HKI-272 for Breast Cancer

Not currently recruiting at 18 trial locations

Overseen By Rachel Freedman, M.D., M.P.H.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Enzyme-inducing antiepileptics

Disqualifiers: Pregnancy, Active infection, Cardiac arrhythmia, 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: 2

Duration: 4 weeks per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of a drug called neratinib (also known as HKI-272) on breast cancer that has spread to the brain. Taken orally, neratinib may help by blocking certain proteins that promote cancer cell growth. The trial also examines how previous treatments might have affected cognitive function and how much neratinib reaches the brain. It is suitable for individuals with HER2-positive breast cancer that has metastasized to the brain, including those who have previously received treatments like lapatinib or trastuzumab. 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 a 2-week period without chemotherapy, certain targeted therapies, or radiation before starting. Hormonal therapy must be stopped during the study, but bisphosphonates can continue if started before neratinib. Some epilepsy medications are not allowed.

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

Research shows that neratinib, the treatment in this trial, has potential in treating HER2-positive breast cancer, even if it spreads to the brain. Studies have found that neratinib, whether used alone or with capecitabine, is generally well-tolerated by patients, including those with brain involvement.

Some side effects, common in cancer treatments, have been reported. These may include diarrhea, nausea, and tiredness, but they are usually manageable. Importantly, doctors have used this treatment in other studies for several years, gaining a good understanding of its safety.

Overall, while some side effects require consideration, research suggests that neratinib is a relatively safe option for patients with advanced breast cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about HKI-272, also known as Neratinib, because it offers a novel approach to treating breast cancer with brain metastases. Unlike standard treatments like Lapatinib and Capecitabine, Neratinib is a potent inhibitor of the HER2 receptor, which plays a critical role in the growth of some breast cancers. This targeted action may result in more effective management of cancer that has spread to the brain. Additionally, Neratinib's oral administration makes it a convenient option compared to traditional intravenous therapies, potentially improving patient compliance and quality of life.

What evidence suggests that this trial's treatments could be effective for breast cancer that has spread to the brain?

Research has shown that neratinib can help treat HER2-positive breast cancer that has spread to the brain. In this trial, participants in different cohorts will receive neratinib in various combinations. Studies have found that neratinib, especially when combined with capecitabine, can better control cancer in the brain and central nervous system (CNS). One study found that patients taking neratinib experienced longer periods without cancer growth or spread. Additionally, neratinib reduced the need for further CNS treatments in patients with brain tumors. These findings suggest that neratinib might help stabilize or shrink brain tumors in people with this type of breast cancer. ^{2 3 5 6 7}

Who Is on the Research Team?

Rachel Freedman, M.D., M.P.H.

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with invasive breast cancer that has spread to the brain (HER2-positive). Participants must have measurable brain lesions, not be on certain treatments like neratinib before, and can't be taking concurrent cancer therapies. Pregnant or breastfeeding individuals, those with specific medical conditions or allergies to similar drugs, and patients who cannot tolerate oral medications are excluded.

Inclusion Criteria

No increase in corticosteroid dose in the week prior to baseline brain MRI.

No prior therapy with neratinib is allowed.

For cohort 1, you need to have a brain lesion that can be measured and is at least 10 millimeters long according to local radiology review. It's okay if you don't have measurable non-brain disease for this study.

Exclusion Criteria

You are receiving other treatments for cancer at the same time as this study, except for certain bone-strengthening medications.

If you have a long-term condition that causes moderate or severe diarrhea, you cannot participate.

Pregnant or breastfeeding individuals are excluded from the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neratinib daily, with additional treatments depending on cohort, for 4-week cycles

4 weeks per cycle

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments including physical exams, imaging, and blood tests

1 month after treatment completion

1 visit (in-person)

Long-term follow-up

Participants' medical conditions are tracked for up to two years post-treatment via phone or mail

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• HKI-272

Trial Overview The study tests how well neratinib works on breast cancer in the brain. It's an oral drug blocking proteins involved in cancer cell growth. The trial examines its effect on tumor size/stability and cognitive function impact while monitoring how much reaches the central nervous system.

How Is the Trial Designed?

Group I: Cohort 3a/3b Active Control 1 Intervention

Cohort 3a will be made up of participants with No Prior Lapatinib Treatment. They will receive Neratinib 240mg Orally daily and 750mg/m2 Capecitabine twice per day for 14 days followed by 7 days rest. Cohort 3b will be made of of participants with Prior Lapatinib Treatment. Cohort 3b participants will receive Neratinib 240mg Orally daily and 750mg/m2 Capecitabine twice per day for 14 days followed by 7 days rest.

Group II: Cohort 4a/4b/4c Active Control 2 Interventions

Cohort 4a will be made up of participants with previously untreated brain metastases. They will receive Neratinib 160mg Orally daily and T-DM1 3.6mg/kg IV every 3 weeks. Cohort 4b will be made up of participants with progressive brain metastases. They will receive Neratinib 160mg Orally daily and T-DM1 3.6mg/kg IV every 3 weeks. Cohort 4c will be made up of participants with progressive brain metastases and prior T-DM1. They will receive Neratinib 160mg Orally daily and T-DM1 3.6mg/kg IV every 3 weeks.

Group III: Cohort 1 Active Control 1 Intervention

Patients With Progressive Brain Metastases Intervention: HKI-272 (Neratinib)340 mg orally, once daily.

Group IV: Cohort 2 Active Control 1 Intervention

Patients Who Are Candidates For Craniotomy. Intervention: HKI-272 (Neratinib) 240 mg orally, once daily. Surgical resection (biopsy). Neratinib concentrations from craniotomy specimen, CSF, plasma Neratinib.

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Translational Breast Cancer Research Consortium

Collaborator

Trials

27

Recruited

3,100+

Puma Biotechnology, Inc.

Industry Sponsor

Trials

58

Recruited

10,100+

Published Research Related to This Trial

In a study of 181 breast cancer patients, low expression of the protein p27kip1 was found in 66.9% of cases, and higher levels were associated with better disease-free survival, indicating a potential link between p27kip1 levels and tumor behavior.

Despite the correlation between p27kip1 expression and various tumor characteristics, it was not determined to be an independent prognostic factor, suggesting that while it may influence cancer progression, other factors also play significant roles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prognostic significance of cyclin-dependent kinase inhibitor p27kip1 expression in human breast cancer]. Wu, J., Shen, Z., Shao, Z.[2006]

Citations

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

Neratinib Generates CNS Responses Across HER2+ ... Neratinib-containing combinations are consistently effective across CNS end points in patients with HER2-positive breast cancer brain metastases.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8342591/

Efficacy of Neratinib Plus Capecitabine in the Subgroup of ... We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.20.02385

Neratinib in HER2-Positive Breast Cancer With Brain ... Neratinib improved progression-free survival in the entire trial cohort and reduced the need for CNS intervention in patients with brain ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01494662

NCT01494662 | HKI-272 for HER2-Positive Breast Cancer ... The purpose of this research study is to determine how well neratinib works in treating breast cancer that has spread to the brain.

5. clinical-breast-cancer.com clinical-breast-cancer.com/article/S1526-8209(20)30258-5/fulltext

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 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9382612/

Neratinib in advanced HER2-positive breast cancer Neratinib monotherapy or in combination with capecitabine is a useful treatment for patients with and without brain metastases.

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

Neratinib for HER2-positive breast cancer with an overlooked ... Neratinib has the potential to effectively control and prevent brain metastasis in patients with advanced BC, providing a therapeutic strategy for HER2- ...