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 trial explores the effectiveness of the drug neratinib when administered before the main treatment for certain types of breast cancer. It specifically targets patients with stage I-III HER2-mutated lobular breast cancer. Neratinib, a kinase inhibitor, helps stop cancer cells from growing and spreading. Individuals with newly diagnosed invasive lobular breast cancer that tests positive for HER2 mutations and estrogen receptors (ER+) might be suitable candidates. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that neratinib, a treatment under study for breast cancer, has some known side effects. The most common is stomach and digestion issues, particularly diarrhea, affecting many patients taking the drug. Other studies have found neratinib generally safe for patients, including older adults with a specific type of breast cancer. It's important to note that this treatment is in a phase 2 trial, so research is still ongoing to fully understand its safety and effectiveness. However, the FDA has already approved neratinib for other types of breast cancer, indicating it has passed some safety checks for those conditions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Neratinib is unique because it specifically targets and inhibits the HER2 protein, which can be overactive in some breast cancers, leading to tumor growth. Unlike standard treatments like chemotherapy or endocrine therapy alone, neratinib works by blocking signals that encourage cancer cell proliferation. Researchers are excited about neratinib because it offers a targeted approach that could potentially improve outcomes and reduce recurrence rates, particularly for patients with HER2-positive breast cancer. Additionally, when combined with endocrine therapy, neratinib provides a dual attack on cancer cells, offering a comprehensive treatment strategy.

What evidence suggests that neratinib might be an effective treatment for HER2 mutated lobular breast cancer?

Research has shown that neratinib may help treat certain breast cancers. One study found that neratinib increased the time patients with HER2-positive breast cancer remained free from cancer spreading when used after trastuzumab-based therapy. More patients stayed cancer-free compared to those who didn't take neratinib. Another study found that 38% of patients experienced tumor shrinkage or stability. In this trial, participants in Treatment B will receive endocrine therapy combined with neratinib, while those in Treatment A will receive endocrine therapy alone. These results suggest that neratinib can be a valuable addition to standard treatments in slowing or stopping cancer growth. ^{2 6 7 8 9}

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.

Known hypersensitivity to investigational product or required therapy

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 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 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]

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]

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]

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 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]

Citations

1.

sciencedirect.com

sciencedirect.com/science/article/pii/S1526820920302585

Final Efficacy Results of Neratinib in HER2-positive ...

The ExteNET trial demonstrated that neratinib given for 1 year following trastuzumab-based therapy significantly improved iDFS in patients with HER2+ breast ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4981294/

Neratinib in HER-2-positive breast cancer: results to date and ...

Efficacy in 15 evaluable patients demonstrated an ORR 38% (CR 2 and PR 6) and overall clinical benefit 52% (including CR, PR and stable disease ⩾24 weeks). It ...

3.

ejcancer.com

ejcancer.com/article/S0959-8049(23)00063-1/fulltext

Overall survival with neratinib after trastuzumab-based ...

With 91% of patients in the neratinib group alive after a median follow-up of 8.1 years in ExteNET and no detrimental effect versus placebo on ...

4.

nerlynxhcp.com

nerlynxhcp.com/

For healthcare professionals NERLYNX® (neratinib) tablets

The primary endpoint of ExteNET was iDFS at 2 years. Results for iDFS in the ITT population (N=2840): 94.2% (95% CI: 92.6%-95.4%) with Nerlynx vs 91.9% (95% CI: ...

5.

targetedonc.com

targetedonc.com/view/8-year-os-similar-between-neratinib-and-placebo-in-her2-breast-cancer

8-Year OS Similar Between Neratinib and Placebo in ...

The 8-year OS rates between the neratinib group vs placebo group was 90.1% (95% CI, 88.3%-91.6%) vs 90.2% (95% CI, 88.4%-91.7%), respectively ...

6.

molmed.biomedcentral.com

molmed.biomedcentral.com/articles/10.1186/s10020-023-00736-0

Neratinib for HER2-positive breast cancer with an overlooked ...

The most common AE of neratinib was gastrointestinal toxicity such as diarrhea; in patients with BC, the response rate of neratinib was ≥ 32%, ...

7.

nerlynxhcp.com

nerlynxhcp.com/metastatic-breast-cancer/

Protect against progression in HER2+ metastatic breast cancer 1

Explore NERLYNX efficacy, study design, safety, and dosing information for metastatic HER2+ breast cancer treatment.

8.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8580161/

Phase II Study of Neratinib in Older Adults with HER2 ...

Conclusions: Neratinib was safe in this population of older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer (BC). Higher CARG toxicity ...

9.

cancerletter.com

cancerletter.com/clinical-roundup/20201120_6e/

Neratinib in HER2-positive HR-negative early stage breast ...

Nerlynx (neratinib) demonstrates a 5.1% invasive disease-free survival benefit versus placebo in the phase III ExteNET trial evaluating Nerlynx ...