Neratinib + Capecitabine for Breast Cancer

Overseen By Jamie Littleton

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Rochester

Must be taking: CDK4/6 inhibitors

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Capecitabine, Leptomeningeal disease, Hypertension, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

22 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new treatment combination for breast cancer that has spread to the brain. It targets patients whose cancer was initially classified as HER2-negative but actually shows abnormal HER2 activity, a protein influencing cancer growth. Participants will receive two drugs: neratinib (a targeted therapy) and capecitabine (a chemotherapy). Ideal candidates have breast cancer that has spread to the brain and exhibit unusual HER2 activity, as confirmed by specific tests. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking strong or moderate CYP3A4 inhibitors and inducers at least 14 days before registration. Additionally, there are specific waiting periods after your last dose of certain treatments, like chemotherapy, hormonal therapy, and targeted therapy, before you can join the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that combining neratinib with capecitabine has a manageable safety profile for patients with HER2-positive metastatic breast cancer. Earlier studies reported some side effects, but they were generally easy to manage. Common side effects included diarrhea and tiredness, typical for these treatments. Importantly, the FDA has already approved neratinib for treating certain breast cancers, indicating thorough safety evaluation. While more studies are needed to confirm its safety in specific situations, current evidence supports its use with capecitabine as having manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for breast cancer?

Unlike the standard treatments for breast cancer, which often rely on chemotherapy or hormone therapy, Neratinib and Capecitabine offer a targeted approach. Neratinib is an oral medication that works by specifically inhibiting the HER2 protein, which can be excessively active in some breast cancers, leading to uncontrolled cell growth. Capecitabine is a chemotherapy agent that becomes active once inside cancer cells, minimizing damage to healthy cells. Researchers are excited about this combination because it has the potential to more effectively target and treat HER2-positive breast cancer with potentially fewer side effects compared to traditional treatments.

What evidence suggests that this treatment might be an effective treatment for breast cancer with brain metastases?

Studies have shown that combining neratinib with capecitabine can effectively treat breast cancer, particularly in advanced stages. In patients with HER2-positive metastatic breast cancer, this combination extended survival by about 3.6 months without cancer progression. The response rate, or the percentage of patients whose cancer shrinks or disappears, reached up to 73% when neratinib was used with drugs like capecitabine. This trial will evaluate the combination of neratinib and capecitabine, which may help control cancer growth in patients with abnormal HER2 activity, even if their tumors do not test HER2-positive in standard assessments. ^{3 6 7 8 9}

Who Is on the Research Team?

Ajay Dhakal

Principal Investigator

University of Rochester

Are You a Good Fit for This Trial?

This trial is for adults with HER2-negative breast cancer that has spread to the brain, showing abnormal HER2 activity. Candidates must have measurable disease, be fit for a biopsy, and not have had certain treatments recently. They should not be pregnant or breastfeeding and must use reliable contraception.

Inclusion Criteria

It has been at least 28 days since my last fulvestrant dose.

My side effects from previous treatments have mostly gone away.

I understand this study is experimental and I can sign the consent form.

Exclusion Criteria

Known hypersensitivity to the study drugs or their components

I have not had whole-brain radiotherapy in the last 3 months.

I have a serious heart condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neratinib and capecitabine for HER2-negative metastatic breast cancer with brain metastases

24 months

Ongoing treatment with regular monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Capecitabine
• Neratinib

Trial Overview The study tests the combination of Neratinib (a targeted therapy) and Capecitabine (chemotherapy) in patients whose tumors are HER2-negative but show unusual HER2 activity. It aims to assess safety and effectiveness specifically for brain metastases from breast cancer.

How Is the Trial Designed?

Group I: Experimental: Capecitabine and Neratinib. Experimental Treatment 1 Intervention

Neratinib 240 mg PO QD Daily On-going Capecitabine 750 mg/m2 PO bid Days 1-14, 7 days off On-going

Capecitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in United States as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Canada as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Japan as Xeloda for:

• Colorectal cancer
• Breast cancer

Who Is Running the Clinical Trial?

University of Rochester

Lead Sponsor

Trials

883

Recruited

555,000+

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 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]

In a study of 72 patients with advanced HER2-positive breast cancer, neratinib, either alone or combined with capecitabine, demonstrated a median progression-free survival (PFS) of 5.9 months and an overall survival (OS) of 15.0 months, indicating its efficacy in a real-world setting.

Diarrhea was the most common side effect, affecting 64% of patients, but with proper anti-diarrheal prophylaxis, the treatment was generally well-tolerated, allowing for safe administration without severe toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib in advanced HER2-positive breast cancer: experience from the royal Marsden hospital. Cunningham, N., Shepherd, S., Mohammed, K., et al.[2022]

Neratinib, an oral pan-HER inhibitor, has been approved for use in combination with capecitabine for adult patients with advanced HER2-positive breast cancer who have undergone two or more prior anti-HER2 treatments, showing improved progression-free survival compared to lapatinib plus capecitabine.

This combination therapy is effective against brain metastases in HER2-positive breast cancer and is included in treatment guidelines, with ongoing trials further exploring its efficacy and safety in various combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib: an option for HER2-positive metastatic breast cancer. O'Shaughnessy, JA., O'Regan, R., Isaacs, C.[2021]

In a phase III trial involving 621 patients with HER2-positive metastatic breast cancer, those with CNS metastases showed improved progression-free survival (PFS) of 7.8 months with neratinib plus capecitabine compared to 5.5 months with lapatinib plus capecitabine.

Neratinib plus capecitabine also resulted in better CNS outcomes, with a lower incidence of progressive CNS disease (26.2% vs. 41.6%) and higher intracranial objective response rates (26.3% vs. 15.4%) compared to lapatinib plus capecitabine, without any new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial. Hurvitz, SA., Saura, C., Oliveira, M., et al.[2022]

In a phase I/II trial involving 105 patients, the combination of neratinib and capecitabine was found to have a manageable safety profile, with diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%) being the most common side effects.

The treatment demonstrated promising efficacy, achieving an objective response rate of 64% in patients without prior lapatinib exposure and 57% in those previously treated with lapatinib, indicating its potential as an effective option for HER2-positive metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. Saura, C., Garcia-Saenz, JA., Xu, B., et al.[2022]

In a phase III trial involving 621 patients with HER2-positive metastatic breast cancer, the combination of neratinib and capecitabine (N+C) showed significant improvement in progression-free survival (PFS) compared to lapatinib and capecitabine (L+C).

Higher levels of HER2 protein expression were linked to longer PFS and greater benefits from N+C treatment, while PIK3CA mutations were associated with shorter PFS, indicating that biomarker status can influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer. Saura, C., Matito, J., Oliveira, M., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8260518/

Neratinib + capecitabine sustains health-related quality of life ... Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens.

2. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)01242-0/fulltext

P90-6 Efficacy and safety of neratinib and capecitabine in ... The combination of Neratinib and Capecitabine has more benefit in improving PFS in HER2+ metastatic breast cancer patients. However, further studies are needed ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8232377/

The Clinical Efficacy and Safety of Neratinib in Combination ... The median duration of response (mDOR) was 4.8 months (95% CI, 1.9–9.5) and the median progression-free survival (mPFS) was 3.6 months (95% CI, ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1526820920302585

Final Efficacy Results of Neratinib in HER2-positive ... In HR+/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, ...

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

Neratinib for HER2-positive breast cancer with an overlooked ... Together, when used with vinorelbine, paclitaxel, or capecitabine for BC, the response rate of neratinib could be as high as 73% and varied ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25287822/

Safety and efficacy of neratinib in combination with ... Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic ...

7. nerlynxhcp.com nerlynxhcp.com/metastatic-breast-cancer/

Protect against progression in HER2+ metastatic breast cancer 1 Nerlynx + capecitabine significantly improved median PFS vs lapatinib + capecitabine: 5.6 months with Nerlynx + capecitabine vs 5.5 months with lapatinib + ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.20.00147

Phase III NALA Trial | Journal of Clinical Oncology Neratinib was approved by the European Medicines Agency for extended adjuvant treatment of early-stage, hormone receptor–positive, HER2-positive ...

9. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-metastatic-her2-positive-breast-cancer

FDA approves neratinib for metastatic HER2-positive ... Median OS was 21 months (95% CI: 17.7, 23.8) for patients receiving neratinib with capecitabine compared to 18.7 months (95% CI: 15.5, 21.2) for ...