAlanineAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic AgentsCetuximabDrug Therapy, CombinationFemaleGastrointestinal NeoplasmsHumansMaleMiddle AgedNeoplasm Recurrence, LocalSalvage TherapySurvival RateTissue DistributionTreatment OutcomeTriazinesVascular Endothelial Growth Factor Receptor-2ConceptsAdvanced gastrointestinal malignanciesGastrointestinal malignanciesPhase I dose-escalation studyAdvanced metastatic colorectal cancerCommon treatment-related toxicitiesMedian progression-free survivalI dose-escalation studyRadiographic partial responseMetastatic colorectal cancerTreatment-related toxicityAcceptable toxicity profileDose-escalation studyPhase III studyProgression-free survivalOverall response rateK-ras mutationsAcneiform dermatitisPrior therapyAdverse eventsIII studyMedian durationMucosal inflammationPartial responseCombination chemotherapyColorectal cancer
2007
First-in-human study of AMG 655, a pro-apoptotic TRAIL receptor-2 agonist, in adult patients with advanced solid tumors
LoRusso P, Hong D, Heath E, Kurzrock R, Wang D, Hsu M, Goyal L, Wiezorek J, Storgard C, Herbst R. First-in-human study of AMG 655, a pro-apoptotic TRAIL receptor-2 agonist, in adult patients with advanced solid tumors. Journal Of Clinical Oncology 2007, 25: 3534-3534. DOI: 10.1200/jco.2007.25.18_suppl.3534.Peer-Reviewed Original ResearchNon-small cell lung cancerMetabolic partial responseAdvanced solid tumorsPartial responseStable diseaseColorectal cancerHuman studiesSolid tumorsMaximum standardized uptake valueDose-linear kineticsElevated serum lipaseSequential dose cohortsOnly grade 3Cell lung cancerReceptor 2 agonistStandardized uptake valueHuman monoclonal agonist antibodyMonoclonal agonist antibodyAnti-tumor activitySensitive tumor cellsTumor response dataSerious AEsDose cohortsProgressive diseaseUnacceptable toxicityA phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full-dose cetuximab in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy
Garrett C, Siu L, Giaccone G, El-Khoueiry A, Marshall J, LoRusso P, Velasquez L, Kollia G, He P, Feltquate D. A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full-dose cetuximab in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy. Journal Of Clinical Oncology 2007, 25: 14018-14018. DOI: 10.1200/jco.2007.25.18_suppl.14018.Peer-Reviewed Original ResearchAdvanced gastrointestinal malignanciesFDG-PETColorectal cancerDay 8Phase I dose-escalation studyI dose-escalation studyPre-treatment FDG-PETDual tyrosine kinase inhibitorBilateral pulmonary emboliOral dual inhibitorPO day 1Treatment-related AEsFDG-PET resultsDose-escalation studyTyrosine kinase inhibitorsReproducible imaging modalityPrior therapyExpansion cohortGastrointestinal malignanciesPulmonary emboliDose escalationIntra-subject CVOral prodrugTumor responseTarget lesions
2006
Phase-1 study of isophosphoramide mustard (IPM)-lysine in advanced cancers
Gale R, Van Vugt A, Rosen L, Chang L, Lorusso P, Valdivieso M, Malburg L, Struck R, Morgan L. Phase-1 study of isophosphoramide mustard (IPM)-lysine in advanced cancers. Journal Of Clinical Oncology 2006, 24: 9524-9524. DOI: 10.1200/jco.2006.24.18_suppl.9524.Peer-Reviewed Original ResearchCNS toxicityAdvanced cancerProximal renal tubular acidosisExtensive prior therapyHuman-mouse xenograftsPhase 1 studyPhase 1 trialRenal tubular acidosisPre-clinical modelsDiverse cancer modelsGI complaintsPrior therapyStable diseaseCancer cell linesLimited diseaseStarting doseHemorrhagic cystitisMedian ageColorectal cancerTubular acidosisThyroid cancerDose levelsCancer modelGreater efficacyHuman cancer cell lines
1999
Phase II study of CI-958 in colorectal cancer
Shields A, Philip P, LoRusso P, Ferris A, Zalupski M. Phase II study of CI-958 in colorectal cancer. Cancer Chemotherapy And Pharmacology 1999, 43: 162-164. PMID: 9923823, DOI: 10.1007/s002800050878.Peer-Reviewed Original ResearchConceptsAdvanced colorectal cancerColorectal cancerCI-958Patient experienced febrile neutropeniaAcute febrile reactionExperienced febrile neutropeniaPhase II studyPhase II trialStart of treatmentFebrile neutropeniaII trialMetastatic settingII studyMajor toxicityMedian survivalMetastatic diseaseObjective responseFebrile reactionsPatientsCancerDoseTreatmentLeukopeniaNeutropeniaRegimen
1997
Phase II study of pyrazoloacridine in patients with advanced colorectal carcinoma
Zalupski M, Philip P, LoRusso P, Shields A. Phase II study of pyrazoloacridine in patients with advanced colorectal carcinoma. Cancer Chemotherapy And Pharmacology 1997, 40: 225-227. PMID: 9219505, DOI: 10.1007/s002800050650.Peer-Reviewed Original ResearchConceptsColorectal cancerBroad preclinical antitumor activityUntreated advanced colorectal cancerPhase II studyAdvanced colorectal cancerPhase II trialSchedule of administrationAdvanced colorectal carcinomaPreclinical antitumor activityPredictable toxicityII trialII studyClinical efficacyColorectal carcinomaClinical developmentPatientsPyrazoloacridinePhase IAntitumor activitySolid tumor selectivityTumor selectivityCancerDoseToxicityMyelosuppression