Capecitabine + Neratinib for Breast Cancer

Not currently recruiting at 9 trial locations

Overseen By Shanu Modi, MD

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Uncontrolled cardiac disease, Hepatitis B/C, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method of using two drugs, capecitabine (Xeloda) and neratinib (Nerlynx), to treat advanced breast cancer. Capecitabine has approval for this type of cancer, but neratinib remains under study. The trial aims to determine if a new dosing schedule is safer and effective for individuals with HER2 positive advanced breast cancer. Those with stage IV breast cancer and the HER2 positive protein marker, who have undergone previous treatments, might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you cannot have received any anti-cancer therapy, including chemotherapy, biological therapy, or hormonal therapy, within 14 days before starting the trial.

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

Research has shown that taking neratinib and capecitabine together generally results in manageable side effects. One study showed promising results for this combination against HER2-positive metastatic breast cancer. However, about 23% of patients experienced severe diarrhea, a common side effect with this drug combination.

The FDA has already approved capecitabine for treating advanced breast cancer, so its safety is well-established. Although neratinib remains experimental for this condition, its approval for other uses in Europe indicates it has undergone some safety studies.

Overall, while these drugs can cause strong side effects, previous studies have found them manageable in many cases. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Capecitabine and Neratinib for breast cancer treatment because these drugs work together to target cancer cells in a unique way. Unlike typical treatments that might focus on one pathway, this combination attacks cancer cells on multiple fronts: Capecitabine is a chemotherapy that disrupts DNA replication, while Neratinib inhibits a protein called HER2, which often fuels cancer growth. This dual action could potentially lead to more effective treatment outcomes, especially for patients with HER2-positive breast cancer, offering hope where other treatments might fall short.

What evidence suggests that this treatment might be an effective treatment for advanced breast cancer?

Research has shown that using capecitabine and neratinib together, as studied in this trial, may help treat advanced breast cancer, particularly in patients with HER2-positive metastatic breast cancer. Studies have found that this combination can extend the time patients live without their cancer worsening. For instance, one study reported that patients using this combination had a median time of 5.6 months before their cancer progressed, compared to 5.5 months with another treatment. Although more research is needed, these findings suggest that capecitabine and neratinib might offer more benefits than some current treatments for certain patients. ^{2 3 5 6 7}

Who Is on the Research Team?

Chau Dang, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with stage IV HER2-positive metastatic breast cancer who've had trastuzumab-based therapy. They can have up to four prior chemo treatments in the metastatic setting but not neratinib with capecitabine. Stable brain lesions are okay, and they must have a good heart function (LVEF ≥50%) and be able to perform daily activities (ECOG 0-1). Women must use effective contraception.

Inclusion Criteria

I have had previous cancer treatments, including neratinib and capecitabine.

My cancer can be measured or not, according to RECIST v1.1 standards.

I've had up to 4 chemotherapy treatments and trastuzumab but not neratinib for my metastatic cancer.

Exclusion Criteria

My heart's electrical cycle is longer than normal or I've had specific heart rhythm issues.

Pregnant patients or currently breast-feeding

I have not had a fever over 101.3°F or any unexplained infection in the last 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive capecitabine and neratinib in a 7/7 schedule to determine the maximum tolerated dose

1 year

Monthly visits (in-person) on Day 1 of each cycle

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 safety of neratinib combined with capecitabine at different doses in patients with advanced breast cancer. Capecitabine is FDA-approved; neratinib isn't yet approved for this use. The focus is on whether changing the dosing schedule can improve safety compared to standard schedules.

How Is the Trial Designed?

Group I: capecitabine 7/7 with neratinib Experimental Treatment 3 Interventions

In the phase I portion of the study, a 3+3 design will be used. Once the MTD is reached, the phase II portion will enroll up to 24 patients. Capecitabine will be taken orally in AM and PM (at the assigned dose per cohort) 7 days on and 7 days off. Neratinib is given as 240 mg daily continuously without stopping. A cycle is 28 days. Patients will be seen on Day 1 of each cycle (+/- 3 days). The MD has been determined as 240mg of neratinib and 1000mg BID of capecitabine.

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Puma Biotechnology, Inc.

Industry Sponsor

Trials

58

Recruited

10,100+

Published Research Related to This Trial

Capecitabine is a well-tolerated treatment for metastatic breast cancer, showing minimal side effects like myelosuppression and hair loss, which makes it a promising option for combination therapies with other anticancer drugs.

Ongoing phase II/III trials are investigating the use of capecitabine in early breast cancer treatment, and preliminary results indicate that it may provide significant benefits when used as part of adjuvant and neoadjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future options with capecitabine (Xeloda) in (neo)adjuvant treatment of breast cancer. Fumoleau, P., Cameron, D.[2019]

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]

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]

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]

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 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]

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 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 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]

Citations

1. 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, ...

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. 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, ...

4. 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 ...

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

Metastatic treatment | NERLYNX® (neratinib) tablets Nerlynx + capecitabine significantly improved median PFS vs lapatinib + capecitabine: 5.6 months with Nerlynx + capecitabine vs 5.5 months with lapatinib + ...

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

Neratinib for HER2-positive breast cancer with an overlooked ... The incidence of grade 3/4 diarrhea was 23%, as expected from the combination of neratinib plus capecitabine associated with GI effects. Phase 2.