Neratinib + Capecitabine for Breast Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Ajay Dhakal

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of neratinib and capecitabine for breast cancer patients with brain metastases. These patients' tumors did not show HER2 activity with usual tests but did with a special test, suggesting they might benefit from this treatment. Neratinib blocks growth proteins in cancer cells, while capecitabine kills them. Neratinib is approved for use in combination with capecitabine for advanced HER2-positive breast cancer.

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.

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

Research shows that the combination of Neratinib and Capecitabine has been effective in improving progression-free survival (the time during which the cancer does not get worse) in patients with HER2-positive metastatic breast cancer, as demonstrated in the NALA study. ^{1 2 3 4 5}

Is the combination of Neratinib and Capecitabine safe for humans?

Neratinib, when used with Capecitabine, has shown acceptable safety in patients with HER2-positive breast cancer, though diarrhea is a common side effect. Other side effects include nausea, abdominal pain, fatigue, and vomiting, but these are generally manageable with standard care. ^{1 2 3 4 6}

How is the drug combination of Neratinib and Capecitabine unique for treating breast cancer?

The combination of Neratinib and Capecitabine is unique because it is an oral treatment specifically for HER2-positive metastatic breast cancer, especially effective for patients who have already tried other anti-HER2 treatments. It is notable for its ability to improve progression-free survival and is effective against brain metastases, which is a challenging aspect of this cancer type. ^{2 3 4 7 8}

Research Team

Ajay Dhakal

Principal Investigator

University of Rochester

Eligibility Criteria

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

I am 18 years old or older.

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

My side effects from previous treatments have mostly gone away.

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.

Trial Timeline

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

Treatment Details

Interventions

• Capecitabine (Antimetabolite)
• Neratinib (Tyrosine Kinase Inhibitor)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Kevin Koch

University of Rochester

Chief Executive Officer since 2020

PhD in Organic Chemistry from the University of Rochester

Brian Druker

University of Rochester

Chief Medical Officer since 2015

MD from Harvard Medical School

Findings from Research

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 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]

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]

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, 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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Neratinib in advanced HER2-positive breast cancer: experience from the royal Marsden hospital. [2022]

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

Neratinib: First Global Approval. [2019]

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

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

4. United States 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. [2022]

5. United States 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. [2023]

6. 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]

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

Neratinib: an option for HER2-positive metastatic breast cancer. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial. [2022]