Neratinib + Endocrine Therapy + Trastuzumab for Breast Cancer

Recruiting at 3 trial locations

Overseen By Amber Ryba

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ruth O'Regan

Must be taking: Aromatase inhibitors

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Metastatic disease, Active infection, 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: 1

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of new and existing drugs to treat a specific type of breast cancer before surgery. The treatment uses neratinib (Nerlynx), an aromatase inhibitor (such as anastrozole or letrozole), and trastuzumab (Herceptin) over 24 weeks to evaluate their effectiveness in shrinking tumors in HER2-positive, ER-positive breast cancer patients. The trial begins with different drug combinations for the first three weeks, followed by the full combination for the remainder. Postmenopausal women with HER2-positive, ER-positive breast cancer larger than 10mm may be suitable candidates for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot use moderate or strong CYP3A4 inhibitors or inducers during the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

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

Research has shown that neratinib, one of the treatments in this trial, is generally safe for patients with HER2-positive breast cancer. Many patients have used it without major problems, though some have experienced diarrhea, the most common side effect, which is usually manageable.

Aromatase inhibitors, such as letrozole and anastrozole, are also part of the trial. These medications have been widely used and are well-tolerated by most patients, helping to lower the risk of cancer recurrence. Some patients might experience joint pain or hot flashes, but these effects are usually mild.

Trastuzumab is another treatment option in the trial and has been used to treat early-stage HER2-positive breast cancer. It has a strong record of improving survival rates. Side effects can include fever and chills, but serious effects are rare.

Overall, these treatments have undergone thorough testing and are considered safe, with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatment options for breast cancer that often involve separate use of endocrine therapy and HER2 inhibitors, this new combination treatment is unique because it integrates Neratinib with endocrine therapy (Anastrozole or Letrozole) and Trastuzumab. Researchers are excited about this approach because Neratinib is a potent, irreversible pan-HER inhibitor which could provide a more comprehensive blockade of the HER2 pathway, potentially leading to better outcomes. Additionally, the combination aims to target cancer cells more effectively by addressing both hormonal pathways and HER2 overexpression simultaneously, which is a strategic move not typically seen in current treatment protocols.

What evidence suggests that this trial's treatments could be effective for breast cancer?

Research has shown that neratinib may effectively treat HER2-positive breast cancer. In some studies, about 38% of patients showed noticeable improvement, and 52% experienced benefits such as disease stabilization. Aromatase inhibitors, like letrozole and anastrozole, have also proven effective. They significantly reduce the risk of breast cancer recurrence and are commonly used for hormone receptor-positive breast cancer. Trastuzumab is a well-known treatment that reduces the recurrence of HER2-positive breast cancer and improves survival rates. In this trial, participants will receive different combinations of these treatments, which may enhance their effectiveness against certain types of breast cancer. ^{4 6 7 8 9}

Who Is on the Research Team?

Ruth O'Regan, MD

Principal Investigator

University of Rochester

Are You a Good Fit for This Trial?

This trial is for postmenopausal women over 18 with stage I-III invasive breast cancer that's larger than 10mm, HER2-positive, and ER-positive. Candidates must have a good performance status, resectable cancer suitable for pre-op therapy, agree to biopsies, and have proper heart function. Excluded are those needing strong CYP3A4 inhibitors/inducers or with active infections, recent major surgery side effects, GI issues affecting drug absorption, metastatic disease or certain cardiovascular conditions.

Inclusion Criteria

You have invasive breast cancer that is stage I, II, or III and is larger than 10 millimeters.

You have been tested positive for HER2 according to the latest ASCO-CAP criteria.

Written informed consent and HIPAA authorization for release of personal health information

Exclusion Criteria

You cannot take certain medications that affect the way your body processes other drugs during the study.

You have a serious infection that needs treatment throughout your body.

Treatment with any investigational drug within 14 days prior to registration or within 5 half-lives of the investigational product, whichever is longer

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Participants receive either Neratinib, Letrozole or Anastrozole, or a combination of Neratinib and an aromatase inhibitor for the first 3 weeks

3 weeks

1 visit (in-person) for breast biopsy prior to Day 1 of week 4

Main Treatment

Participants receive Neratinib, Letrozole or Anastrozole, and Trastuzumab for 24 weeks prior to surgery

24 weeks

Post-Surgery Treatment

Participants receive standard of care HER2-directed and endocrine therapy at the treating physician's discretion

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Anastrozole
• Letrozole
• Neratinib
• Trastuzumab

Trial Overview

The study tests the combination of Neratinib (a targeted therapy), an aromatase inhibitor (Letrozole or Anastrozole), and Trastuzumab (an immune therapy) given for 24 weeks before surgery in treating HER2-positive breast cancer. The initial three weeks involve varying combinations of these drugs followed by standard care after surgery.

How Is the Trial Designed?

Group I: A Experimental Treatment 3 Interventions

Weeks 1-3\* patients receive either (a) Neratinib, (b) Letrozole or Anastrozole or (c) Neratinib + Letrozole or Anastrozole Weeks 4-24 patients receive Neratinib + Letrozole or Anastrozole and Trastuzumab \*Starting drug intervention varies for the first 3 weeks depending on arms: a, b, and c by randomization.

Anastrozole is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Arimidex for:

• Breast cancer
• Early breast cancer in postmenopausal women

Approved in United States as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer

Approved in Canada as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• Treatment of postmenopausal women with hormone receptor-positive advanced breast cancer

Approved in Japan as Arimidex for:

• Breast cancer

Who Is Running the Clinical Trial?

Ruth O'Regan

Lead Sponsor

Trials

1

Recruited

30+

Puma Biotechnology, Inc.

Industry Sponsor

Trials

58

Recruited

10,100+

University of Rochester

Collaborator

Trials

883

Recruited

555,000+

Published Research Related to This Trial

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 II study involving 103 women with advanced HER2+ breast cancer, the combination of enzalutamide and trastuzumab showed a clinical benefit rate of 24% at 24 weeks, indicating some patients experienced durable disease control despite prior treatments.

The treatment was generally well tolerated, with 94% of patients experiencing side effects, primarily fatigue, but serious adverse events were relatively low, suggesting a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer. Wardley, A., Cortes, J., Provencher, L., et al.[2021]

In a phase III trial involving postmenopausal women with HER2 and hormone receptor co-positive metastatic breast cancer, the combination of trastuzumab and anastrozole significantly improved median progression-free survival compared to anastrozole alone.

The combination therapy also showed higher overall response and clinical benefit rates without any new or unexpected adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab : in HER2 and hormone receptor co-positive metastatic breast cancer. Orman, JS., Perry, CM.[2021]

Trastuzumab significantly improves treatment outcomes for women with HER2 positive breast cancer, as shown in four large randomized trials.

The main safety concerns associated with trastuzumab are serious infusion-related reactions and cardiotoxicity, highlighting the need to weigh the benefits against these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab in the adjuvant treatment of breast cancer. Svetlovska, D., Mardiak, J., Kristova, V.[2016]

Neratinib, an irreversible HER kinase inhibitor, shows promise as an extended adjuvant therapy for patients with early-stage HER2+ breast cancer who have already received trastuzumab, potentially improving outcomes for those at risk of relapse.

In Phase II trials, neratinib demonstrated effectiveness in treating trastuzumab-resistant metastatic HER2+ breast cancer and HER2-mutated breast cancers, suggesting it could be a valuable treatment option for patients with limited current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of neratinib in HER2-driven breast cancer. Cherian, MA., Ma, CX.[2020]

In a phase III trial, lapatinib combined with letrozole significantly improved progression-free survival (PFS) in postmenopausal women with HER2-negative, low estrogen receptor (ER) expression metastatic breast cancer, showing a median PFS of 13.6 months compared to 6.7 months with letrozole alone.

No benefit from lapatinib was observed in patients with higher ER expression, indicating that low ER levels may be a key factor in determining which patients benefit from this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative ER and PgR assessment as predictors of benefit from lapatinib in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Finn, RS., Press, MF., Dering, J., et al.[2018]

Letrozole, a third-generation aromatase inhibitor, has been shown to be more effective than tamoxifen in delaying disease progression in hormone receptor-positive breast cancer, making it a preferred treatment option in various settings including adjuvant and neoadjuvant therapy.

Combining letrozole with other agents like lapatinib or everolimus enhances its efficacy, particularly in patients with both HR+ and HER2+ breast cancer, suggesting that dual-targeted therapies can effectively overcome treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overview of letrozole in postmenopausal women with hormone-responsive breast cancer. Barnadas, A., Estévez, LG., Lluch-Hernández, A., et al.[2018]

Anastrozole, a highly specific aromatase inhibitor, has emerged as a potentially better tolerated and more effective treatment for postmenopausal patients with hormone-sensitive breast cancer compared to tamoxifen, which has safety and tolerability issues.

The ongoing Arimidex, Tamoxifen, Alone or in Combination trial indicates that anastrozole is an effective and well-tolerated option for adjuvant endocrine treatment in early breast cancer, suggesting its potential role in chemoprevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of anastrozole in adjuvant therapy for postmenopausal patients. Buzdar, AU.[2019]

In trials, combining lapatinib with letrozole (LAP + LET) significantly improved time to progression in post-menopausal women with hormone receptor-positive and HER2-positive metastatic breast cancer compared to aromatase inhibitor monotherapy.

However, from a cost-effectiveness perspective, LAP + LET is unlikely to be cost-effective compared to standard aromatase inhibitors, with a probability of only 1.4% versus letrozole and 9.2% versus anastrozole, but it may be more cost-effective compared to trastuzumab plus anastrozole, with a 51% probability, despite some uncertainty.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of Lapatinib plus Letrozole in Post-Menopausal Women with Hormone Receptor-and HER2-Positive Metastatic Breast Cancer. Delea, TE., Hawkes, C., Amonkar, MM., et al.[2021]

Trastuzumab (Herceptin) is highly effective in treating metastatic breast cancers that overexpress the HER-2/neu receptor, showing response rates comparable to traditional chemotherapy with significantly lower toxicity.

The success of trastuzumab in advanced cases has prompted ongoing clinical trials to explore its potential benefits in early-stage HER-2/neu-overexpressing breast cancer, indicating a shift towards more targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab: targeted therapy for the management of HER-2/neu-overexpressing metastatic breast cancer. Emens, LA.[2015]

In a study of 150 breast cancer patients, those receiving sequential treatment with letrozole and tamoxifen showed a higher overall response rate and fewer adverse reactions compared to those on letrozole alone.

Both treatment methods resulted in similar survival rates, but the sequential therapy group had a significantly lower recurrence rate and better improvement in blood lipid levels, indicating a potentially better prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, Safety, and Prognosis of Sequential Therapy with Tamoxifen and Letrozole versus Letrozole Monotherapy for Breast Carcinoma. Lu, X., Qian, C.[2023]

The eLEcTRA trial demonstrated that combining letrozole with trastuzumab significantly improves median time to progression in patients with HER2 and hormone receptor positive metastatic breast cancer (MBC), with 14.1 months for the combination therapy compared to 3.3 months for letrozole alone.

The clinical benefit rate was also higher for the combination therapy (65%) compared to letrozole alone (39%), indicating that letrozole plus trastuzumab is a safe and effective treatment option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer - results of the eLEcTRA trial. Huober, J., Fasching, PA., Barsoum, M., et al.[2018]

In a study involving 392 patients with hormone receptor-positive and HER2-positive metastatic breast cancer, trastuzumab combined with endocrine therapy showed a median progression-free survival of 19.2 months, which was noninferior to the 14.8 months observed with trastuzumab plus chemotherapy.

The combination of trastuzumab and endocrine therapy resulted in significantly lower toxicity compared to the chemotherapy group, suggesting it may be a safer first-line treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Hua, X., Bi, XW., Zhao, JL., et al.[2023]

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