Myeloid Inhibition + Radiation for Breast Cancer

Overseen By Clinical Trial Recruitment Navigator

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Stephen Shiao

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Metastatic disease, Active TB, 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: Unknown

Duration: 7 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for high-risk triple-negative breast cancer (TNBC), which does not respond to hormonal therapy. The study focuses on using pembrolizumab (a type of immunotherapy), radiation therapy, and axatilimab (an experimental treatment) to determine if they can eliminate cancer in the breast and lymph nodes. It is open to women diagnosed with TNBC who plan to start neoadjuvant therapy (treatment given before the main treatment). Participants should have specific cancer characteristics, such as a low score of immune cells in the tumor or certain protein markers. The goal is to assess the effectiveness and safety of this treatment combination in stopping cancer progression and improving survival rates. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on systemic steroid therapy or any immunosuppressive therapy within 7 days before the trial, or if you've had certain cancer treatments recently. It's best to discuss your specific medications with the trial team.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy or any immunosuppressive therapy, you must stop these at least 7 days before starting the trial treatment.

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

Research shows that pembrolizumab is usually well-tolerated. Studies have demonstrated that adding pembrolizumab to chemotherapy extends the lives of patients with triple-negative breast cancer (TNBC). Common side effects include tiredness and skin reactions, which are usually manageable.

Research indicates that axatilimab is also well-tolerated. Common side effects are tiredness and mild skin reactions, and most patients manage these effects without stopping treatment.

Radiation therapy is a common treatment for breast cancer. It can cause skin irritation and tiredness, but these effects often improve after treatment ends.

Overall, these treatments have been tested in people and are generally safe, with typically manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for breast cancer because it combines Axatilimab and Pembrolizumab with radiation therapy, offering a novel approach to a challenging condition. Unlike standard treatments, which typically include surgery, chemotherapy, and hormone therapy, this combination targets myeloid cells, potentially enhancing the immune response against cancer cells. Axatilimab specifically inhibits the colony-stimulating factor-1 receptor (CSF-1R), reducing the immunosuppressive environment that tumors often create. This innovative mechanism, alongside Pembrolizumab's immune checkpoint inhibition, could lead to more effective treatment outcomes by bolstering the body's natural defenses against tumor growth.

What evidence suggests that this trial's treatments could be effective for high-risk TNBC?

This trial will study the combination of pembrolizumab, axatilimab, and radiation therapy for individuals with high-risk triple-negative breast cancer (TNBC). Research has shown that pembrolizumab with chemotherapy can extend the lives of TNBC patients, with 86.6% of those receiving this combination surviving after five years. Axatilimab has proven effective in treating other conditions, achieving a 74% success rate in chronic graft-versus-host disease, suggesting potential usefulness in cancer treatment. Radiation therapy is a well-established method for treating breast cancer, reducing recurrence by up to 15% and lowering long-term death rates. This trial will evaluate the combined effectiveness of these treatments for high-risk TNBC. ^{1 2 3 6 7}

Who Is on the Research Team?

Stephen L Shiao, MD, PhD

Principal Investigator

CSMC

Are You a Good Fit for This Trial?

This trial is for women over 18 with high-risk triple negative breast cancer (TNBC) who haven't had certain treatments recently. They must have low immune cell counts in their tumors, be able to provide tissue samples, and show good organ function. Pregnant or breastfeeding women can't join, nor can those with recent other cancers, serious infections like HIV or hepatitis, autoimmune diseases treated within the last two years, or brain metastases.

Inclusion Criteria

I am willing to provide a new biopsy sample if my old cancer tissue is not available.

Written informed consent obtained from subject and ability for subject to comply with the requirements of the study, including consent for research blood draws and use of available archived tissue

Your tumor has a low amount of certain immune cells called tumor-infiltrating lymphocytes (TIL), which is measured as stromal TIL (sTIL) being less than or equal to 40%.

Exclusion Criteria

I have an active tuberculosis infection.

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

I am not pregnant or breastfeeding and do not plan to become pregnant during the trial.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab in combination with radiation therapy and CSF-1R inhibition

7 weeks

Weekly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Regular follow-up visits

Long-term follow-up

Participants are monitored for event-free survival and overall survival

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Axatilimab
• Pembrolizumab
• Radiation Therapy

Trial Overview The study tests pembrolizumab combined with radiation therapy and CSF-1R inhibition (Axatilimab) on TNBC patients. It aims to see if this combo increases the rate of complete disappearance of cancer from the breast and lymph nodes after standard treatment. Other goals include checking safety and how long patients live without cancer progression.

How Is the Trial Designed?

Group I: Pembrolizumab with Radiation Therapy and Axatilimab Experimental Treatment 3 Interventions

Axatilimab is already approved in United States for the following indications:

Approved in United States as Axatilimab for:

• Chronic Graft-Versus-Host Disease

Who Is Running the Clinical Trial?

Stephen Shiao

Lead Sponsor

Trials

2

Recruited

100+

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

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Published Research Related to This Trial

In a study of 343 esophageal cancer patients treated with definitive chemoradiotherapy, proton beam therapy (PBT) showed significantly better overall survival and progression-free survival compared to intensity-modulated radiation therapy (IMRT).

PBT was particularly beneficial for patients with stage III disease, demonstrating a 5-year overall survival rate of 34.6% compared to 25.0% for IMRT, while no significant differences were found for patients with earlier stages of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Outcomes After Definitive Chemoradiotherapy Using Proton Beam Therapy Versus Intensity Modulated Radiation Therapy for Esophageal Cancer: A Retrospective, Single-Institutional Analysis. Xi, M., Xu, C., Liao, Z., et al.[2018]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

A 74-year-old woman with lung adenocarcinoma developed fatal immune thrombocytopenia after receiving pembrolizumab following radiotherapy, highlighting a potential risk of severe immune-related adverse events (irAEs) when combining these treatments.

Flow cytometry analysis showed increased PD-1 and Ki-67 expression in T cells post-radiotherapy, suggesting that radiotherapy may enhance immune activation and contribute to the development of irAEs in patients undergoing anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy. Tamanoi, D., Saruwatari, K., Imamura, K., et al.[2022]

Pembrolizumab, an immunotherapy targeting PD-1, showed limited effectiveness in a patient with metastatic renal cell carcinoma, highlighting that only 20-40% of patients benefit from such treatments due to individual tumor biology and immune checkpoint diversity.

The patient's rapid disease progression during treatment may be linked to a lack of tumor-infiltrating lymphocytes (TILs) and the specific radiation dose and schedule used, which could affect the tumor microenvironment and the potential synergy with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. Alexander, GS., Palmer, JD., Tuluc, M., et al.[2022]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

The study found that combining ionizing radiation therapy (RT) with checkpoint immunotherapy can effectively cure certain breast cancers, but responses vary based on the tumor's immune characteristics.

In tumors that did not respond to treatment, the overexpression of the Axl receptor was linked to reduced immune response and increased tumor growth; knocking out Axl improved radiosensitivity and enhanced the immune response, suggesting Axl plays a role in suppressing effective anti-tumor immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reprogramming the immunological microenvironment through radiation and targeting Axl. Aguilera, TA., Rafat, M., Castellini, L., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

Arc-modulated cone beam therapy (AMCBT) provides comparable dose distribution quality to helical tomotherapy for prostate cancer, with advantages of faster treatment delivery and lower integral dose.

While AMCBT is effective for simpler tumor geometries, it may not achieve the same level of dose shaping for highly complex cases as helical tomotherapy, but remains clinically acceptable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of arc-modulated cone beam therapy and helical tomotherapy for three different types of cancer. Ulrich, S., Sterzing, F., Nill, S., et al.[2019]

Checkpoint inhibitors alone have shown limited effectiveness in breast cancer, with response rates up to 19%, but combining them with radiation therapy (RT) may enhance their efficacy.

Preclinical studies suggest that RT not only boosts the immune response against tumors but also can trigger responses in areas outside the radiation field, making it a promising adjuvant therapy alongside checkpoint inhibitors in breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Radiation Therapy and Immune Checkpoint Blockade Therapy for Breast Cancer. Hu, ZI., Ho, AY., McArthur, HL.[2018]

Radiation therapy (RT) can enhance the effectiveness of immunotherapy, particularly through mechanisms like the abscopal effect, where localized treatment can lead to systemic anti-tumor responses.

Combining hyperfractionated radiation therapy with immune checkpoint blockade shows promise for improving clinical outcomes in cancer treatment, suggesting a synergistic approach to targeting tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy and immunotherapy-a potential combination in cancer treatment. Asna, N., Livoff, A., Batash, R., et al.[2019]

Intensity-modulated radiation therapy (IMRT) is becoming a more popular option for treating breast cancer, as it allows for more precise targeting of tumors while minimizing damage to surrounding healthy tissue.

The review discusses important planning issues and potential clinical toxicities associated with IMRT, highlighting its growing role in breast cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Modalities of breast cancer irradiation in 2016: Aims and indications of intensity modulated radiation therapy]. Bourgier, C., Fenoglietto, P., Lemanski, C., et al.[2017]

Proton beam therapy (PBT) for prostate cancer patients receiving pelvic radiation significantly reduces acute gastrointestinal (GI) toxicity compared to intensity modulated radiation therapy (IMXT), with rates of grade 1, 2, and 3 GI toxicity at 16.4%, 2.4%, and 0%, respectively.

The study involved 85 patients with a median follow-up of 14.5 months, and while GU toxicity was higher, the results suggest that PBT may spare the small bowel, leading to less GI side effects, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minimal toxicity after proton beam therapy for prostate and pelvic nodal irradiation: results from the proton collaborative group REG001-09 trial. Chuong, MD., Hartsell, W., Larson, G., et al.[2018]

In a pooled analysis of 312 HER-2 positive breast cancer patients, those who achieved a complete nodal pathological response (ypN0) after primary systemic therapy showed excellent loco-regional recurrence-free survival (LRRFS) rates of 97%, suggesting that post-mastectomy radiation therapy (PMRT) may not be necessary for these patients.

Conversely, patients with ypN2-3 disease who received PMRT had a significantly better 5-year LRRFS of 92% compared to 75% for those who did not, indicating that PMRT provides substantial benefits for patients with more advanced nodal involvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-mastectomy radiation therapy in HER-2 positive breast cancer after primary systemic therapy: Pooled analysis of TRYPHAENA and NeoSphere trials. Saifi, O., Bachir, B., Panoff, J., et al.[2023]

Citations

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Safety and Efficacy of Axatilimab at 3 Different Doses in ... Karolina Faysman, RN, MSN, AOCNP, DNPc, highlights efficacy, safety, and patient-reported outcomes from the phase 2 AGAVE-201 trial ...

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Safety and Efficacy Results from AGAVE-201 (Axatilimab ... 74% overall response rate · Median time to response of 1.4-1.7 months · Median failure-free survival of approximately 11 months · Main adverse ...

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AXALAP: Phase Ib study of axatilimab in combination with ... In the Phase I SNDX-6352-0502 study for advanced solid tumors, axatilimab showed tolerability at the highest dose (6 mg/kg), with biomarker ...

4. onclive.com onclive.com/view/dr-kitko-on-clinical-outcomes-with-axatilimab-according-to-prior-lines-of-therapy-for-chronic-gvhd

Dr Kitko on Clinical Outcomes With Axatilimab According to ... For patients who received axatilimab at 0.3 mg/kg, the ORRs were 63.3% (95% CI, 43.9%-80.1%) in the prior CR/PR group (n = 30), 81.3% (95% CI, ...

5. targetedonc.com targetedonc.com/view/agave-201-outcomes-support-low-dose-of-axatilimab-for-chronic-gvhd

AGAVE-201 Outcomes Support Low Dose of Axatilimab for ... In the joints and fascia, there was a good response rate at 76%, but similar to what we saw with belumosudil [Rezurock] there was a low CR rate.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06488378

Phase Ib Study of Axatilimab in Combination With Olaparib ... This is a non-randomized, open-label, proof-of-concept phase 1 study to evaluate the safety and tolerability of a drug known as Axatilimab in combination with ...

7. aacrjournals.org aacrjournals.org/clincancerres/article/31/17/3607/764195/FDA-Approval-Summary-Axatilimab-for-Adult-and

Axatilimab for Adult and Pediatric Patients Weighing at Least ... The median duration of response was 1.9 months (95% CI, 1.6–3.5), but 60% (95% CI, 43–74) of responding patients remained alive without new systemic therapy for ...