Neoadjuvant Neratinib in Stage I-III HER2-Mutated Lobular Breast Cancers

NCT05919108 | Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: VICC-NCBRE23172NCI-2023-044681R01CA273246-01A1
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 5

Brief Summary

This phase II trial tests how well neratinib prior to the primary treatment (neoadjuvant) works in treating patients with stage I-III HER2 mutated lobular breast cancers. Neratinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving neratinib in addition to normal therapy may work better in treating cancer than the endocrine therapy patients would normally receive.

Conditions

Anatomic Stage I Breast Cancer; Anatomic Stage II Breast Cancer; Anatomic Stage III Breast Cancer; Invasive Breast Lobular Carcinoma

Outcome Measures

Primary Outcomes (1)

• Preoperative endocrine prognostic index score

  Up to 5 years

Secondary Outcomes (5)

• Pathological complete response rate

  Up to 5 years

• Change in Ki67

  At 4 weeks

• Residual cancer burden index

  Up to 5 years

• Rates of breast conservation therapy

  Up to 5 years

• Incidence of adverse events (NCI Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0)

  Up to 5 years

Study Arms (2)

Treatment A (endocrine therapy)

ACTIVE COMPARATOR

Patients receive standard of care endocrine therapy over 4 weeks for 1 cycle. Patients undergo breast tissue biopsy during the lead-in window/cycle 1. Patients then endocrine therapy and neratinib PO daily for 20 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo breast surgery during weeks 24-25. Patients undergo collection of blood samples every 4 weeks while on treatment, at weeks 4 and 24, and at time of surgery. Patients undergo mammogram, ultrasound, or breast MRI prior to surgery.

Procedure: Endocrine Therapy; Procedure: Biopsy of breast; Drug: Neratinib; Procedure: Biospecimen Collection; Procedure: Mammogram; Procedure: Magnetic Resonance Imaging; Procedure: Breast Surgery

Treatment B (endocrine therapy, neratinib)

EXPERIMENTAL

Patients receive standard of care endocrine therapy and neratinib PO over 4 weeks for 1 cycle. Patients undergo breast tissue biopsy during the lead-in window/cycle 1. Patients then continue endocrine therapy and neratinib PO daily for 20 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo breast surgery during weeks 24-25. Patients undergo collection of blood samples every 4 weeks while on treatment, at weeks 4 and 24, and at time of surgery. Patients undergo mammogram, ultrasound, or breast MRI prior to surgery.

Procedure: Endocrine Therapy; Procedure: Biopsy of breast; Drug: Neratinib; Procedure: Biospecimen Collection; Procedure: Mammogram; Procedure: Magnetic Resonance Imaging; Procedure: Breast Surgery; Procedure: Ultrasound

Interventions

Endocrine Therapy PROCEDURE

Undergo endocrine therapy

Treatment A (endocrine therapy); Treatment B (endocrine therapy, neratinib)

Biopsy of breast PROCEDURE

Undergo breast biopsy

Treatment A (endocrine therapy); Treatment B (endocrine therapy, neratinib)

Neratinib DRUG

Taken by mouth

Treatment A (endocrine therapy); Treatment B (endocrine therapy, neratinib)

Biospecimen Collection PROCEDURE

Undergo collection of blood samples

Treatment A (endocrine therapy); Treatment B (endocrine therapy, neratinib)

Mammogram PROCEDURE

Undergo Mammogram

Treatment A (endocrine therapy); Treatment B (endocrine therapy, neratinib)

Magnetic Resonance Imaging PROCEDURE

Undergo breast Magnetic Resonance Imaging

Treatment A (endocrine therapy); Treatment B (endocrine therapy, neratinib)

Breast Surgery PROCEDURE

Undergo Breast Surgery

Treatment A (endocrine therapy); Treatment B (endocrine therapy, neratinib)

Ultrasound PROCEDURE

Undergo Ultrasound

Treatment B (endocrine therapy, neratinib)

Eligibility Criteria

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

You may qualify if:

• Each patient will be entered into this study only if all of these criteria are met:
• Subjects aged 18 years or older at signing of informed consent.
• New diagnosis of clinical stage I-III HR+ histologically-proven (i.e. absent or decreased e-cadherin expression) invasive lobular carcinoma
• Synchronous breast tumors are permitted as long as the synchronous tumor is ER+ and HER2-negative.
• ER+ disease defined as ≥1% estrogen receptor (ER) positive consistent with current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or European Society of Medical Oncology (ESMO) guidelines)
• At the time of screening, histologically confirmed cancers in patients with previously documented activating HER2 mutation (see Appendix A) confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent laboratory.
• Archival tissue availability (if not available a fresh tumor biopsy will be required) and subject must agree to submission of sample for central testing
• Minimum tumor size of ≥1.5 cm by US, mammogram, MRI imaging, or clinical breast exam
• ECOG performance status 0 or 1
• Patients must have adequate hematologic, hepatic, and renal function. All laboratory tests must be obtained within 1 month of study entry. This includes:
• Estimated glomerular filtration rate of ≥50 mL/min
• Albumin ≥ 2.5 g/dL
• ANC ≥1500/mm\^3
• Platelet count ≥100,000/mm\^3
• HgB ≥ 9 g/dL

You may not qualify if:

• Evidence of distant metastatic disease
• Synchronous breast cancer that is estrogen receptor negative OR HER2-amplified OR requires treatment with neoadjuvant chemotherapy per the judgement of the treating physician
• Patients harboring ineligible somatic HER2 mutations, such as those that are subclonal in nature or those resulting in the expression of truncated proteins including alterations that result in premature stop codon or a change in reading frame (ie, frame shift mutations).
• Prior endocrine therapy for breast cancer within the last 2 years
• Women who are pregnant, are planning to become pregnant, or are breast-feeding
• Any investigational treatment for the current diagnosis of breast cancer
• HER2 amplification by FISH (HER2:CEP17 ratio \>2.0) or IHC (HER2 (3+)
• Hepatic function impairment as defined by AST or ALT \> 3x ULN OR total serum bilirubin \> 1.5 (in patients with known Gilbert syndrome, a total bilirubin of \> 3.0 x ULN or direct bilirubin \> 1.5 x ULN)
• Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn's disease, malabsorption, or Grade ≥2 National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events Version 4.0 \[CTCAE version 4.0\] diarrhea of any etiology at baseline.
• Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigator's judgment, make the patient inappropriate for this study.
• Known hypersensitivity to any component of the investigational product, required combination therapy, or loperamide.
• Unable or unwilling to swallow tablets.
• Unable or unwilling to complete study procedures such as research biopsies or imaging
• Any medical condition that in the judgement of the co-investigator would impair the patient's ability to complete the planned study therapy

Sponsors & Collaborators

• Vanderbilt-Ingram Cancer Center: lead
• National Cancer Institute (NCI): collaborator
• Puma Biotechnology, Inc.: collaborator

Study Sites (5)

Emory University/ Winship Cancer Institute

Atlanta, Georgia, 30322, United States

NOT YET RECRUITING

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

NOT YET RECRUITING

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37203, United States

RECRUITING

University of Texas, Southwestern

Dallas, Texas, 75390, United States

RECRUITING

Baylor College of Medicine

Houston, Texas, 77030, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Carcinoma, Lobular

Interventions

neratinib; Magnetic Resonance Spectroscopy; Mastectomy, Segmental; High-Energy Shock Waves

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Ductal, Lobular, and Medullary; Breast Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques; Mastectomy; Surgical Procedures, Operative; Ultrasonic Waves; Sound; Radiation, Nonionizing; Radiation; Physical Phenomena

Study Officials

• Laura Kennedy, MD, PhD

  Vanderbilt University/Ingram Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Vanderbilt-Ingram Services for Timely Access

CONTACT

800-811-8480; cip@vumc.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: June 15, 2023
• First Posted: June 26, 2023
• Study Start: May 30, 2024
• Primary Completion (Estimated): April 30, 2030
• Study Completion (Estimated): April 30, 2031
• Last Updated: September 9, 2025

Record last verified: 2025-09

Locations

US (5)