Hormone Therapy + Immunotherapy for Advanced Breast Cancer

Recruiting at 595 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must be taking: Ovarian suppression

Must not be taking: Anti-VEGF, VEGFR inhibitors

Disqualifiers: Active malignancy, CNS metastases, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 27

Duration: Up to 5 years

394 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase III trial studies tamoxifen citrate or letrozole together with bevacizumab to see how well it works compared with tamoxifen citrate or letrozole alone in treating women with stage IIIB or stage IV breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate or letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Immunotherapy with monoclonal antibodies, such as bevacizumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving hormone therapy is more effective with or without bevacizumab in treating advanced breast cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you recently started tamoxifen or an aromatase inhibitor for metastatic breast cancer, you may need to switch to letrozole to participate. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Letrozole in treating advanced breast cancer?

Letrozole, a drug used in postmenopausal women with breast cancer, has been shown to improve disease-free survival and is more effective than tamoxifen in delaying disease progression in advanced breast cancer. It is also effective when used in combination with other treatments to overcome resistance in certain types of breast cancer. ^{1 2 3 4 5}

Is the combination of hormone therapy and immunotherapy safe for advanced breast cancer?

Letrozole, a hormone therapy, is generally safe but can cause bone loss and increase fracture risk, and may lead to more heart attacks compared to tamoxifen. Tamoxifen, another hormone therapy, has a higher risk of causing blood clots and endometrial cancer. Safety data for immunotherapy like Bevacizumab (Avastin) is not provided in the articles. ^{1 4 6 7 8}

How does the drug Letrozole differ from other treatments for advanced breast cancer?

Letrozole is unique because it is a third-generation aromatase inhibitor (a drug that lowers estrogen levels) that has shown to be more effective than tamoxifen in delaying disease progression in postmenopausal women with advanced breast cancer. It is often used in combination with other therapies to overcome resistance and improve outcomes in hormone receptor-positive and HER2-positive breast cancers. ^{1 2 4 8 9}

Research Team

Hope S Rugo

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

This trial is for postmenopausal women or premenopausal women on ovarian suppression with stage IIIB or IV breast cancer that responds to hormones. Participants should not have had major surgery recently, no history of significant bleeding, fistulas, or abdominal abscesses, and no severe cardiovascular issues. They must have a life expectancy of at least 12 weeks and be in good physical condition (ECOG <=1).

Inclusion Criteria

My kidney function test shows less than 1g of protein in my urine over 24 hours.

My breast cancer has been confirmed by tissue analysis.

The amount of protein in your urine is low.

Exclusion Criteria

Your platelet count is less than 100,000 per microliter.

Your creatinine level is higher than 2.0 mg/dL.

I have another active cancer besides non-melanoma skin cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive endocrine therapy (tamoxifen citrate or letrozole) with or without bevacizumab. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Up to 5 years

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 6 months for the first 2 years, then annually for up to 3 years.

Up to 3 years

Every 6 months for 2 years, then annually

Treatment Details

Interventions

• Bevacizumab
• Letrozole
• Tamoxifen Citrate

Trial Overview The study is testing the effectiveness of hormone therapies tamoxifen citrate or letrozole alone versus combined with the monoclonal antibody bevacizumab in advanced breast cancer. The goal is to see if adding bevacizumab improves outcomes by altering the immune system's response to tumor cells.

Participant Groups

Group I: Arm I (endocrine therapy with monoclonal antibody) Experimental Treatment 5 Interventions

Patients receive endocrine therapy\* (tamoxifen citrate\* or letrozole) PO QD on days 1-21 and bevacizumab 15 mg/kg IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (endocrine therapy) Active Control 4 Interventions

Patients receive endocrine therapy\* (tamoxifen citrate\* or letrozole) PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Femara for:

• Breast cancer in postmenopausal women
• Increasing the chance of ovulation in women with polycystic ovary syndrome

Approved in European Union as Letrozole for:

• Early breast cancer in postmenopausal women
• Advanced breast cancer in postmenopausal women

Approved in Canada as Letrozole for:

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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Letrozole is an effective treatment for postmenopausal women with early-stage or advanced hormone-sensitive breast cancer, showing a 43% reduction in disease recurrences when used as extended adjuvant therapy beyond standard tamoxifen treatment.

In advanced breast cancer, letrozole outperformed tamoxifen in terms of time to disease progression (9.4 months vs. 6.0 months) and has a similar tolerability profile, making it a recommended first-line therapy according to treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in postmenopausal women with breast cancer. Simpson, D., Curran, MP., Perry, CM.[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]

Letrozole significantly outperformed tamoxifen in delaying disease progression and treatment failure in postmenopausal women with advanced breast cancer, with median times of 9.4 months versus 6.0 months, respectively.

While the overall survival (OS) was slightly better for letrozole (34 months) compared to tamoxifen (30 months), this difference was not statistically significant; however, letrozole did show improved survival rates during the first two years of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. Mouridsen, H., Gershanovich, M., Sun, Y., et al.[2022]

In a study involving 6182 postmenopausal women with hormone-receptor-positive breast cancer, sequential treatment with tamoxifen and letrozole did not significantly improve disease-free survival compared to letrozole monotherapy, indicating that letrozole alone may be sufficient for treatment.

The updated analysis showed no statistically significant difference in overall survival between letrozole and tamoxifen monotherapy, suggesting that both treatments have similar long-term outcomes, with adverse events consistent with previous reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. Mouridsen, H., Giobbie-Hurder, A., Goldhirsch, A., et al.[2022]

Letrozole has been fully approved by the FDA for treating postmenopausal women with hormone receptor-positive early breast cancer, showing a significant improvement in disease-free survival compared to tamoxifen, with a hazard ratio of 0.87 in the adjuvant trial.

While letrozole is effective, it is associated with a higher risk of bone fractures and myocardial infarction compared to tamoxifen, which has its own risks such as endometrial cancer and thromboembolic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval summary: letrozole (Femara® tablets) for adjuvant and extended adjuvant postmenopausal breast cancer treatment: conversion of accelerated to full approval. Cohen, MH., Johnson, JR., Justice, R., et al.[2021]

In a study of 1065 postmenopausal women with early breast cancer receiving letrozole, immediate treatment with zoledronic acid significantly increased lumbar spine bone mineral density (BMD) by 5.7% compared to a delayed treatment strategy, which resulted in bone loss.

Both immediate and delayed zoledronic acid regimens were well tolerated, but the immediate group experienced more bone pain due to acute-phase reactions, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. Bundred, NJ., Campbell, ID., Davidson, N., et al.[2022]

In a study of 907 postmenopausal women with advanced breast cancer, letrozole was found to be more effective than tamoxifen, showing a longer time to progression (TTP) in both younger (<70 years) and older (≥70 years) patients.

Letrozole also demonstrated a significantly higher objective response rate (ORR) in older patients (38% vs. 18% for tamoxifen), while the ORR in younger patients was similar for both treatments (26% for letrozole vs. 22% for tamoxifen).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of first-line letrozole versus tamoxifen as a function of age in postmenopausal women with advanced breast cancer. Mouridsen, H., Chaudri-Ross, HA.[2018]

In a study of 40 postmenopausal women with locally advanced breast cancer, both Letrozole and Tamoxifen were found to be effective as neoadjuvant hormone therapies, with 25% of patients on Tamoxifen and 20% on Letrozole not achieving a complete response, leading to subsequent radiotherapy.

The study indicated that neoadjuvant hormone therapy was generally well-tolerated, with side effects occurring in 55% of patients on Letrozole and 60% on Tamoxifen, suggesting that these treatments could improve clinical outcomes and allow for successful radical mastectomy in patients with better prognoses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Letrozole vs. tamoxifen as neoadjuvant therapy for postmenopausal patients with hormone-dependent locally-advanced breast cancer]. Novoa Vargas, A., Font López, KC., Amador, DD.[2018]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in postmenopausal women with breast cancer. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

An overview of letrozole in postmenopausal women with hormone-responsive breast cancer. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. [2022]

5. India pubmed.ncbi.nlm.nih.gov

Results of letrozole in postmenopausal women after tamoxifen treatment for advanced breast cancer. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Approval summary: letrozole (Femara® tablets) for adjuvant and extended adjuvant postmenopausal breast cancer treatment: conversion of accelerated to full approval. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy of first-line letrozole versus tamoxifen as a function of age in postmenopausal women with advanced breast cancer. [2018]

9. Mexico pubmed.ncbi.nlm.nih.gov

[Letrozole vs. tamoxifen as neoadjuvant therapy for postmenopausal patients with hormone-dependent locally-advanced breast cancer]. [2018]