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

35 Participants Needed

Trial Summary

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.

What data supports the idea that Myeloid Inhibition + Radiation for Breast Cancer is an effective treatment?

The available research does not provide specific data on the effectiveness of Myeloid Inhibition + Radiation for Breast Cancer. The studies mentioned focus on different types of radiation therapies and their applications in other cancers, such as prostate and esophageal cancer, rather than breast cancer specifically. Therefore, there is no direct evidence from the provided information to support the effectiveness of this treatment for breast cancer. ^{1 2 3 4 5}

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

Research shows that intensity-modulated radiation therapy (IMRT), a part of this treatment, is increasingly used for breast cancer management due to its precise targeting, which can help reduce side effects. Additionally, proton beam therapy, another component, has been shown to reduce damage to normal organs in other cancers, suggesting potential benefits for breast cancer as well. ^{1 2 3 4 5}

What safety data exists for Myeloid Inhibition + Radiation in breast cancer treatment?

The safety data for treatments involving pembrolizumab (Keytruda), a PD-1 inhibitor, indicate potential immune-related adverse events (irAEs) such as type 1 diabetes mellitus (0.2% of cases), pneumonitis (1%-5% of cases), and other immune-mediated reactions like colitis, hepatitis, and thyroid disorders. Additionally, combining pembrolizumab with radiotherapy may increase the risk of irAEs, as seen in a case of immune thrombocytopenia following radiotherapy. These findings suggest that while pembrolizumab is effective, it carries risks of significant irAEs, especially when combined with radiotherapy. ^{6 7 8 9 10}

Is the combination of pembrolizumab and radiation therapy generally safe for humans?

Pembrolizumab, used in cancer treatment, can cause immune-related side effects like type 1 diabetes and pneumonitis (lung inflammation) in a small percentage of patients. When combined with radiation therapy, there may be an increased risk of immune-related side effects, such as immune thrombocytopenia (a condition where the immune system attacks platelets, leading to bleeding). ^{6 7 8 9 10}

Is the treatment Axatilimab, Pembrolizumab, and Radiation Therapy promising for breast cancer?

Yes, combining radiation therapy with drugs like Pembrolizumab and Axatilimab shows promise for breast cancer. Radiation can boost the immune system's response to cancer, making it a good partner for drugs that help the immune system fight tumors. This combination could potentially improve treatment outcomes for breast cancer patients. ^{10 11 12 13 14}

What makes the treatment with Axatilimab, Pembrolizumab, and Radiation Therapy unique for breast cancer?

This treatment is unique because it combines radiation therapy, which can stimulate the immune system, with pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, and axatilimab, which targets the Axl receptor to enhance the immune response. This combination aims to overcome the resistance of breast cancer to checkpoint inhibitors alone by modifying the tumor environment and boosting the body's immune response. ^{10 11 12 13 14}

What is the purpose of this trial?

This is an open-label prospective, single institution, Phase II study of pembrolizumab in combination with radiation therapy and CSF-1R inhibition in patients with high-risk TNBC. The primary objective is to assess the pathologic complete response (pCR) rate where pCR is defined as the absence of invasive disease in the breast and lymph nodes at the time of standard of care (SOC) treatment. Secondary objectives include evaluating the change in tumor infiltrating lymphocytes (TILs), safety and tolerability of the combination, progression-free survival, event-free survival, overall survival, and node clearance.

Research Team

Stephen L Shiao, MD, PhD

Principal Investigator

CSMC

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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, 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]

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]

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]

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]

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]

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]

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]

References

1. France pubmed.ncbi.nlm.nih.gov

[Modalities of breast cancer irradiation in 2016: Aims and indications of intensity modulated radiation therapy]. [2017]

2. England 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. [2018]

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

Comparison of arc-modulated cone beam therapy and helical tomotherapy for three different types of cancer. [2019]

4. Ireland 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. [2023]

5. United States 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. [2018]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

10. Japan 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. [2022]

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

Combined Radiation Therapy and Immune Checkpoint Blockade Therapy for Breast Cancer. [2018]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Radiation therapy and immunotherapy-a potential combination in cancer treatment. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Reprogramming the immunological microenvironment through radiation and targeting Axl. [2022]