Immunotherapy + Radiation for Hormone-Sensitive Breast Cancer

(CBCV Trial)

Recruiting at4 trial locations

Overseen by Silvia Formenti

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Weill Medical College of Cornell University

Must be taking: Hormonal therapy

Must not be taking: Chemotherapy, Endocrine therapy, HER2 therapy, Immunotherapy

Disqualifiers: Connective tissue disorders, Autoimmune disease, Immunodeficiency, others

Stay on Your Current Meds

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests different treatments in post-menopausal women with a specific type of breast cancer. The goal is to find the best way to lower hormones, kill cancer cells, or boost the immune system to fight the disease. One of the treatments being tested is a medication used for treating postmenopausal women with hormone-sensitive 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, you cannot participate if you are currently using systemic chemotherapy, endocrine therapy, or HER2-neu targeted therapy.

What data supports the effectiveness of this treatment for hormone-sensitive breast cancer?

Research suggests that combining radiation therapy with immunotherapy, like PD-1 blockade, can enhance the immune system's ability to fight cancer, as seen in studies with other types of cancer. This combination has shown promise in making tumors more responsive to treatment by activating immune cells and reducing suppressive cells in the tumor environment. ^{1 2 3 4 5}

Is hypofractionated radiation therapy safe for breast cancer patients?

Research shows that hypofractionated radiation therapy (a type of radiation treatment given in larger doses over fewer sessions) is generally safe and effective for breast cancer patients, with similar safety profiles to traditional radiation therapy. However, there are still concerns about potential side effects and local recurrence, especially in younger women. ^{2 5 6 7 8}

What makes the treatment of Immunotherapy + Focal Radiation therapy unique for hormone-sensitive breast cancer?

This treatment is unique because it combines focal hypofractionated radiation therapy, which delivers high doses of radiation in fewer sessions, with immunotherapy to potentially enhance the immune system's ability to attack cancer cells. This combination may lead to both local and distant (abscopal) effects, where the immune response is activated not only at the site of radiation but also in other parts of the body. ^{1 2 3 9 10}

Research Team

Silvia Formenti

Principal Investigator

Weill Cornell Medicine - New York Presbyterian Hospital

Eligibility Criteria

Post-menopausal women over 18 with stage I-III HR+HER2- breast cancer, who can sign consent and have good performance status (ECOG 0-1). They must have adequate organ function and no prior treatments with certain immune drugs, severe allergies to pembrolizumab, or immunosuppressive therapies. Excluded are those with active infections, certain viral diseases like HIV or hepatitis B/C, recent live vaccines, autoimmune diseases requiring treatment in the past 2 years, other cancers within 3 years.

Inclusion Criteria

My breast cancer is ER positive, may or may not be PR positive, and is HER2 negative.

My breast cancer is between stage I (larger than 1.5cm if no lymph node involvement) and III.

Patient needs to be able to understand and demonstrate willingness to sign a written informed consent document

Exclusion Criteria

Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

I haven't needed systemic treatment for an autoimmune disease in the last 2 years.

I have an active tuberculosis infection.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 4 months of standard neoadjuvant hormonal therapy with letrozole, with additional treatments depending on the assigned arm, including focal hypo-fractionated radiation therapy and potentially pembrolizumab or FLT3L.

16 weeks

Multiple visits for treatment administration

Surgery

Breast surgery is performed at the end of the treatment phase.

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a one-month follow-up period after surgery.

4 weeks

1-2 visits (in-person)

Treatment Details

Interventions

• CDX-301 (Cancer Vaccine)
• Focal Radiation therapy (Radiation)
• Pembrolizumab (Immune Checkpoint Inhibitor)

Trial Overview The trial is testing focal radiation therapy alone or combined with immunotherapy drugs Pembrolizumab and CDX-301 on patients already receiving standard hormonal therapy. Participants are randomly assigned to one of four groups at five US academic institutions.

Participant Groups

Group I: ARM 3 Active Control 2 Interventions

Ftl-3 ligand, self-administered by subcutaneous injections at week 1, daily, for 5 consecutive days + Focal hypo-fractionated radiation therapy - 8 Gy x 3 fractions starting day 8, (every other day (M/W/F or W/F/M or F/M/W).

Group II: ARM 2 Active Control 2 Interventions

Focal hypo-fractionated radiation therapy - 8 Gy x 3 fractions starting day 8, every other day (M/W/F or W/F/M or F/M/W). + Pembrolizumab, on day 12 (last day of radiotherapy), infused over 200mg IV over 30 minutes and then repeated every 3 weeks until disease progression or unacceptable toxicity.

Group III: ARM 4 Active Control 3 Interventions

Ftl-3 ligand, self administered subcutaneous injections at day 1 for 5 consecutive days+ Focal hypo-fractionated Radiation therapy starting day 8, - 8 Gy x 3 fractions, every other day (M/W/F or W/F/M or F/M/W). + Pembrolizumab, on day 12 (last day of radiotherapy), 200mg IV infused over 30 minutes then repeated every 3 weeks until disease progression or unacceptable toxicity.

Group IV: ARM 1 Active Control 1 Intervention

Focal hypo-fractionated radiation therapy 8 Gy x 3 fractions, starting day 8, every other day (M/W/F or W/F/M or F/M/W).

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Dr. Robert Min

Weill Medical College of Cornell University

Chief Executive Officer since 2024

MD, MBA

Dr. Adam R. Stracher

Weill Medical College of Cornell University

Chief Medical Officer since 2024

MD

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Celldex Therapeutics

Industry Sponsor

Trials

66

Recruited

5,900+

Anthony S. Marucci

Celldex Therapeutics

Chief Executive Officer since 2008

MBA from Columbia University, MHL from Brown University

Diane C. Young

Celldex Therapeutics

Chief Medical Officer since 2019

MD from Harvard Medical School, AB in Biochemical Sciences from Harvard University

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Pete Hegseth

United States Department of Defense

Chief Executive Officer

Bachelor's degree in Political Science from Princeton University, JD from Harvard Law School

Lisa Hershman

United States Department of Defense

Chief Medical Officer since 2021

MD from Uniformed Services University of the Health Sciences

Findings from Research

In patients with head and neck squamous cell carcinoma undergoing definitive radiation therapy, treatment increased levels of circulating CD-8+ T-effector cells, indicating a potential immune activation, but also raised levels of myeloid-derived suppressor cells and regulatory T cells, which can suppress immune responses.

The study found significant changes in immune mediators, including decreased CXCL10 and increased CXCL16, suggesting that fractionated chemoradiation has both immune-stimulating and suppressive effects, highlighting the potential for future combinations with immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer. Sridharan, V., Margalit, DN., Lynch, SA., et al.[2022]

In a study of 27 early breast cancer patients, hypofractionated whole-breast irradiation with a daily boost showed low skin toxicity, with 92.6% of patients experiencing no skin toxicity after 18 months.

The treatment resulted in excellent cosmetic outcomes, with minimal breast edema and skin changes, suggesting it is a feasible alternative to traditional longer radiation schedules, although longer follow-up is needed to confirm local control rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated hypofractionated whole-breast irradiation with concomitant daily boost in early breast cancer. Kyrgias, G., Zygogianni, A., Theodorou, K., et al.[2022]

Hypofractionated radiation therapy (hRT) combined with anti-PD1 antibody treatment effectively inhibits tumor growth and improves survival in mice, regardless of whether a short (3 days) or extended (5 days) hRT schedule is used, highlighting the treatment's efficacy.

The study found that the presence of regional lymph nodes is crucial for generating sufficient tumor-specific T cells, which are necessary for the antitumor effects, suggesting that both short and extended hRT schedules can be effective if T cell infiltration is maintained.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abscopal Effects With Hypofractionated Schedules Extending Into the Effector Phase of the Tumor-Specific T-Cell Response. Zhang, X., Niedermann, G.[2019]

Focal radiation therapy (RT) significantly enhances the effectiveness of PD-1 blockade and VISTA blockade in treating metastatic triple-negative breast cancer (TNBC) in a murine model, suggesting a potential new strategy for overcoming resistance to immunotherapy.

Combining RT with cyclophosphamide and dual PD-1/VISTA blockade resulted in superior therapeutic effects, linked to increased activation of CD8+ T cells and reduced levels of suppressive immune cells, indicating a promising multipronged approach for improving treatment outcomes in TNBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Converging focal radiation and immunotherapy in a preclinical model of triple negative breast cancer: contribution of VISTA blockade. Pilones, KA., Hensler, M., Daviaud, C., et al.[2021]

In a study of 348 patients under 50 years old who received hypofractionated whole-breast radiation therapy after breast-conserving surgery, the treatment showed high efficacy with a 99.6% overall survival rate and 96.3% disease-free survival rate at a median follow-up of 66.9 months.

The cosmetic outcomes were favorable, with 93.4% of clinician-rated cases being excellent or good, although patients tended to rate their own cosmetic results lower than clinicians did, indicating a discrepancy in perception.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated Whole-Breast Irradiation in Women Less Than 50 Years Old Treated on 4 Prospective Protocols. Shaikh, F., Chew, J., Hochman, T., et al.[2019]

In a study of 274 early breast cancer patients treated with hypofractionated radiation treatment (HFRT) over a median follow-up of 7 years, the local recurrence-free survival rate was very high at 97.2%, indicating that HFRT is effective in preventing local cancer recurrence.

The acute toxicity associated with HFRT was generally low, with most patients experiencing less than grade 3 side effects, suggesting that HFRT is a safe treatment option for eligible patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated radiation treatment in early breast cancer: Results in a New Zealand setting. James, ML., Dehn, G., Robinson, BA.[2018]

In a study of 2309 breast cancer patients, those receiving hypofractionated radiotherapy experienced significantly less acute skin reactions and pain compared to those receiving conventional fractionation, indicating a safer treatment option.

Hypofractionation also resulted in lower levels of patient-reported symptoms like burning, swelling, and fatigue during treatment, suggesting it may enhance patient comfort without compromising long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences in the Acute Toxic Effects of Breast Radiotherapy by Fractionation Schedule: Comparative Analysis of Physician-Assessed and Patient-Reported Outcomes in a Large Multicenter Cohort. Jagsi, R., Griffith, KA., Boike, TP., et al.[2022]

In a study of 339 breast cancer patients receiving hypofractionated radiotherapy, the majority experienced mild to moderate acute skin toxicity, with only 4% reporting severe reactions, indicating a generally well-tolerated treatment.

Radiation pneumonitis occurred in 3.2% of patients, primarily those receiving regional lymphatics radiotherapy, suggesting that while hypofractionated schedules are effective, careful monitoring is needed for specific side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated radiotherapy for breast cancer patients treated by breast-conserving surgery: short-term morbidity and preliminary results. Plataniotis, GA., Theofanopoulou, MA., Sotiriadou, K., et al.[2018]

The FORCE study is a phase II trial involving 130 patients with stage IV non-squamous non-small cell lung cancer, investigating the effects of nivolumab combined with hypofractionated palliative radiotherapy, aiming to assess its safety and efficacy in improving response rates and survival outcomes.

Preliminary data suggest that combining nivolumab with radiation therapy may enhance immune responses against tumors, potentially leading to better treatment outcomes compared to nivolumab alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fostering efficacy of anti-PD-1-treatment: Nivolumab plus radiotherapy in advanced non-small cell lung cancer - study protocol of the FORCE trial. Bozorgmehr, F., Hommertgen, A., Krisam, J., et al.[2020]

Spatially Fractionated Radiation Therapy (SFRT) delivers radiation in a unique pattern that can enhance immune activation in tumors, potentially improving treatment outcomes for metastatic cancer.

Combining SFRT with immune checkpoint inhibitors (ICIs) may overcome the limitations of ICIs in 'cold' tumor environments, leading to better efficacy in cancer treatment as supported by both preclinical and clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining spatially fractionated radiation therapy (SFRT) and immunotherapy opens new rays of hope for enhancing therapeutic ratio. Lu, Q., Yan, W., Zhu, A., et al.[2023]

References

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

Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer. [2022]

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

Accelerated hypofractionated whole-breast irradiation with concomitant daily boost in early breast cancer. [2022]

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

Abscopal Effects With Hypofractionated Schedules Extending Into the Effector Phase of the Tumor-Specific T-Cell Response. [2019]

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

Converging focal radiation and immunotherapy in a preclinical model of triple negative breast cancer: contribution of VISTA blockade. [2021]

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

Hypofractionated Whole-Breast Irradiation in Women Less Than 50 Years Old Treated on 4 Prospective Protocols. [2019]

6. Australia pubmed.ncbi.nlm.nih.gov

Hypofractionated radiation treatment in early breast cancer: Results in a New Zealand setting. [2018]

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

Differences in the Acute Toxic Effects of Breast Radiotherapy by Fractionation Schedule: Comparative Analysis of Physician-Assessed and Patient-Reported Outcomes in a Large Multicenter Cohort. [2022]

8. Japan pubmed.ncbi.nlm.nih.gov

Hypofractionated radiotherapy for breast cancer patients treated by breast-conserving surgery: short-term morbidity and preliminary results. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Fostering efficacy of anti-PD-1-treatment: Nivolumab plus radiotherapy in advanced non-small cell lung cancer - study protocol of the FORCE trial. [2020]

10. Ireland pubmed.ncbi.nlm.nih.gov

Combining spatially fractionated radiation therapy (SFRT) and immunotherapy opens new rays of hope for enhancing therapeutic ratio. [2023]