Radiation + Immunotherapy for Breast Cancer

(BreastVAX Trial)

Overseen By Michelle Gelman

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Abramson Cancer Center of the University of Pennsylvania

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: Pregnancy, Autoimmune disease, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

27 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary objective is to determine the feasibility of combining pembrolizumab with a single fraction radiation boost in patients with early/ operable breast cancer. The secondary objectives are to assess clinical response on pre- and post-treatment clinical, imaging, and histology exams, and to assess immune response on pre and post treatment blood and tissue samples by tracking change in Ki67 + CD8 T cells in peripheral blood and in extent of tumor infiltrating lymphocytes. A clinically significant partial response is defined as \>30% tumor shrinkage post-clinical trial intervention.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that participants should not have received certain cancer therapies recently and should not have active infections requiring treatment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment combining radiation and immunotherapy for breast cancer?

Research shows that combining radiation with immunotherapy, like pembrolizumab (Keytruda), can enhance the body's immune response against tumors. This combination has shown promise in various cancers, including breast cancer, by potentially improving outcomes and increasing the effectiveness of the treatment. ^{1 2 3 4 5}

Is the combination of radiation and pembrolizumab (Keytruda) generally safe for humans?

Pembrolizumab (Keytruda) has been used in various cancer treatments and is generally considered safe, but it can cause side effects like fatigue, cough, nausea, and more serious immune-related issues like pneumonitis (lung inflammation) and thyroid disorders. These side effects have been observed in treatments for conditions like melanoma and head and neck cancer. ^{6 7 8 9 10}

How is the treatment of pembrolizumab with radiation unique for breast cancer?

This treatment is unique because it combines pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells, with radiation therapy, which can enhance the immune response against tumors. This combination aims to improve the effectiveness of treatment by using the body's own defenses alongside traditional radiation. ^{2 3 6 9 10}

Research Team

Julia C Tchou, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

This trial is for adults over 18 with early-stage breast cancer who can handle radiation therapy and have good overall health. They must not have had recent cancer treatments, no severe psychiatric or substance abuse issues, no active infections or certain viruses like HIV, Hepatitis B/C, and should not be pregnant.

Inclusion Criteria

My blood, kidney, liver, thyroid, and bone marrow are functioning well.

I am fully active or restricted in physically strenuous activity but can do light work.

My breast cancer is in the early stages and I'm not receiving certain types of chemotherapy.

Exclusion Criteria

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

Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial

I have been diagnosed with HIV.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preoperative Treatment

Participants receive either pembrolizumab followed by radiotherapy or radiotherapy followed by pembrolizumab

2 weeks

2 visits (in-person)

Surgery

Participants undergo surgery on day 0

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including blood and tissue sampling

2 years

Regular visits (in-person) for blood and tissue sampling

Treatment Details

Interventions

• Blood and tissue sampling
• Hypofractionated radiotherapy
• Pembrolizumab

Trial Overview The study tests if adding a single dose of radiation (hypofractionated radiotherapy) to pembrolizumab (an immune therapy drug) is feasible in treating early breast cancer. It also looks at how the tumor responds clinically and immunologically before and after treatment.

Participant Groups

Group I: Arm 4 (Historical Controls) Experimental Treatment 1 Intervention

Arm 4 will not receive any study treatment. Subjects will undergo surgery on day 0 and follow a preoperative (Day 0) and postoperative blood (Day 30) and tissue (Day 0) sampling schedule.

Group II: Arm 2 Active Control 3 Interventions

Arm 2 will receive pembrolizumab on day -14 and radiotherapy on day -7. Subjects in all arms will undergo surgery on day 0 and follow the same postoperative blood sampling and safety schedule.

Group III: Arm 1 Active Control 3 Interventions

Arm 1 will receive radiotherapy on day -14 and pembrolizumab on day -7. Subjects in all arms will undergo surgery on day 0 and follow the same postoperative blood sampling and safety schedule.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Abramson Cancer Center of the University of Pennsylvania

Lead Sponsor

Trials

360

Recruited

108,000+

Abramson Cancer Center at Penn Medicine

Lead Sponsor

Trials

425

Recruited

464,000+

Findings from Research

In a study of 98 patients with advanced non-small-cell lung cancer (NSCLC), those who had previously received radiotherapy experienced significantly longer progression-free survival (4.4 months) and overall survival (10.7 months) when treated with pembrolizumab compared to those without prior radiotherapy.

The safety profile was acceptable, with similar rates of severe pulmonary toxicity between patients who had and had not received thoracic radiotherapy, suggesting that combining radiotherapy with pembrolizumab may be a beneficial treatment strategy for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Shaverdian, N., Lisberg, AE., Bornazyan, 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 (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

In a study involving 8 patients with hormone receptor-positive metastatic breast cancer, combining pembrolizumab with palliative radiation therapy did not result in any objective responses, leading to the study's closure.

The median progression-free survival was only 1.4 months and overall survival was 2.9 months, indicating limited efficacy of this treatment combination in heavily pre-treated patients, although the treatment was generally safe with only one significant adverse event reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer. Barroso-Sousa, R., Krop, IE., Trippa, L., et al.[2021]

Radiation therapy not only helps eliminate cancer cells but also modifies the tumor microenvironment, potentially enhancing the body's immune response against tumors.

Combining radiation with immune checkpoint inhibitors has shown promise in early clinical trials for breast cancer, suggesting a synergistic effect that could improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Combining Radiation and Immunotherapy in Breast Cancer. Nguyen, AT., Shiao, SL., McArthur, HL.[2021]

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) received accelerated FDA approval for treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) based on a study of 174 patients, showing an objective response rate of 16% and a duration of response ranging from 2.4 to 27.7 months.

The safety profile included serious adverse reactions such as pneumonia and respiratory failure, but the overall benefit-risk assessment was deemed acceptable, marking pembrolizumab as the first new treatment option for HNSCC since 2006.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. Larkins, E., Blumenthal, GM., Yuan, W., et al.[2019]

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, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

References

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

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. [2022]

2. 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]

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

New Approved Use for Keytruda. [2022]

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

A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer. [2021]

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

Advances in Combining Radiation and Immunotherapy in Breast Cancer. [2021]

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

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

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

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. [2019]

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

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

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

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

10. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]