Neratinib for Resistant or Recurrent Cancer

Not currently recruiting at 8 trial locations

Overseen By Sameer Farouk Sait

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Corticosteroids, Immunosuppressive therapy

Disqualifiers: Uncontrolled infection, Cardiac disease, others

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

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety of a drug called neratinib (Nerlynx) and assess its effects on patients with certain resistant or recurring cancers. It targets individuals with solid tumors, such as brain tumors or lymphoma, who have not found success with other treatments. Candidates who have tried at least one unsuccessful therapy and have available tissue for analysis might be suitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have had systemic chemotherapy or biologic therapy within 2 weeks or 5 half-lives of the agent used, whichever is shorter, before starting neratinib.

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

Research has shown that neratinib, a treatment tested for hard-to-treat or recurring cancer, has been used in other studies. These studies found diarrhea as the most common side effect of neratinib. Some patients, particularly Asian patients, also experienced skin issues. However, the treatment has proven effective in certain cancers, such as breast cancer, suggesting potential benefits. Since the trial is in its early stages, it primarily focuses on determining the right dose and monitoring side effects. While some safety information is available, researchers are still learning about how well patients tolerate neratinib. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Neratinib is unique because it targets cancer cells with a specific focus on blocking the HER2 protein, which is often overactive in certain resistant or recurrent cancers. Unlike standard treatments that may not specifically target HER2, neratinib offers a more precise approach, potentially leading to better outcomes for patients whose cancers have stopped responding to conventional therapies. Researchers are excited about neratinib because it represents a new mechanism of action that could provide an effective option for those who have limited choices due to the resistance or recurrence of their cancer.

What evidence suggests that neratinib might be an effective treatment for resistant or recurrent cancer?

Research has shown that neratinib, the investigational treatment in this trial, may help treat certain types of HER2-positive breast cancer. In some studies, neratinib improved survival rates and benefited at least 32% of patients with breast cancer. Another study found a 38% success rate with neratinib, with some patients experiencing complete or partial tumor shrinkage. Additionally, for patients whose cancer spread to the brain, those taking neratinib had a longer time before their cancer worsened compared to those on another treatment. While side effects like diarrhea occur, these findings suggest that neratinib could be effective for cancers that are hard to treat or have recurred. ^{6 7 8 9 10}

Who Is on the Research Team?

Tanya Trippett, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 3 to 21 with recurrent or resistant cancers like brain tumors, lymphoma, leukemia, and solid tumors. They must have tried at least one treatment before, be able to swallow tablets or use a feeding tube, and have no severe heart issues. Females of childbearing age and males must agree to effective contraception.

Inclusion Criteria

I can swallow pills or have a feeding tube.

Women who could become pregnant must have a negative pregnancy test within 7 days before starting neratinib therapy.

Female patients of reproductive potential must agree and commit to the use of a highly effective method of contraception, as determined to be acceptable by the investigator, from the time of informed consent until 28 days after the last dose of the investigational product

Exclusion Criteria

Pregnant or breast-feeding women

I am not being treated for another cancer, except for skin cancer or early-stage cervical cancer.

I have not had chemotherapy, biologic therapy, or radiation recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Phase I)

Neratinib is tested in groups of 3-6 patients to establish the maximum tolerated dose (MTD)

Variable, until MTD is established

Treatment (Phase II)

Determine whether the MTD shows a response to the tumor

1 year

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 study is testing the safety of different doses of Neratinib on young patients with cancer that has returned or didn't respond to previous treatments. It aims to discover both positive and negative effects this drug may have on their condition.

How Is the Trial Designed?

Group I: Neratinib Experimental Treatment 1 Intervention

There are 2 parts to this study: a Phase I part and a Phase II part. The Phase I portion is known as the dose escalation phase where neratinib will be tested in groups of 3-6 patients to establish the maximum tolerated dose (MTD). The phase II portion will determine whether the MTD shows a response to the tumor.

Neratinib is already approved in United States, European Union for the following indications:

Approved in United States as Nerlynx for:

• Extended adjuvant treatment of women with early-stage HER2-positive breast cancer

Approved in European Union as Nerlynx for:

• Extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Milton S. Hershey Medical Center

Collaborator

Trials

515

Recruited

2,873,000+

M.D. Anderson Cancer Center

Collaborator

Trials

3,107

Recruited

1,813,000+

Stanford University

Collaborator

Trials

2,527

Recruited

17,430,000+

Arkansas Children's Hospital Research Institute

Collaborator

Trials

141

Recruited

5,025,000+

Alberta Children's Hospital

Collaborator

Trials

58

Recruited

44,700+

Phoenix Children's Hospital

Collaborator

Trials

78

Recruited

5,014,000+

University of Texas

Collaborator

Trials

193

Recruited

143,000+

Published Research Related to This Trial

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]

Neratinib has been shown to improve 2-year invasive disease-free survival in early-stage HER2-positive breast cancer patients after trastuzumab treatment, particularly in HER2+/HR+ tumors, according to the phase III ExteNET trial.

In phase II trials, neratinib demonstrated efficacy as both a standalone treatment and in combination with other therapies for HER2-positive metastatic breast cancer, with manageable side effects like diarrhea through early prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. Kourie, HR., Chaix, M., Gombos, A., et al.[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]

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]

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, 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10559443/

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%, ...

2. 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, ...

3. onclive.com onclive.com/view/neratinib-generates-cns-responses-across-her2-breast-cancer-brain-metastases-subgroups

Neratinib Generates CNS Responses Across HER2+ ... In the NALA CNS subgroup, the median CNS progression-free survival was 12.4 months in the neratinib arm vs 8.3 months in the lapatinib arm. At 1 ...

4. 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 ...

5. nature.com nature.com/articles/s41416-024-02665-z

Neratinib could be effective as monotherapy or in ... This study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low breast cancers.

6. ema.europa.eu ema.europa.eu/en/documents/product-information/nerlynx-epar-product-information_en.pdf

Nerlynx, INN-neratinib - European Medicines Agency Pooled safety data of 1 710 patients treated with Nerlynx monotherapy showed a higher incidence of dermatologic toxicities in Asian patients (57.1%) versus ...

7. 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, ...

8. 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%, ...

9. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)01241-9/fulltext

P90-3 Safety and efficacy of neratinib in patients with HER ... According to the clinical trial, Neratinib proved effective against breast cancer patients. In one of the clinical trials, showing that the medications were ...

10. nerlynxhcp.com nerlynxhcp.com/pdf/NALA-Trial-mBC-Brochure.pdf/

NERLYNX® NALA Trial (mBC) Brochure NERLYNX safety for patients with. HER2+ mBC in NALA1. NERLYNX + capecitabine ... A phase 2 trial of neratinib and capecitabine for patients with HER2+ breast ...