Combination Chemotherapy for Breast Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Autoimmune diseases, Active infections, Cardiac disease, others

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

Compensation: Varies

Number of Visits: 1

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for breast cancer that has spread to other parts of the body. It tests the effectiveness of neratinib (a targeted therapy), paclitaxel (a chemotherapy drug), and potentially pertuzumab and trastuzumab, which may stop tumor growth and enhance the immune response. The trial seeks participants with HER2+ breast cancer that is either metastatic or at an advanced stage and who have not received certain previous cancer treatments. Those diagnosed with this type of breast cancer and considering surgery might find this trial suitable. As a Phase 1, Phase 2 trial, it aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering a chance to contribute to early-stage research.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that using neratinib and paclitaxel together can cause some side effects. One study found that diarrhea was common, affecting about 38% of patients, but these side effects were usually manageable. When combined with paclitaxel, pertuzumab, and trastuzumab, neratinib has effectively treated breast cancer, though the safety details of this combination remain unclear.

The combination of doxorubicin and cyclophosphamide is a standard treatment for breast cancer. Research indicates it is generally safe, but it can cause side effects like heart-related issues. These are well-known, and doctors monitor them closely.

Overall, while some side effects occur, these treatments are often well-tolerated, especially with medical supervision. Each treatment option in the study aims to balance effectiveness with safety, so discussing potential side effects with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for breast cancer because they combine multiple drugs with different mechanisms to tackle the disease more comprehensively. Neratinib is an oral medication that targets HER2 receptors, potentially enhancing the effectiveness of standard treatments like trastuzumab and pertuzumab, which also target HER2 but through different pathways. This combination approach aims to prevent cancer cells from adapting and resisting treatment. Additionally, the integration of chemotherapy agents like paclitaxel, and later doxorubicin and cyclophosphamide, offers a robust attack on cancer cells, aiming for better outcomes by reducing the chance of disease progression or recurrence. These innovative combinations present a promising advancement over traditional treatments.

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

In this trial, participants will join different treatment groups to evaluate the effectiveness of various drug combinations for breast cancer. Studies have shown that using neratinib with paclitaxel, which participants in Group C may receive, can achieve a response rate of up to 73% in treating breast cancer. Research indicates that adding pertuzumab and trastuzumab to this treatment, as in Groups A and B, significantly improves outcomes for patients with advanced HER2-positive breast cancer. This combination of medications is linked to better recovery chances and longer periods without disease recurrence. Additionally, participants in Groups B and C will receive doxorubicin and cyclophosphamide, which have proven effective in breast cancer treatment, showing results similar to longer treatment cycles. Overall, evidence suggests these combinations are promising for managing advanced breast cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Rachel M Layman

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with confirmed breast cancer that has spread and who can take oral meds. They must have good heart function, normal blood counts, liver function within certain limits, and agree to use birth control. It's not for those breastfeeding, with a history of certain autoimmune diseases or other recent cancers, uncontrolled high blood pressure, serious infections or hepatitis B/C.

Inclusion Criteria

Able to provide written informed consent for the trial

Your platelet count is at least 100,000 per microliter.

Your hemoglobin level is at least 9 grams per deciliter.

Exclusion Criteria

I had surgery to remove part or all of my breast tumor.

I haven't had any cancer except for some skin cancers and treated cervical cancer in the last 5 years.

I have not received any cancer treatments for my current diagnosis, except if I'm in phase Ib of cohort 1.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neratinib, paclitaxel, pertuzumab, and trastuzumab, followed by doxorubicin and cyclophosphamide

12 weeks

Weekly visits for drug administration

Surgery

Participants undergo standard of care surgery after completion of chemotherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Doxorubicin
• Neratinib
• Paclitaxel
• Pertuzumab
• Trastuzumab

Trial Overview

The study tests neratinib combined with paclitaxel chemotherapy and possibly pertuzumab and trastuzumab before more chemo. The goal is to find the best dose of neratinib and see how well it works in stopping tumor growth when used with these drugs in metastatic or locally advanced breast cancer.

How Is the Trial Designed?

Group I: Group C (Cohort 2) Experimental Treatment 5 Interventions

Patients receive neratinib PO QD on days 1-21, paclitaxel IV over 1-3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery/ Patients then receive doxorubicin and cyclophosphamide as in Group B. Patients then undergo standard of care surgery.

Group II: Group B (Cohort 1 Phase II) Experimental Treatment 7 Interventions

Patients receive neratinib, paclitaxel, pertuzumab, and trastuzumab as in Group A. Patients then receive doxorubicin IV and cyclophosphamide IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery.

Group III: Group A (Cohort 1 Phase Ib) Experimental Treatment 5 Interventions

Patients receive neratinib PO QD on days 1-21, paclitaxel IV over 1-3 hours on days 1, 8, and 15, pertuzumab IV over 1 hour on day 1, and trastuzumab IV over 1-2 hours on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients without progression or excessive toxicity with metastatic disease may receive up to 4 additional courses and with locally advanced disease may receive up to 2 additional courses.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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 study of 266 patients with HER2-positive metastatic breast cancer, the majority received a treatment regimen of trastuzumab, pertuzumab, and a taxane, which aligns with the standard first-line therapy.

The median progression-free survival (PFS) for patients was 16.9 months, and the safety profile, including common side effects like fatigue and diarrhea, was consistent with findings from the pivotal CLEOPATRA trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HER2-Positive Metastatic Breast Cancer Patients Receiving Pertuzumab in a Community Oncology Practice Setting: Treatment Patterns and Outcomes. Robert, NJ., Goertz, HP., Chopra, P., et al.[2020]

In the TRAIN-2 study involving 110 patients with HER2-positive breast cancer, the addition of pertuzumab to chemotherapy regimens resulted in neutropenia as the most common hematologic toxicity, affecting 53% of patients in the FEC-T arm and 51% in the PTC arm.

While both regimens showed manageable toxicity, the FEC-T arm had a higher incidence of asymptomatic ejection fraction decrease (24%) compared to the PTC arm (11%), and diarrhea was more common in the PTC arm (18% vs. 5%), indicating different toxicity profiles depending on the chemotherapy backbone used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of dual HER2-blockade with pertuzumab added to anthracycline versus non-anthracycline containing chemotherapy as neoadjuvant treatment in HER2-positive breast cancer: The TRAIN-2 study. van Ramshorst, MS., van Werkhoven, E., Honkoop, AH., 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 III trial involving patients with high-risk HER2-positive early breast cancer, the addition of atezolizumab to standard treatment (pertuzumab-trastuzumab and chemotherapy) did not significantly improve the rates of pathologic complete response (pCR) compared to placebo, with pCR rates being 62.7% for placebo and 62.4% for atezolizumab in the overall population.

While the safety profile of atezolizumab was consistent with previous studies, it was associated with a higher frequency of serious adverse events, including five grade 5 adverse events, indicating a need for careful consideration of its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial. Huober, J., Barrios, CH., Niikura, N., et al.[2022]

In a study of 17 patients with advanced HER2/neu overexpressing breast cancer, the combination of trastuzumab and paclitaxel resulted in a response rate of 59%, with 2 complete responses and a median overall survival of 23 months.

The treatment was generally well-tolerated, with manageable side effects; however, some patients experienced significant toxicities, including hypersensitivity reactions and grade 3 neuropathy, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

4-years results of weekly trastuzumab and paclitaxel in the treatment of women with HER2/neu overexpressing advanced breast cancer: single institution prospective study. Janku, F., Pribylova, O., Zimovjanova, M., et al.[2015]

In a study of 152 patients with HER2-positive metastatic breast cancer, the combination of taxanes with trastuzumab and pertuzumab showed a significant progression-free survival (PFS) advantage over vinorelbine in patients with newly diagnosed metastatic disease, indicating a potential benefit for this specific group.

Overall, there was no significant difference in overall survival (OS) between the two treatment groups, suggesting that both taxanes and vinorelbine are viable options when combined with trastuzumab and pertuzumab for first-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study. Reinhorn, D., Kuchuk, I., Shochat, T., et al.[2021]

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