Hormone Therapy + Immunotherapy for Advanced Breast Cancer

No longer recruiting at 607 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining hormone therapy with immunotherapy is more effective than hormone therapy alone for treating advanced breast cancer. Hormone therapy uses tamoxifen citrate or letrozole to block estrogen, helping to prevent cancer growth. The immunotherapy drug bevacizumab (also known as Avastin) may enhance the immune system to stop cancer cells from growing and spreading. The trial seeks women with advanced breast cancer that is estrogen or progesterone receptor-positive. Participants should not have another active cancer and must have completed any other cancer treatments, such as surgery or chemotherapy, before joining. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research shows that patients generally tolerate bevacizumab well when combined with letrozole or tamoxifen citrate. Studies have found that bevacizumab can cause expected side effects like high blood pressure, headaches, and protein in the urine, but these are manageable.

Previous studies have shown that using bevacizumab with letrozole is safe under medical supervision. Similarly, another study found that bevacizumab can be used with hormone therapy like tamoxifen citrate without causing severe side effects.

Additionally, a large review of studies confirmed that bevacizumab does not cause serious side effects requiring treatment discontinuation, even when used with other cancer therapies.

These findings suggest that the treatment is considered safe based on current evidence. However, discussing potential risks with a healthcare provider before joining any trial is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for advanced breast cancer because they combine hormone therapy with immunotherapy, which offers a new way to tackle the disease. Unlike traditional approaches that primarily rely on hormone therapy alone, this treatment adds bevacizumab, a monoclonal antibody, which helps to inhibit blood vessel growth in tumors. This dual approach not only aims to slow down cancer progression more effectively but also potentially enhances the body’s immune response against the cancer. By integrating these strategies, the treatment offers hope for more comprehensive management of advanced breast cancer.

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

Research has shown that combining bevacizumab with letrozole, a combination tested in this trial, can slow the progression of hormone-sensitive advanced breast cancer. In one study, patients receiving this combination experienced an average of 17.1 months before their cancer worsened. Additionally, adding bevacizumab reduced the risk of cancer progression by 30% when used with various treatments. For tamoxifen citrate, another treatment option in this trial, combining it with bevacizumab also lowered the risk of cancer progression. Overall, these combinations appear to slow the spread of advanced breast cancer. ^{2 3 6 7 8}

Who Is on the Research Team?

Hope S Rugo

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5012690/

Phase III Trial Evaluating Letrozole As First-Line Endocrine ... The addition of bevacizumab to letrozole improved PFS in hormone receptor–positive MBC, but this benefit was associated with a markedly increased risk of grade ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT00461773

Randomized Phase II Study of Preoperative Letrozole ... The purpose of this study is to evaluate the objective response rate of a combination of letrozole (Femara) and bevacizumab (Avastin) given preoperatively ...

3. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2014.57.2388

Phase III Trial Evaluating the Addition of Bevacizumab to ... The addition of bevacizumab to ET in first-line treatment failed to produce a statistically significant increase in PFS or OS in women with HER2 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3248767/

Bevacizumab Treatment for Advanced Breast Cancer - PMC The PFS results from the three trials showed a lower risk for cancer progression or death, with PFS intervals of 9.2 months and 6.7 months for patients treated ...

5. vivo.weill.cornell.edu vivo.weill.cornell.edu/display/pubid19841327

Feasibility trial of letrozole in combination with ... Partial responses were seen in 9% of patients and stable disease >or= 24 weeks was noted in 67%. Median PFS was 17.1 months. CONCLUSION: ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/19841327/

Feasibility trial of letrozole in combination with bevacizumab in ... Combination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29789969/

Identification of Risk Factors for Toxicity in Patients ... - PubMed Background: In hormone receptor-positive advanced breast cancer, a progression-free survival benefit was reported with addition of bevacizumab to first-line ...

8. karger.com karger.com/ort/article/45/10/608/826083/Efficacy-and-Safety-of-Bevacizumab-in-Pretreated

Efficacy and Safety of Bevacizumab in Pretreated ... Efficacy and safety of bevacizumab in pretreated metastatic breast cancer: a systematic review and meta-analysis.