Neratinib for Breast Cancer

Recruiting at 4 trial locations

Overseen By Vanderbilt-Ingram Services for Timely Access

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Vanderbilt-Ingram Cancer Center

Must not be taking: Hormonal contraceptives

Disqualifiers: Metastatic disease, HER2-amplified, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24-25 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, hormone-based oral contraceptives are not allowed during the study.

Is neratinib safe for human use?

Neratinib is generally safe for human use, but it commonly causes diarrhea, which can be severe and may lead to stopping the treatment. Other side effects include nausea, abdominal pain, fatigue, vomiting, rash, and muscle spasms, but these are usually manageable with dose adjustments and standard medical care. ^{1 2 3 4 5}

How is the drug neratinib different from other breast cancer treatments?

Neratinib is unique because it is an oral medication that irreversibly inhibits multiple human epidermal growth factor receptors (HER1, HER2, and HER4), and it is specifically used as an extended adjuvant therapy for early-stage HER2-positive breast cancer after trastuzumab treatment. It is the first of its kind approved in the EU for this setting, offering a novel option to reduce the risk of cancer recurrence. ^{1 2 3 6 7}

What data supports the effectiveness of the drug Neratinib for breast cancer?

Research shows that Neratinib significantly reduces the risk of breast cancer returning in patients with early-stage HER2-positive breast cancer who have completed previous treatment with trastuzumab. In a major study, patients taking Neratinib had a higher rate of being free from invasive disease compared to those taking a placebo. ^{1 2 3 4 8}

Who Is on the Research Team?

Laura Kennedy, MD, PhD

Principal Investigator

Vanderbilt University/Ingram Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with stage I-III HER2-mutated lobular breast cancer, who haven't had prior treatments. Participants must have a tumor size of at least 1.5 cm, be in good physical condition (ECOG 0 or 1), and agree to use contraception post-treatment. Excluded are those with HER2 amplification, significant liver function issues, known drug hypersensitivity, gastrointestinal disorders causing diarrhea, or any illness that could interfere with the study.

Inclusion Criteria

I can provide previous biopsy samples or agree to a new biopsy for testing.

My cancer is estrogen receptor positive.

My blood, liver, and kidney functions are all within normal ranges.

Exclusion Criteria

I cannot or do not want to follow the study's procedures.

My cancer does not have the specific HER2 mutations that qualify.

My cancer has spread to distant parts of my body.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive endocrine therapy and neratinib for 20 weeks, with breast surgery during weeks 24-25

24-25 weeks

Bi-weekly visits for blood samples and imaging

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Neratinib

Trial Overview The trial tests neratinib as an early treatment for patients with specific breast cancer before standard therapy. Neratinib is a kinase inhibitor aiming to slow down cancer by blocking abnormal proteins that encourage cell multiplication. The goal is to see if adding neratinib improves outcomes compared to just endocrine therapy.

How Is the Trial Designed?

Group I: Treatment B (endocrine therapy, neratinib) Experimental Treatment 8 Interventions

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.

Group II: Treatment A (endocrine therapy) Active Control 7 Interventions

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.

Who Is Running the Clinical Trial?

Vanderbilt-Ingram Cancer Center

Lead Sponsor

Trials

221

Recruited

64,400+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Puma Biotechnology, Inc.

Industry Sponsor

Trials

58

Recruited

10,100+

Published Research Related to This Trial

Neratinib is an oral, irreversible inhibitor targeting HER1, HER2, and HER4, specifically developed for treating HER2-positive breast cancer, and is approved in the USA for patients who have previously received trastuzumab-based therapy.

The drug is currently in various stages of clinical development for other cancers, including metastatic breast cancer and solid tumors like non-small cell lung cancer and glioblastoma, indicating its potential broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib: First Global Approval. Deeks, ED.[2019]

Neratinib significantly reduces the risk of invasive disease recurrence or death in women with early-stage HER2-positive breast cancer who have completed trastuzumab therapy, as shown in the ExteNET trial over 12 months, with benefits observed at both 2 and 5 years post-treatment.

Patients with hormone receptor-positive disease and those who start neratinib within 1 year of completing trastuzumab experience greater benefits, leading to its approval in the EU as an extended adjuvant therapy for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib in Early-Stage Breast Cancer: A Profile of Its Use in the EU. Dhillon, S.[2021]

Neratinib combined with paclitaxel showed a high overall response rate of 73% in patients with HER2-positive breast cancer, indicating its efficacy as a treatment option.

The combination therapy had manageable side effects, with common adverse events including diarrhea and peripheral sensory neuropathy, but no dose-limiting toxicities were observed during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Chow, LW., Xu, B., Gupta, S., et al.[2023]

In a phase I study involving 21 women with HER2-positive metastatic breast cancer, the combination of neratinib, trastuzumab, and paclitaxel showed significant clinical benefits, with 38% of patients achieving objective responses and 52% experiencing clinical benefit lasting at least 24 weeks.

The recommended dose of neratinib was found to be 200 mg/day, and while common side effects included diarrhea and fatigue, the implementation of prophylactic measures effectively managed severe diarrhea, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2‑positive breast cancer: an NSABP Foundation Research Program phase I study. Jankowitz, RC., Abraham, J., Tan, AR., et al.[2019]

Neratinib was approved by the FDA for the extended treatment of early-stage HER2-positive breast cancer, showing a significant improvement in invasive disease-free survival (iDFS) with a 2-year rate of 94.2% compared to 91.9% for placebo in a study of 2,840 women.

While neratinib is effective, it is associated with a high incidence of diarrhea (40% grade 3 or 4), which is the most common reason for treatment discontinuation, though most adverse effects are manageable and reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer. Singh, H., Walker, AJ., Amiri-Kordestani, L., et al.[2019]

Neratinib is an oral pan HER inhibitor that irreversibly blocks the activity of HER2 and other related receptors, showing promise in improving outcomes for patients with HER2-amplified breast cancer, which affects 20% to 25% of cases.

Current clinical trials are evaluating neratinib's safety and efficacy across various cancer types, including breast cancer, with a focus on its use in different treatment settings such as metastatic and adjuvant therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor. Tiwari, SR., Mishra, P., Abraham, J.[2019]

The TBCP-1 model developed in this study effectively mimics the spread of HER2-positive breast cancer to the brain, making it a valuable tool for testing new treatments and understanding the disease.

Neratinib not only inhibits tumor growth and metastasis, including to the brain, but also induces a unique form of cell death called ferroptosis, suggesting it could be a promising neoadjuvant therapy for patients with HER2-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2+ve breast cancer metastasis. Nagpal, A., Redvers, RP., Ling, X., et al.[2020]

Neratinib, a tyrosine kinase inhibitor, shows promising efficacy in treating HER2-positive breast cancer, with a higher response rate when used in combination with other therapies compared to monotherapy.

While neratinib is associated with a high incidence of adverse events, particularly diarrhea (83.9% of patients), these side effects are generally manageable, and the drug has been linked to improved survival outcomes in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy Profile of Neratinib: A Systematic Review and Meta-Analysis of 23 Prospective Clinical Trials. Tao, Z., Li, SX., Shen, K., et al.[2021]

Citations

1. New Zealand pubmed.ncbi.nlm.nih.gov

Neratinib: First Global Approval. [2019]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Neratinib in Early-Stage Breast Cancer: A Profile of Its Use in the EU. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2‑positive breast cancer: an NSABP Foundation Research Program phase I study. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2+ve breast cancer metastasis. [2020]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and Efficacy Profile of Neratinib: A Systematic Review and Meta-Analysis of 23 Prospective Clinical Trials. [2021]