Neu Direction: Testing the Efficacy of Adding HER Inhibition to Standard of Care in Metastatic MLH1-low Endocrine-resistant ER+/HER2- Breast Cancer

NCT07729046 | Not Yet Recruiting Phase 2 FDA Drug

• 2 other identifiers: BC250474813310
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to learn if neratinib, an FDA-approved oral pan-HER2/3/4 inhibitor, improves disease control for participants with metastatic endocrine-resistant ER+/HER2-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:

1. 1.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?
2. 2.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.
3. 3.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
4. 4.Visit the clinic every 3 months for checkups, tests and imaging studies

Conditions

Metastatic Invasive Breast Cancer; Resistant Breast Cancer; ER+, HER2-, Metastatic Breast Cancer

Keywords

endocrine-resistant; DNA mismatch repair; MLH1; dMMR; metastatic breast cancer; ER+ breast cancer; endocrine-resistance; HER2 negative; HER2-; neratinib

Outcome Measures

Primary Outcomes (2)

• Median Progression-Free Survival

  From enrollment through study completion, an average of 1 year.

• 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

  From enrollment through study completion, an average of 1 year.

Study Arms (2)

Standard of Care

ACTIVE COMPARATOR

Standard of Care 2nd or 3rd line endocrine therapy with or without CDK4/6 inhibitor

Drug: Endocrine therapy may include one of the following therapies: letrozole, anastrozole, exemestane, tamoxifen or fulvestrant; Drug: CDK4/6 + Endocrine therapy

Stanard of Care + Neratinib

EXPERIMENTAL

Standard of Care 2nd or 3rd line endocrine therapy with or without CDK4/6 inhibitor + Neratinib

Drug: Neratinib + endocrine therapy; Drug: CDK4/6 + Endocrine therapy

Interventions

Neratinib + endocrine therapy DRUG

Neratinib 120mg daily for 1 week, 160mg daily for 1 week and then 240mg daily thereafter

Also known as: neratinib

Stanard of Care + Neratinib

CDK4/6 + Endocrine therapy DRUG

Endocrine therapy with or without CDK 4/6 inhibitor

Stanard of Care + Neratinib; Standard of Care

Endocrine therapy may include one of the following therapies: letrozole, anastrozole, exemestane, tamoxifen or fulvestrant DRUG

Endocrine therapy with out without CDK4/6 inhibitor

Standard of Care

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female over the age of 18 at the time of study enrollment
• Not pregnant, planning to become pregnant or breast feeding
• Metastatic ER+/HER2- breast cancer that has progressed on 1st line therapy including endocrine therapy +/- CDK4/6 inhibitors
• At least one metastatic lesion visible on imaging (including FDG-PET)
• 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)
• Tumors must be MLH1-low defined by \<50% tumor cells positive for nuclear MLH1 expression on immunohistochemistry
• Standard of care next line endocrine therapy can include any endocrine therapy
• Performance status ECOG \> 3
• Life expectancy \> 1 year
• Ability to get serial imaging studies

You may not qualify if:

• History of concurrent use of other HER2-targeted therapy
• Concurrent use of other targeted systemic therapy
• History of other cancers other than non-melanoma skin cancer
• Actionable mutations on tumor genomic sequencing will be ineligible, and those participants encouraged to proceed with the relevant targeted therapy
• 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)
• Contraindications to Neratinib use including allergy or hypersensitivity
• Baseline grade 3+ diarrhea

Sponsors & Collaborators

• University of California, San Diego: lead

Study Sites (1)

UC San Diego Health Moores Cancer Center

La Jolla, California, 92037, United States

Location

Related Publications (5)

• 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/s41467-025-67257-8.

  PMID: 41372237 BACKGROUND

• 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/s12935-021-01976-y.

  PMID: 34001143 BACKGROUND

• 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: 10.1158/1078-0432.CCR-17-3702. Epub 2018 May 23.

  PMID: 29793947 BACKGROUND

• 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 CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer. Cancer Discov. 2017 Oct;7(10):1168-1183. doi: 10.1158/2159-8290.CD-16-1179. Epub 2017 Aug 11.

  PMID: 28801307 BACKGROUND

• 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/s41467-021-23271-0.

  PMID: 34011995 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Interventions

neratinib; Anastrozole; exemestane; Tamoxifen; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Asona Lui, MD, PhD

  UC San Diego

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Asona Lui, MD, PhD

CONTACT

858-822-4319; ajlui@health.ucsd.edu

Alyssa Beck, MD

CONTACT

858-657-7000; a4beck@health.ucsd.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Physician

Study Record Dates

• First Submitted: July 14, 2026
• First Posted: July 27, 2026
• Study Start (Estimated): July 1, 2027
• Primary Completion (Estimated): May 1, 2032
• Study Completion (Estimated): June 1, 2035
• Last Updated: July 27, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Beginning 6 months and ending 3 years after publication of results
• Access Criteria: Proposal that describes planned analyses must be submitted and approved by the Principle Investigator, Asona Lui and data sharing agreement must be signed with the requesters institution. Evidence of IRB approval must be provided by the requestor prior to the sharing of any data.

Locations

US (1)