Neratinib or Neratinib + Palbociclib for Cancer

Recruiting at 172 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Tyrosine kinase inhibitors, CDK4/6 inhibitors

Disqualifiers: Breast cancer, RB1 loss, 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: 4

Duration: Up to 2 years

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of the drug neratinib alone versus its combination with palbociclib in treating solid tumors with excess HER2 protein. Both drugs are kinase inhibitors that block certain proteins to prevent cancer cells from spreading. Individuals with HER2-positive solid tumors (excluding breast cancer) that have recurred or are persistent may qualify, particularly if they have not tried certain similar treatments. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop any cancer-directed therapy at least 3 weeks before joining, and for oral therapies, you need to stop them for a period equal to or greater than 5 times the drug's half-life. You cannot have had prior therapy with certain drugs like neratinib or CDK4/6 inhibitors.

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

Research has shown that neratinib is usually well-tolerated, though some patients may experience stomach issues like diarrhea. In studies with breast cancer patients, neratinib achieved a response rate of 32% or more. When combined, neratinib and palbociclib effectively killed cancer cells, suggesting potential in managing HER2-positive cancers, though limited safety data exists for this combination.

Palbociclib alone is known to slow disease progression when used with certain hormone therapies, indicating potential benefits when combined with neratinib. While both treatments are still under evaluation for safety and effectiveness in this trial, previous research and their use in other conditions suggest they are reasonably safe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a novel approach to targeting cancer cells. Unlike most treatments that generally target one pathway, Neratinib is a targeted therapy that blocks the HER2 receptor, crucial in certain types of breast cancer. When combined with Palbociclib, a CDK4/6 inhibitor, it offers a dual-action approach that not only targets the HER2 pathway but also disrupts the cell cycle, potentially preventing cancer cells from multiplying. This combination could enhance effectiveness and provide an option for patients who may not respond well to existing therapies.

What evidence suggests that this trial's treatments could be effective for HER2 positive solid tumors?

Research has shown that neratinib, which participants in this trial may receive, may help treat HER2-positive cancers. One study found that patients who took neratinib after their usual treatment lived slightly longer over eight years. This trial will also test a combination of neratinib with palbociclib, another treatment option in this trial. Studies suggest that adding palbociclib can slow the cancer's growth. This combination targets HER2, a protein that helps cancer cells grow, which may shrink or stabilize tumors. These findings offer hope for people with HER2-positive cancers seeking effective treatments. ^{2 6 7 8 9}

Who Is on the Research Team?

Haider Mahdi, MD

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for patients with HER2 positive solid tumors, excluding breast cancer. Participants can have up to five prior treatments and treated brain metastases if stable for 3+ months without steroids. They must not have leptomeningeal disease or RB1 loss/mutation, agree to a biopsy (or provide recent tissue), and show measurable disease.

Inclusion Criteria

Not pregnant and not nursing

No history of allergic reaction to study agents or similar compounds

Total bilirubin level ≤ 1.5 x institutional ULN

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive neratinib alone or in combination with palbociclib in 28-day cycles

Up to 2 years

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Every 3 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Neratinib
• Palbociclib

Trial Overview The study compares the effectiveness of neratinib alone versus its combination with palbociclib in treating HER2 positive solid tumors. These kinase inhibitors block proteins that cause cancer cells to multiply, potentially shrinking or stabilizing the tumor.

How Is the Trial Designed?

Group I: Arm II (neratinib maleate, palbociclib) Experimental Treatment 8 Interventions

Patients receive neratinib maleate PO QD on days 1-14 of cycle 0 in the absence of disease progression or unacceptable toxicity. Patients then receive neratinib maleate PO QD on days 1-28 and palbociclib PO QD on days 1-21 of each subsequent cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening and on study, and CT or MRI and collection of blood samples throughout the trial. Patients may also undergo tumor biopsy during screening and on study.

Group II: Arm I (neratinib maleate) Active Control 7 Interventions

Patients receive neratinib maleate PO QD on days 1-14 of cycle 0 in the absence of disease progression or unacceptable toxicity. Patients then receive neratinib maleate PO QD on days 1-28 of each subsequent cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience progression may crossover to Arm II. Patients undergo ECHO or MUGA during screening and on study, and CT or MRI and collection of blood samples throughout the trial. Patients may also undergo tumor biopsy during screening and on study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

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]

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]

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 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 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 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 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 investigating treatments for HER2+ breast cancer and triple-negative breast cancer (TNBC), combining neratinib with everolimus (an mTOR inhibitor) or trametinib (a MEK inhibitor) significantly enhanced tumor growth inhibition compared to using neratinib alone, achieving up to 81% inhibition in xenograft models.

The combination therapies not only improved anti-tumor effects but also activated apoptosis pathways, indicating a potential mechanism for their enhanced efficacy, making these combinations promising options for treating these aggressive breast cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PI3K and MAPK Pathways as Targets for Combination with the Pan-HER Irreversible Inhibitor Neratinib in HER2-Positive Breast Cancer and TNBC by Kinome RNAi Screening. Lee, J., Liu, H., Pearson, T., et al.[2021]

Citations

1. 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, ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33183970/

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

Overall survival with neratinib after trastuzumab-based ... Eight-year overall survival rates were 90.1% (95% CI 88.3–91.6) with neratinib and 90.2% (95% CI 88.4–91.7) with placebo (stratified hazard ...

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

Neratinib for HER2-positive breast cancer with an overlooked ... The ExteNET study showed that neratinib given within 1 year of trastuzumab significantly improved iDFS in patients with HER2-positive BC, and ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10398073/

Cost-Effectiveness Analysis of Adjuvant Neratinib ... Based on 5-year data from ExteNET, neratinib following adjuvant trastuzumab is not projected to be cost-effective, even among those patients shown to derive the ...

6. 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%, ...

7. esmoopen.com esmoopen.com/article/S2059-7029(24)00875-5/fulltext

119P HER2+ early-stage breast cancer treated with ... Here we present data on neratinib treatment patterns, safety, and 2-year effectiveness. Results. As of Jan 31, 2023, 108 patients were included in the full ...

8. 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.

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 ...