2023
Uterine leiomyosarcomas harboring MAP2K4 gene amplification are sensitive in vivo to PLX8725, a novel MAP2K4 inhibitor
McNamara B, Harold J, Manavella D, Bellone S, Mutlu L, Hartwich T, Zipponi M, Yang-Hartwich Y, Demirkiran C, Verzosa M, Yang K, Choi J, Dong W, Buza N, Hui P, Altwerger G, Huang G, Andikyan V, Clark M, Ratner E, Azodi M, Schwartz P, Burton E, Inagaki H, Albers A, Zhang C, Bollag G, Schlessinger J, Santin A. Uterine leiomyosarcomas harboring MAP2K4 gene amplification are sensitive in vivo to PLX8725, a novel MAP2K4 inhibitor. Gynecologic Oncology 2023, 172: 65-71. PMID: 36958197, PMCID: PMC10192120, DOI: 10.1016/j.ygyno.2023.03.009.Peer-Reviewed Original ResearchConceptsUterine leiomyosarcomaPDX modelsGain of functionMedian overall survivalPhase I trialOral gavage dailyVivo activityTumor growth inhibitionTumor volume differencesTumor cell proliferationOverall survivalTolerable toxicityI trialOral treatmentTreatment cohortsGavage dailyAggressive tumorsSCID miceULMS patientsPK studiesTumor samplesWestern blotCell proliferationControl vehicleLeiomyosarcoma
2022
Elimusertib (BAY1895344), a novel ATR inhibitor, demonstrates in vivo activity in ATRX mutated models of uterine leiomyosarcoma
Harold J, Bellone S, Manavella D, Mutlu L, McNamara B, Hartwich T, Zipponi M, Yang-Hartwich Y, Demirkiran C, Verzosa M, Choi J, Dong W, Buza N, Hui P, Altwerger G, Huang G, Andikyan V, Clark M, Ratner E, Azodi M, Schwartz P, Santin A. Elimusertib (BAY1895344), a novel ATR inhibitor, demonstrates in vivo activity in ATRX mutated models of uterine leiomyosarcoma. Gynecologic Oncology 2022, 168: 157-165. PMID: 36442427, PMCID: PMC9797429, DOI: 10.1016/j.ygyno.2022.11.014.Peer-Reviewed Original ResearchConceptsPatient-derived xenograftsUterine leiomyosarcomaVivo activityVehicle control treatmentMedian overall survivalTumor volume differencesOral scheduleWestern blot analysisOverall survivalOral gavageAggressive malignancyPDX modelsClinical trialsSCID miceTumor measurementsULMS patientsSignificant growth inhibitionNovel ATR inhibitorTumor samplesSignificant toxicityWestern blotKinase inhibitorsATRX mutationsGene mutationsControl vehicleLenvatinib plus Pembrolizumab for Advanced Endometrial Cancer
Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Sakata J, Yonemori K, Kim YM, Guerra EM, Sanli UA, McCormack MM, Smith AD, Keefe S, Bird S, Dutta L, Orlowski RJ, Lorusso D. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. New England Journal Of Medicine 2022, 386: 437-448. PMID: 35045221, DOI: 10.1056/nejmoa2108330.Peer-Reviewed Original ResearchConceptsAdvanced endometrial cancerProgression-free survivalEndometrial cancerOverall survivalMedian progression-free survivalPlatinum-based chemotherapy regimenLonger progression-free survivalEnd pointBlinded independent central reviewMedian overall survivalPrimary end pointPhase 3 trialResponse Evaluation CriteriaPlatinum-based chemotherapyIndependent central reviewChemotherapy regimenAdverse eventsStandard therapyCentral reviewPembrolizumabGrade 3LenvatinibChemotherapyPhysician's choicePatients
2020
Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial
Oaknin A, Friedman CF, Roman LD, D’Souza A, Brana I, Bidard F, Goldman J, Alvarez EA, Boni V, ElNaggar AC, Passalacqua R, T.M. K, Santin AD, Keyvanjah K, Xu F, Eli LD, Lalani AS, Bryce RP, Hyman DM, Meric-Bernstam F, Solit DB, Monk BJ. Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial. Gynecologic Oncology 2020, 159: 150-156. PMID: 32723675, PMCID: PMC8336424, DOI: 10.1016/j.ygyno.2020.07.025.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultDiarrheaFemaleHumansKaplan-Meier EstimateMiddle AgedMutationNauseaNeoplasm Recurrence, LocalProgression-Free SurvivalProtein Kinase InhibitorsQuinolinesReceptor, ErbB-2Response Evaluation Criteria in Solid TumorsSeverity of Illness IndexUterine Cervical NeoplasmsConceptsProgression-free survivalClinical benefit rateObjective response rateCervical cancerOverall survivalHER2 mutationsBasket trialsMetastatic/recurrent cervical cancerAdvanced/recurrent diseaseMedian progression-free survivalCommon HER2 mutationsGrade 3 diarrheaGrade 4 eventsHER2-mutant cancersSafety of neratinibCommon adverse eventsMedian overall survivalRecurrent cervical cancerMetastatic cervical cancerNew safety signalsPhase II basket trialPlatinum-based treatmentTyrosine kinase inhibitorsWarrants further investigationEligible patientsSacituzumab govitecan (SG) in patients (pts) with previously treated metastatic endometrial cancer (mEC): results from a phase I/II study.
Santin A, Komiya T, Goldenberg D, Sharkey R, Hong Q, Wegener W, Goswami T, Bardia A. Sacituzumab govitecan (SG) in patients (pts) with previously treated metastatic endometrial cancer (mEC): results from a phase I/II study. Journal Of Clinical Oncology 2020, 38: 6081-6081. DOI: 10.1200/jco.2020.38.15_suppl.6081.Peer-Reviewed Original ResearchMetastatic endometrial cancerObjective response rateClinical benefit rateProgression-free survivalDuration of responseMedian overall survivalSacituzumab govitecanOverall survivalTrop-2 expressionPlatinum therapyPhase I/II studySolid tumorsTrop-2Median progression-free survivalNeutrophil count decreasePrevious preclinical findingsPrior platinum therapySimilar safety profileAdvanced solid tumorsCT/MRI scansMetastatic solid tumorsLimited treatment optionsFurther clinical investigationFebrile neutropeniaPrior chemotherapyPhase II evaluation of copanlisib, a selective inhibitor of Pi3kca, in patients with persistent or recurrent endometrial carcinoma harboring PIK3CA hotspot mutations: An NRG Oncology study (NRG-GY008)
Santin AD, Filiaci V, Bellone S, Ratner ES, Mathews CA, Cantuaria G, Gunderson CC, Rutledge T, Buttin BM, Lankes HA, Frumovitz M, Khleif SN, Huh WK, Birrer MJ. Phase II evaluation of copanlisib, a selective inhibitor of Pi3kca, in patients with persistent or recurrent endometrial carcinoma harboring PIK3CA hotspot mutations: An NRG Oncology study (NRG-GY008). Gynecologic Oncology Reports 2020, 31: 100532. PMID: 31934607, PMCID: PMC6951478, DOI: 10.1016/j.gore.2019.100532.Peer-Reviewed Original ResearchProgression-free survivalStable diseaseOverall survivalMixed histologyPIK3CA mutationsGrade 5 adverse eventsMedian progression-free survivalCommon grade 3Common PIK3CA mutationCTCAE version 4GOG performance statusNRG Oncology StudyMedian overall survivalObjective tumor responsePhase II trialPhase II evaluationBest overall responsePIK3CA gene mutationsPIK3CA hotspot mutationsSelective inhibitorEligible patientsMeasurable diseaseHotspot PIK3CA mutationsII trialPrimary endpoint
2019
Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study
Matulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, Raspagliesi F, Sonke GS, Birrer M, Provencher DM, Sehouli J, Colombo N, González-Martín A, Oaknin A, Ottevanger PB, Rudaitis V, Katchar K, Wu H, Keefe S, Ruman J, Ledermann JA. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Annals Of Oncology 2019, 30: 1080-1087. PMID: 31046082, DOI: 10.1093/annonc/mdz135.Peer-Reviewed Original ResearchConceptsRecurrent ovarian cancerObjective response rateDisease control rateProgression-free survivalTreatment-free intervalDuration of responseAdvanced recurrent ovarian cancerPD-L1 expressionPlatinum-free intervalCohort AOverall survivalPrior linesCohort BOvarian cancerHigh PD-L1 expressionLow objective response rateMedian DORSolid Tumors version 1.1End pointGynecologic cancer-related deathBlinded independent central reviewSafety of pembrolizumabSingle-agent pembrolizumabMedian overall survivalPhase II study
2016
Efficacy and tolerability of combination cisplatin and ifosfamide chemotherapy with vaginal cuff brachytherapy in the first line treatment of uterine carcinosarcoma.
Abu-Khalaf MM, Raza MA, Hatzis C, Wang H, Lin K, Higgins S, Ratner E, Silasi DA, Azodi M, Rutherford TJ, Santin AD, Schwartz PE. Efficacy and tolerability of combination cisplatin and ifosfamide chemotherapy with vaginal cuff brachytherapy in the first line treatment of uterine carcinosarcoma. European Journal Of Gynaecological Oncology 2016, 37: 199-203. PMID: 27172745.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAnemiaAntineoplastic Combined Chemotherapy ProtocolsBrachytherapyCarcinosarcomaChemoradiotherapyCisplatinDisease-Free SurvivalFemaleHumansIfosfamideMesnaMiddle AgedNeoplasm StagingNeutropeniaProtective AgentsRetrospective StudiesTreatment OutcomeUterine NeoplasmsConceptsVaginal cuff brachytherapyProgression-free survivalFirst-line treatmentOverall survivalUterine carcinosarcomaStage ILine treatmentStage IIIDay 1Anemia grade 1Most common toxicitiesNeutropenia grade 3Cycles of cisplatinMedian overall survivalStage IV diseaseCommon toxicitiesMedian followTreatment discontinuationFree survivalPatient withdrawalCombination cisplatinDose modificationMedian ageRetrospective studyGrade 3
2013
Class III β-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel
Roque DM, Buza N, Glasgow M, Bellone S, Bortolomai I, Gasparrini S, Cocco E, Ratner E, Silasi DA, Azodi M, Rutherford TJ, Schwartz PE, Santin AD. Class III β-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel. Clinical & Experimental Metastasis 2013, 31: 101-110. PMID: 24005572, PMCID: PMC3947146, DOI: 10.1007/s10585-013-9614-5.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCarboplatinCystadenocarcinoma, SerousDrug Resistance, NeoplasmFemaleHumansImmunohistochemistryNeoadjuvant TherapyOvarian NeoplasmsPaclitaxelPrognosisReal-Time Polymerase Chain ReactionTubulinTumor MicroenvironmentUp-RegulationConceptsClass III β-tubulinIII β-tubulinClass III β-tubulin expressionNeoadjuvant chemotherapyPoor overall survivalOverall survivalΒ-tubulin expressionClass III β-tubulin overexpressionPrimary cytoreductionNeoadjuvant carboplatin/paclitaxelPoor median overall survivalTumor microenvironmentAdvanced ovarian carcinomaCarboplatin/paclitaxelMedian overall survivalOvarian cancer patientsCell linesCancer stem cellsNeoadjuvant carboplatinPrimary debulkingVitro chemosensitivityClinical outcomesPatient populationCancer patientsStromal expression
2012
Weekly ixabepilone with or without concurrent bevacizumab in the treatment of recurrent endometrial cancer.
Roque D, Ratner E, Silasi D, Azodi M, Schwartz P, Rutherford T, Santin A. Weekly ixabepilone with or without concurrent bevacizumab in the treatment of recurrent endometrial cancer. Journal Of Clinical Oncology 2012, 30: e15526-e15526. DOI: 10.1200/jco.2012.30.15_suppl.e15526.Peer-Reviewed Original ResearchRecurrent endometrial cancerConcurrent bevacizumabEndometrial cancerWeekly ixabepiloneDemographic/disease characteristicsCycles of ixabepiloneMedian overall survivalPR/SDPhase II studyExperienced progressionQ21 daysDisease stabilizationGastrointestinal toxicityFirst recurrenceII studyMedian survivalOverall survivalPartial responseCA 125Median timeDisease characteristicsDosing strategiesInstitutional experienceBevacizumabIxabepilone