Immunotherapy + Radiation for Hormone-Sensitive Breast Cancer

(CBCV Trial)

Recruiting at 4 trial locations

Overseen By Sharanya Chandrasekhar, M.S.

Age: 18+

Sex: Female

Trial Phase: Phase 2

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 You can continue your current medications while participating

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 16 weeks

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how combining radiation therapy with immunotherapy can improve treatment for hormone-sensitive breast cancer. Participants will receive standard hormone therapy and then be randomly assigned to receive either radiation alone or with different combinations of immunotherapy, including Pembrolizumab (KEYTRUDA) and CDX-301 (an experimental treatment). It targets post-menopausal women newly diagnosed with stage II-III breast cancer that tests positive for hormone receptors but negative for HER2. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research shows that each treatment option in the trial has undergone prior testing in people and has established safety records.

Studies have found focal radiation therapy to be generally well-tolerated. Patients might experience side effects like skin irritation or tiredness, but these are usually manageable. Long-term side effects are under close observation, but this treatment is commonly used in cancer care.

Pembrolizumab, an immunotherapy drug, has treated various cancers. It can cause immune system-related side effects that might affect different organs, but these are often mild and manageable. More severe reactions are rare but possible, so they are monitored closely.

Trials have shown that the Flt3 ligand (CDX-301) is mostly well-tolerated, with serious side effects being rare. It helps boost certain immune cells and has been tested with other treatments like radiation.

Overall, these treatments have safety data from previous studies. While side effects can occur, ongoing trials are crucial to better understand safety in specific groups, such as those with hormone-sensitive breast cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for hormone-sensitive breast cancer because they combine immunotherapy and targeted radiation in innovative ways. Unlike standard treatments, which often involve hormone therapy or chemotherapy, these investigational options introduce FT3 ligand and pembrolizumab to boost the immune system's response against cancer cells. The FT3 ligand, delivered through subcutaneous injections, stimulates immune activity, while pembrolizumab, an immune checkpoint inhibitor, is given intravenously to enhance the body's ability to fight the cancer. Additionally, focal hypo-fractionated radiation delivers concentrated doses of radiation over a shorter period, potentially reducing treatment time and improving effectiveness. This combination could offer a more targeted approach, minimizing side effects and maximizing cancer cell destruction.

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

In this trial, participants will receive different combinations of treatments to evaluate their effectiveness for hormone-sensitive breast cancer. One treatment arm involves focal hypo-fractionated radiation therapy. Previous studies have shown that this method effectively lowers the risk of breast cancer returning by using higher doses of radiation over fewer sessions. Another arm includes pembrolizumab, a drug that helps the immune system fight cancer. It has improved outcomes for some breast cancer patients when combined with other treatments, particularly for those with hormone receptor-positive breast cancer. Additionally, CDX-301, part of another treatment arm, has been effective in increasing immune cells that help fight cancer. These findings suggest that the various combinations of treatments tested in this trial could effectively treat hormone-sensitive breast cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Silvia Formenti

Principal Investigator

Weill Cornell Medicine - New York Presbyterian Hospital

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• CDX-301
• Focal Radiation therapy
• Pembrolizumab

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.

How Is the Trial Designed?

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).

Focal Radiation therapy is already approved in United States, European Union for the following indications:

Approved in United States as Radiation Therapy for:

• Breast cancer
• Various types of cancer

Approved in European Union as Radiation Therapy for:

• Breast cancer
• Various types of cancer

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4532305/

Efficacy and safety of CDX-301, recombinant human Flt3L ... CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells, and key subsets of myeloid DC and plasmacytoid DC.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04616248

NCT04616248 | In Situ Immunomodulation With CDX-301, ... This phase I trial evaluates the safety and effectiveness of in situ immunomodulation with CDX-301, radiotherapy, CDX-1140 and Poly-ICLC (Cohort A) and ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12289982/

The untapped potential of radiation and immunotherapy for ... Hormone receptor-positive breast cancers are a diverse group of tumours, with only some responding well to immunotherapy.

4. researchgate.net researchgate.net/publication/275525039_Efficacy_and_safety_of_CDX-301_recombinant_human_Flt3L_at_expanding_dendritic_cells_and_hematopoietic_stem_cells_in_healthy_human_volunteers

(PDF) Efficacy and safety of CDX-301, recombinant human ... CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0305737224001816

Estrogen Signaling in Early-Stage Breast Cancer This review aims to capitalize on the existing translational and clinical evidence on predictors of treatment response in patients with early-stage BC treated ...

6. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/77/NCT04536077/Prot_SAP_000.pdf

Testing the immunologic effects of CDX-301 and ... Adverse events requiring cessation of treatment were rare (<5%). However, FLT3 ligand did not demonstrate definitive anti-tumor activity in ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11247315/

Phase I Study of GS-3583, an FMS-like Tyrosine Kinase 3 ... In patients with advanced non–small cell lung cancer, CDX-301 plus stereotactic body radiotherapy was well tolerated and demonstrated clinical activity (22); ...