Immunotherapy + Hormone Therapy for Advanced Breast Cancer

Recruiting at 7 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must be taking: Letrozole, Fulvestrant, Palbociclib

Must not be taking: Immunosuppressants, Steroids, others

Disqualifiers: Immunodeficiency, Active TB, Autoimmune, 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: 21

Duration: Up to 24 months

47 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that patients should not be on certain immunosuppressive therapies or have received certain treatments like chemotherapy or radiation therapy within a specific timeframe before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination of palbociclib, letrozole, and pembrolizumab for advanced breast cancer?

Research shows that combining palbociclib with letrozole significantly improves progression-free survival in patients with advanced breast cancer. Additionally, combining palbociclib with pembrolizumab has shown potential immune-related benefits in hormone receptor-positive metastatic breast cancer. ^{1 2 3 4 5}

Is the combination of palbociclib and letrozole safe for treating advanced breast cancer?

In clinical trials, the combination of palbociclib (Ibrance) and letrozole for advanced breast cancer was generally safe, but the most common side effect was neutropenia (a low level of white blood cells), which was not often linked to fever. ^{5 6 7 8 9}

What makes the drug combination of Fulvestrant, Letrozole, Palbociclib, and Pembrolizumab unique for advanced breast cancer?

This drug combination is unique because it combines hormone therapy with immunotherapy and a CDK4/6 inhibitor, which may enhance the immune response and improve outcomes in hormone receptor-positive advanced breast cancer, especially in patients who have developed resistance to standard hormone therapies. ^{1 4 5 6 8}

What is the purpose of this trial?

This phase II trial studies how well pembrolizumab works when given together with endocrine therapy and palbociclib in treating postmenopausal patients with newly diagnosed stage IV estrogen receptor positive breast cancer that has spread to other parts of the body (metastatic). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Estrogen can cause the growth of breast cancer cells. Fulvestrant blocks the use of estrogen by the tumor cells. Letrozole lowers the amount of estrogen made by the body. This may help stop the growth of tumor cells that need estrogen to grow. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab, palbociclib, and letrozole or fulvestrant may be an effective treatment for patients with stage IV estrogen receptor positive breast cancer.

Research Team

Joanne Mortimer

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for postmenopausal women with newly diagnosed stage IV estrogen receptor positive breast cancer. Participants must be over 18, willing to provide consent and tissue samples, have a life expectancy of at least 3 months, and meet specific health criteria. They cannot join if they have brain metastases, received certain vaccines or treatments recently, are pregnant/breastfeeding, or have serious health issues like active autoimmune diseases.

Inclusion Criteria

I am not pregnant and agree to use birth control.

My breast cancer is stage IV, ER positive, HER2 negative, and confirmed by tests.

I can take care of myself and am up and about more than half of the day.

Exclusion Criteria

I don't have any health issues that could affect the trial's results.

I have a history of HIV or active hepatitis B/C.

I have not received a live vaccine in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive letrozole, palbociclib, and pembrolizumab or fulvestrant in cycles. Letrozole is taken daily, palbociclib is taken for 3 weeks with a 1-week break, and pembrolizumab is administered every 21 days.

Up to 24 months

Regular visits every 21-28 days for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes assessments at 30 days post-treatment, every 6 months for 3 years, and then annually for 1 year.

4 years

Follow-up visits at specified intervals

Treatment Details

Interventions

• Fulvestrant
• Letrozole
• Palbociclib
• Pembrolizumab

Trial Overview The study tests pembrolizumab (an immunotherapy drug) combined with endocrine therapy (fulvestrant or letrozole) and palbociclib against metastatic breast cancer. It aims to see if this combination can help the immune system fight cancer and stop tumor growth by blocking hormones and enzymes that cancer cells need.

Participant Groups

Group I: Cohorts 1 and 2 (letrozole, palbociclib, pembrolizumab) Experimental Treatment 4 Interventions

Patients receive letrozole PO QD on days 1-28 and palbociclib PO QD for 3 weeks. Cycles with letrozole and palbociclib repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1. Cycles with pembrolizumab repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group II: Cohort 3 (letrozole, palbociclib, fulvestrant, pembrolizumab) Experimental Treatment 5 Interventions

Patients receive either letrozole PO QD on days -28 to -1 and days 1-28, or fulvestrant on days -28, -14, and day 1 of subsequent cycles. Patients also receive palbociclib PO QD for 3 weeks. Cycles with palbociclib, and letrozole or fulvestrant repeat every 28 days in the absence disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1. Cycles with pembrolizumab repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in United States as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Canada as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Japan as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In patients with hormone receptor-positive metastatic breast cancer, higher levels of specific immune cells (effector memory CD8+ and CD4+ T cells) before treatment were associated with better responses to the combination therapy of palbociclib, pembrolizumab, and letrozole, compared to those receiving only pembrolizumab and letrozole.

The combination therapy also led to significant changes in myeloid cell composition, including increased mature dendritic cells and decreased classical monocytes, which may enhance the immune response against the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer. Egelston, C., Guo, W., Yost, S., et al.[2021]

In a study of 1430 patients with hormone receptor-positive, HER2-negative metastatic breast cancer, the combination of palbociclib and letrozole significantly improved progression-free survival (20.0 months) compared to letrozole alone (11.9 months).

The combination treatment also showed a trend towards better overall survival, with a 2-year survival rate of 78.3% for the palbociclib group compared to 68.0% for those on letrozole alone, indicating its effectiveness in a real-world clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2- metastatic breast cancer in US real-world clinical practice. DeMichele, A., Cristofanilli, M., Brufsky, A., et al.[2022]

In a study of 126 patients with hormone receptor-positive, HER2-negative metastatic breast cancer, palbociclib combined with letrozole showed a clinical benefit rate of 30% for those with prior endocrine therapy and 26% for those with prior chemotherapy, indicating its effectiveness even after multiple treatments.

Patients who had received two or more prior lines of therapy had 6-month and 12-month progression-free survival rates of 35% and 21%, respectively, and overall survival rates of 62% at 12 months and 35% at 24 months, demonstrating that palbociclib + letrozole can provide meaningful outcomes in heavily pretreated populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Patterns and Outcomes Associated With Palbociclib Plus Letrozole for Postmenopausal Women With HR+/HER2- Advanced Breast Cancer Enrolled in an Expanded Access Program. Brufsky, A., Mitra, D., Davis, KL., et al.[2020]

Palbociclib, a selective CDK4/6 inhibitor, has been shown to be effective when combined with letrozole or fulvestrant in treating HR+/HER2- advanced breast cancer, particularly in cases where patients have developed resistance to standard endocrine therapies.

The combination of palbociclib with endocrine therapy is well tolerated by patients, making it a valuable addition to treatment options for locally advanced and metastatic ER+/HER2- breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Palbociclib combinations as new therapeutic strategies in the treatment of HR+/HER2- advanced breast cancer]. Boér, K.[2019]

In a study with a median follow-up of about 38 months, palbociclib combined with letrozole significantly improved progression-free survival (PFS) in women with advanced estrogen receptor-positive (ER+)/HER2-negative breast cancer, with a median PFS of 27.6 months compared to 14.5 months for the placebo group.

The treatment not only prolonged PFS but also delayed the need for chemotherapy and maintained a favorable safety profile and quality of life for patients, suggesting that palbociclib-letrozole should be the standard first-line therapy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Rugo, HS., Finn, RS., Diéras, V., et al.[2023]

Oral palbociclib is an effective treatment for HR-positive, HER2-negative advanced or metastatic breast cancer, significantly prolonging progression-free survival when used with letrozole or fulvestrant in clinical trials involving postmenopausal women.

The most common side effect was neutropenia, which was manageable and rarely led to serious complications, indicating that palbociclib can be safely administered without significantly compromising its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer. Kim, ES., Scott, LJ.[2022]

Palbociclib, an inhibitor of CDK4 and CDK6, was granted accelerated FDA approval for treating advanced breast cancer in postmenopausal women when combined with letrozole, based on a trial involving 165 patients that showed significant improvement in progression-free survival (PFS).

The trial demonstrated a nearly 50% reduction in the risk of disease progression for patients receiving the combination therapy compared to those on letrozole alone, although the most common side effect noted was neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. Beaver, JA., Amiri-Kordestani, L., Charlab, R., et al.[2022]

In the PALOMA-2 trial, palbociclib combined with letrozole significantly improved progression-free survival (PFS) in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer, with a median PFS of 37.2 months compared to 27.4 months for the placebo group.

The study found that 44% of patients on palbociclib achieved an objective response, and even those who did not achieve a response still experienced a significant prolongation of PFS, indicating that palbociclib + letrozole offers substantial clinical benefits regardless of the response status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progression-free Survival Outcome Is Independent of Objective Response in Patients With Estrogen Receptor-positive, Human Epidermal Growth Factor Receptor 2-negative Advanced Breast Cancer Treated With Palbociclib Plus Letrozole Compared With Letrozole: Analysis From PALOMA-2. Rugo, HS., Finn, RS., Gelmon, K., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2- metastatic breast cancer in US real-world clinical practice. [2022]

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

Treatment Patterns and Outcomes Associated With Palbociclib Plus Letrozole for Postmenopausal Women With HR+/HER2- Advanced Breast Cancer Enrolled in an Expanded Access Program. [2020]

4. Hungary pubmed.ncbi.nlm.nih.gov

[Palbociclib combinations as new therapeutic strategies in the treatment of HR+/HER2- advanced breast cancer]. [2019]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. [2023]

6. France pubmed.ncbi.nlm.nih.gov

Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer. [2022]

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

FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. [2022]

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

Progression-free Survival Outcome Is Independent of Objective Response in Patients With Estrogen Receptor-positive, Human Epidermal Growth Factor Receptor 2-negative Advanced Breast Cancer Treated With Palbociclib Plus Letrozole Compared With Letrozole: Analysis From PALOMA-2. [2021]

9. Japan pubmed.ncbi.nlm.nih.gov

Palbociclib in combination with letrozole in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-2 subgroup analysis of Japanese patients. [2022]