2019
Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial
Konstantinopoulos PA, Barry WT, Birrer M, Westin SN, Cadoo KA, Shapiro GI, Mayer EL, O'Cearbhaill RE, Coleman RL, Kochupurakkal B, Whalen C, Curtis J, Farooq S, Luo W, Eismann J, Buss MK, Aghajanian C, Mills GB, Palakurthi S, Kirschmeier P, Liu J, Cantley LC, Kaufmann SH, Swisher EM, D'Andrea AD, Winer E, Wulf GM, Matulonis UA. Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. The Lancet Oncology 2019, 20: 570-580. PMID: 30880072, PMCID: PMC7025391, DOI: 10.1016/s1470-2045(18)30905-7.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Ovarian EpithelialDose-Response Relationship, DrugDrug-Related Side Effects and Adverse ReactionsFemaleGenome, HumanHumansMaximum Tolerated DoseMiddle AgedMutationOvarian NeoplasmsPhosphoinositide-3 Kinase InhibitorsPhthalazinesPiperazinesPoly(ADP-ribose) Polymerase InhibitorsThiazolesTreatment OutcomeConceptsEpithelial ovarian cancerPhase 2 dosePI3K inhibitor alpelisibPrimary peritoneal cancerPhase 1b trialRecurrent breast cancerGermline BRCA mutationsOvarian cancerBreast cancerDose levelsPeritoneal cancerBRCA mutationsFallopian tubeCommon treatment-related grade 3High-grade serous histologyTreatment-related grade 3Breast Cancer Research FoundationDecreased neutrophil countDose-escalation cohortsDose-expansion cohortsTreatment-related deathsTriple negative histologyResponse Evaluation CriteriaSolid Tumors 1.1Key eligibility criteria
2017
Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer
Matulonis U, Wulf G, Barry W, Birrer M, Westin S, Farooq S, Bell-McGuinn K, Obermayer E, Whalen C, Spagnoletti T, Luo W, Liu H, Hok R, Aghajanian C, Solit D, Mills G, Taylor B, Won H, Berger M, Palakurthi S, Liu J, Cantley L, Winer E. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Annals Of Oncology 2017, 28: 512-518. PMID: 27993796, PMCID: PMC5834157, DOI: 10.1093/annonc/mdw672.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAminopyridinesBRCA1 ProteinBRCA2 ProteinBreast NeoplasmsDose-Response Relationship, DrugFemaleGerm-Line MutationHumansMiddle AgedMorpholinesNeoplasm GradingNeoplasm Recurrence, LocalOvarian NeoplasmsPhosphoinositide-3 Kinase InhibitorsPhthalazinesPiperazinesPoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesConceptsGermline BRCA mutationsOvarian cancerStudy treatmentPARP inhibitorsRandomized phase II studyDose-expansion cohortsPhase II studyPhase I trialDose-escalation designWild-type patientsBiomarkers of responsePARP inhibitor combinationsCombination of BKM120Polymerase inhibitor olaparibPoly (ADP-ribose) polymerase (PARP) inhibitor olaparibPI3K inhibitorsAdditional DLTsOlaparib 300Preclinical synergyRecurrent breastEscalation studyII studyI trialClinical benefitBRCA mutationsA Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer
Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL. A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer. Clinical Cancer Research 2017, 23: 26-34. PMID: 27126994, PMCID: PMC5085926, DOI: 10.1158/1078-0432.ccr-16-0134.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Combined Chemotherapy ProtocolsAromatase InhibitorsBiomarkers, TumorBreast NeoplasmsCell Line, TumorDNA Mutational AnalysisFemaleHumansIn Situ Hybridization, FluorescenceLetrozoleMaximum Tolerated DoseMiddle AgedMutationNeoplasm MetastasisNeoplasm StagingNitrilesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsReceptor, ErbB-2Receptor, Fibroblast Growth Factor, Type 1Receptors, EstrogenThiazolesTreatment OutcomeTriazolesConceptsMaximum-tolerated doseBreast cancer cellsEndocrine therapyClinical benefitCommon drug-related adverse eventsDrug-related adverse eventsMutant breast cancer cellsBreast cancer refractoryPIK3CA mutation statusPIK3CA-mutated tumorsClinical benefit ratePhase Ib studyPI3K catalytic subunit p110αDose-limiting toxicityCancer cellsSelective oral inhibitorOverexpression of FGFR1Combination of letrozoleSynergistic antitumor activityCatalytic subunit p110αCancer refractoryFGFR1/2 amplificationMetastatic ERAdverse eventsObjective response
2016
Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases
Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, Luu V, Marco E, Ramkissoon LA, Kang YJ, Hayashi M, Nguyen QD, Ligon AH, Du R, Claus EB, Alexander BM, Yuan GC, Wang ZC, Iglehart JD, Krop IE, Roberts TM, Winer EP, Lin NU, Ligon KL, Zhao JJ. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nature Medicine 2016, 22: 723-726. PMID: 27270588, PMCID: PMC4938731, DOI: 10.1038/nm.4120.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAminopyridinesAnimalsAntineoplastic AgentsApoptosisBrain NeoplasmsBreast NeoplasmsCarrier ProteinsCaspase 3Cell Cycle ProteinsDNA RepairDrug Resistance, NeoplasmDrug Therapy, CombinationEukaryotic Initiation FactorsEverolimusFemaleGene Expression ProfilingGenomic InstabilityHumansImmunohistochemistryKi-67 AntigenMagnetic Resonance ImagingMechanistic Target of Rapamycin Complex 1MiceMice, SCIDMolecular Targeted TherapyMorpholinesMultiprotein ComplexesNeoplasm TransplantationPhosphoinositide-3 Kinase InhibitorsPhosphoproteinsPhosphorylationReceptor, ErbB-2Remission InductionTOR Serine-Threonine KinasesXenograft Model Antitumor AssaysConceptsBreast cancer brain metastasesCancer brain metastasesBrain metastasesHER2-positive breast cancer brain metastasesOrthotopic patient-derived xenograftsPI3KPatient-derived xenograftsDurable remissionsTherapeutic responseMouse modelCombined inhibitionCombination inhibitionMetastasisInhibitionRemissionXenograftsMice
2015
PIK3CAH1047R- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling
Cheng H, Liu P, Ohlson C, Xu E, Symonds L, Isabella A, Muller WJ, Lin NU, Krop IE, Roberts TM, Winer EP, Arteaga CL, Zhao JJ. PIK3CAH1047R- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene 2015, 35: 2961-2970. PMID: 26640141, PMCID: PMC4896860, DOI: 10.1038/onc.2015.377.Peer-Reviewed Original ResearchConceptsBreast cancerPIK3CA mutationsMammary tumorsHER2 amplification/overexpressionHER2-positive breast cancerHER2-positive cancersPrimary mammary tumorsHER2/HER3PIK3CA-activating mutationsHER2/neuHuman breast cancerEffective treatment approachAmplification/overexpressionCompound mouse modelMEK-ERK signalingMouse mammary glandWorse prognosisCombination therapyMammary tumorigenesisMouse modelMutant PIK3CATreatment approachesHER2Combined inhibitionCompensatory activationPI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers
Wang Q, Liu P, Spangle JM, Von T, Roberts TM, Lin NU, Krop IE, Winer EP, Zhao JJ. PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 2015, 35: 3607-3612. PMID: 26500061, PMCID: PMC4846581, DOI: 10.1038/onc.2015.406.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCell SurvivalClass I Phosphatidylinositol 3-KinasesDrug Resistance, NeoplasmFemaleHumansLapatinibMammary Neoplasms, ExperimentalMice, KnockoutMolecular Targeted TherapyPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseQuinazolinesReceptor, ErbB-2Signal TransductionThiazolesTumor BurdenXenograft Model Antitumor AssaysConceptsBreast tumorsP110β inhibitorsHuman epidermal growth factor receptor 2 (HER2) amplificationP110α inhibitionPTEN lossInhibition of HER2Treatment of HER2Human cancersPI3K pathway activationPTEN-deficient breast cancersGenetic mouse modelsPI3K/Akt signalingPTEN-deficient tumorsPI3K/AktDual HER2Therapeutic regimenHER2 inhibitionPIK3CA mutationsTumor regressionBreast cancerMouse modelXenograft modelHER2Null tumorsHER2 activation
2014
Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer
Tolaney S, Burris H, Gartner E, Mayer IA, Saura C, Maurer M, Ciruelos E, Garcia AA, Campana F, Wu B, Xu Y, Jiang J, Winer E, Krop I. Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. Breast Cancer Research And Treatment 2014, 149: 151-161. PMID: 25537644, DOI: 10.1007/s10549-014-3248-4.Peer-Reviewed Original ResearchConceptsHER2-positive metastatic breast cancerMetastatic breast cancerAdverse eventsBreast cancerArm 2Arm 1Phase I/II dose-escalation studyMetastatic HER2-positive breast cancerPhase I/II studyTreatment-related adverse eventsHER2-positive breast cancerTreatment-related gradeAcceptable safety profileDose-escalation studyDose-limiting toxicityDose-escalation designPan-class IEvaluable patientsPaclitaxel armPrior taxanePrior trastuzumabErythematous rashII studyPartial responsePeripheral neuropathyStand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer
Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, Sanders ME, Yap JT, Van den Abbeele AD, Li Y, Cantley LC, Winer E, Arteaga CL. Stand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. Journal Of Clinical Oncology 2014, 32: 1202-1209. PMID: 24663045, PMCID: PMC3986383, DOI: 10.1200/jco.2013.54.0518.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAminopyridinesAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsCell Line, TumorClass I Phosphatidylinositol 3-KinasesDose-Response Relationship, DrugDrug Administration ScheduleFemaleFluorodeoxyglucose F18HumansLetrozoleMiddle AgedMorpholinesMultimodal ImagingNitrilesPhosphoinositide-3 Kinase InhibitorsPositron-Emission TomographyProtein Kinase InhibitorsRadiopharmaceuticalsReceptor, ErbB-2Receptors, EstrogenTomography, X-Ray ComputedTriazolesConceptsMaximum-tolerated dosePhase Ib studyPET/CTEndocrine therapyDisease progressionBreast cancerIb studyCommon drug-related adverse eventsDrug-related adverse eventsPIK3CA hot spot mutationsPositive breast cancer cell linesER-positive breast cancerPositron emission tomography/Human epidermal growth factor receptorBreast cancer refractoryClinical benefit rateOral reversible inhibitorPIK3CA mutation statusPhase III trialsMetastatic breast cancerRapid disease progressionEmission tomography/Different administration schedulesBreast cancer cell linesMetabolic disease progression