[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"trial:NCT07729046":3,"trial-entities:NCT07729046":127,"trial-summary:NCT07729046":134},{"id":4,"nct_id":4,"org_study_id":5,"brief_title":6,"official_title":7,"overall_status":8,"completion_date":9,"status_verified_date":10,"last_update_date":11,"start_date":12,"sponsor_name":13,"lead_sponsor_class":14,"has_dmc":15,"brief_summary":16,"detailed_description":17,"conditions":18,"keywords":22,"study_type":33,"primary_purpose":34,"phases":35,"enrollment_info":37,"interventions":40,"primary_outcomes":57,"secondary_outcomes":64,"sex":65,"minimum_age":66,"maximum_age":67,"healthy_volunteers":15,"eligibility_criteria":68,"std_ages":72,"locations":75,"central_contacts":99,"overall_officials":106,"references":109,"see_also_links":126},"NCT07729046","BC250474","Neu Direction: Testing the Efficacy of Adding HER Inhibition to Standard of Care in Metastatic MLH1-low Endocrine-resistant ER+\u002FHER2- Breast Cancer","Neu Direction: A Single Center Phase II Randomized Clinical Trial to Assess the Efficacy of Adding HER Inhibition to Standard of Care in Patients With Metastatic MLH1-low Endocrine-resistant ER+\u002FHER2- Breast Cancer","NOT_YET_RECRUITING","2035-06","2026-07","2026-07-27","2027-07","University of California, San Diego","OTHER",false,"The goal of this clinical trial is to learn if neratinib, an FDA-approved oral pan-HER2\u002F3\u002F4 inhibitor, improves disease control for participants with metastatic endocrine-resistant ER+\u002FHER2-negative breast cancer. Neratinib is already approved for the treatment of HER2-postive breast cancers. The study will also learn about the safety of adding this drug to standard of care treatments. The main questions it aims to answer are:\n\n1. Does adding neratinib to standard of care systemic therapy improve disease control for patients with metastatic hormone-driven breast cancer that is resistant to endocrine therapy?\n2. What side effects do participants have when adding neratinib to standard of care therapy? Researchers will compare standard of care endocrine therapy regimens with and without neratinib to see if neratinib improves control of treatment-resistant metastatic breast cancer that has continued to progress while eon first line endocrine therapy.\n\nParticipants will:\n\n1. Take standard of care endocrine therapy for metastatic endocrine-resistant breast cancer as determined by their medical oncologist or standard of care therapy with neratinib daily\n2. Visit the clinic every 3 months for checkups, tests and imaging studies","This is a prospective 2-arm Phase II study testing the efficacy of adding neratinib to standard of care therapy in patients with MLH1-low ER+\u002FHER2- endocrine-resistant breast cancer . Patients with endocrine-resistant ER+\u002FHER2- breast cancer who have lesions visible on CT scan will be recruited as they are seen in breast medical oncology and radiation oncology clinics at UC San Diego Health. Patients will be eligible if they have measurable persistent, recurrent, progressive or metastatic disease on imaging (including FDG PET scan) while on endocrine therapy. At least one lesion must be biopsied and confirmed ER+ by immunohistochemistry and HER2- within 6 months of study screening. Genomic mutation profile will be analyzed along with trial results to identify other potential mutations associated with MLH1 expression and\u002For neratinib response. Participants will be stratified by nuclear MLH1 expression on their biopsy tissue using immunohistochemistry. MLH1negative (nuclear MLH1 detectable in \\\u003C5% of tumor cells) and MLH1-low patients (\\\u003C50% tumor cells positive) hereafter grouped as \"MLH1-low\" will be randomized to standard of care without (75 participants) or with (75 participants) the addition of neratinib in Arm 1 and Arm 2 respectively . Standard of care therapy can include any endocrine therapy with or without CDK4\u002F6 inhibitors. Prior exposure to CDK4\u002F6 inhibitors is acceptable but not prior HER2-targeted therapy. Neratinib will be administered with a standard ramp up to therapeutic dose to minimize side effects with 120mg daily for 1 week, 160mg daily for 1 week and then 240mg daily thereafter. Treatment response will be monitored via imaging every 3 months while on study and measured using RECIST v. 1.1 criteria and\u002For mPERCIST criteria as appropriate using FDG-PET. Participants will remain on study until cessation due to side effects or disease progression. Biopsy at disease progression will be encouraged but not required.",[19,20,21],"Metastatic Invasive Breast Cancer","Resistant Breast Cancer","ER+, HER2-, Metastatic Breast Cancer",[23,24,25,26,27,28,29,30,31,32],"endocrine-resistant","DNA mismatch repair","MLH1","dMMR","metastatic breast cancer","ER+ breast cancer","endocrine-resistance","HER2 negative","HER2-","neratinib","INTERVENTIONAL","TREATMENT",[36],"PHASE2",{"count":38,"type":39},150,"ESTIMATED",[41,48,53],{"type":42,"name":43,"description":44,"armGroupLabels":45,"otherNames":47},"DRUG","Neratinib + endocrine therapy","Neratinib 120mg daily for 1 week, 160mg daily for 1 week and then 240mg daily thereafter",[46],"Stanard of Care + Neratinib",[32],{"type":42,"name":49,"description":50,"armGroupLabels":51},"Endocrine therapy may include one of the following therapies: letrozole, anastrozole, exemestane, tamoxifen or fulvestrant","Endocrine therapy with out without CDK4\u002F6 inhibitor",[52],"Standard of Care",{"type":42,"name":54,"description":55,"armGroupLabels":56},"CDK4\u002F6 + Endocrine therapy","Endocrine therapy with or without CDK 4\u002F6 inhibitor",[46,52],[58,61],{"measure":59,"timeFrame":60},"Median Progression-Free Survival","From enrollment through study completion, an average of 1 year.",{"measure":62,"description":63,"timeFrame":60},"Number of participants with treatment-related adverse events as assessed by CTCAE v4.0","Adverse events will be quantified using the CTCAE v4.0 every 3 months",[],"FEMALE","18 Years",null,{"inclusion":69,"exclusion":70,"raw_text":71},[],[],"Inclusion Criteria:\n\n1. Female over the age of 18 at the time of study enrollment\n2. Not pregnant, planning to become pregnant or breast feeding\n3. Metastatic ER+\u002FHER2- breast cancer that has progressed on 1st line therapy including endocrine therapy +\u002F- CDK4\u002F6 inhibitors\n4. At least one metastatic lesion visible on imaging (including FDG-PET)\n5. At least one metastatic lesion must be biopsied and confirmed ER+ and HER2- by immunohistochemistry within 6 months of study screening (HER2 equivocal disease will be confirmed HER2- by FISH)\n6. Tumors must be MLH1-low defined by \\\u003C50% tumor cells positive for nuclear MLH1 expression on immunohistochemistry\n7. Standard of care next line endocrine therapy can include any endocrine therapy\n8. Performance status ECOG \\> 3\n9. Life expectancy \\> 1 year\n10. Ability to get serial imaging studies\n\nExclusion Criteria:\n\n1. History of concurrent use of other HER2-targeted therapy\n2. Concurrent use of other targeted systemic therapy\n3. History of other cancers other than non-melanoma skin cancer\n4. Actionable mutations on tumor genomic sequencing will be ineligible, and those participants encouraged to proceed with the relevant targeted therapy\n5. Participants where there is not at least one imaging apparent lesion that has not been treated with prior targeted therapy (for example palliative radiation or cryoablation)\n6. Contraindications to Neratinib use including allergy or hypersensitivity\n7. Baseline grade 3+ diarrhea",[73,74],"ADULT","OLDER_ADULT",[76],{"facility":77,"city":78,"state":79,"zip":80,"country":81,"contacts":82,"geoPoint":96},"UC San Diego Health Moores Cancer Center","La Jolla","California","92037","United States",[83,88,91,94],{"name":84,"role":85,"phone":86,"email":87},"Sauntee Braddock","CONTACT","858-534-8248","sbraddock@health.ucsd.edu",{"name":89,"role":90},"Asona Lui, MD, PhD","PRINCIPAL_INVESTIGATOR",{"name":92,"role":93},"Alyssa Beck, MD","SUB_INVESTIGATOR",{"name":95,"role":93},"Svasti Haricharan, PhD",{"lat":97,"lon":98},32.84727,-117.2742,[100,103],{"name":89,"role":85,"phone":101,"email":102},"858-822-4319","ajlui@health.ucsd.edu",{"name":92,"role":85,"phone":104,"email":105},"858-657-7000","a4beck@health.ucsd.edu",[107],{"name":89,"affiliation":108,"role":90},"UC San Diego",[110,114,117,120,123],{"pmid":111,"type":112,"citation":113},"41372237","BACKGROUND","Mazumder A, Dewitt J, Oropeza E, Punturi N, Lozano D, Raghunathan M, Piscitelli J, Sajjadi E, GueriniRocco E, Venetis K, Ivanova M, Mane E, Dercole M, Concardi A, Fusco N, Manhart C, Bainbridge M, Haricharan S. Aberrant cytoplasmic localization of MLH1 characterizes a cell population that seeds breast cancer recurrence. Nat Commun. 2025 Dec 10;17(1):564. doi: 10.1038\u002Fs41467-025-67257-8.",{"pmid":115,"type":112,"citation":116},"34001143","Sajjadi E, Venetis K, Piciotti R, Invernizzi M, Guerini-Rocco E, Haricharan S, Fusco N. Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization. Cancer Cell Int. 2021 May 17;21(1):266. doi: 10.1186\u002Fs12935-021-01976-y.",{"pmid":118,"type":112,"citation":119},"29793947","Anurag M, Punturi N, Hoog J, Bainbridge MN, Ellis MJ, Haricharan S. Comprehensive Profiling of DNA Repair Defects in Breast Cancer Identifies a Novel Class of Endocrine Therapy Resistance Drivers. Clin Cancer Res. 2018 Oct 1;24(19):4887-4899. doi: 10.1158\u002F1078-0432.CCR-17-3702. Epub 2018 May 23.",{"pmid":121,"type":112,"citation":122},"28801307","Haricharan S, Punturi N, Singh P, Holloway KR, Anurag M, Schmelz J, Schmidt C, Lei JT, Suman V, Hunt K, Olson JA Jr, Hoog J, Li S, Huang S, Edwards DP, Kavuri SM, Bainbridge MN, Ma CX, Ellis MJ. Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4\u002F6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer. Cancer Discov. 2017 Oct;7(10):1168-1183. doi: 10.1158\u002F2159-8290.CD-16-1179. Epub 2017 Aug 11.",{"pmid":124,"type":112,"citation":125},"34011995","Punturi NB, Seker S, Devarakonda V, Mazumder A, Kalra R, Chen CH, Li S, Primeau T, Ellis MJ, Kavuri SM, Haricharan S. Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer. Nat Commun. 2021 May 19;12(1):2940. doi: 10.1038\u002Fs41467-021-23271-0.",[],{"nct_id":4,"conditions":128,"biomarkers":130},[129],"Breast Carcinoma",[131,132,133],"DNA Mismatch Repair Protein Mlh1","ERBB3 wt Allele","ERBB4 wt Allele",{"nct_id":4,"found":135,"summary":136,"prompt_version":146},true,{"design":137,"status":138,"heading":139,"summary":140,"follow_up":141,"word_count":142,"commitments":143,"compensation":144,"drugs_mentioned":145},"This is a Phase II study that will enroll 150 participants. You would be randomly assigned to receive either standard care alone or standard care plus neratinib.","completed","Neu Direction: Testing Neratinib for Metastatic ER+\u002FHER2- Breast Cancer","This study is looking at whether adding neratinib, an FDA-approved medicine, can help control metastatic breast cancer that is estrogen receptor-positive (ER+) and HER2-negative (HER2-), and has become resistant to standard hormone therapy. Neratinib is currently used for HER2-positive breast cancers. You might be able to join if you are a woman over 18 with this type of breast cancer that has progressed after initial treatment, and you have at least one visible tumor. Researchers will also be looking at the safety of adding neratinib to standard treatments like letrozole, anastrozole, exemestane, tamoxifen, or fulvestrant, with or without CDK4\u002F6 inhibitors. The study aims to enroll 150 participants and will measure how long people live without their cancer getting worse, and what side effects they experience.","Your progress and any side effects will be monitored from when you join until the study ends, which is expected to be about one year on average.",125,"Not specified in the trial record.","Not stated in the trial record.",[],"v2"]