Radiation + Pembrolizumab + Olaparib for Breast Cancer

Recruiting at 6 trial locations

Overseen By Atif Khan, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Pregnancy, Active infection, Autoimmune disease, 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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

34 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether adding pembrolizumab, with or without olaparib, to standard radiation therapy is a safe and effective treatment for metastatic breast cancer, , and to see whether the study treatment is better than, the same as, or worse than the usual approach (radiation therapy alone).

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

The trial requires a washout period (time without taking certain medications) of at least 2 weeks for all anti-cancer agents and certain other medications before starting the study treatment. If you are taking strong or moderate CYP3A inhibitors or inducers, specific washout periods of 2 to 5 weeks are required. Please consult with the trial team to discuss your specific medications.

What data supports the effectiveness of the treatment Radiation + Pembrolizumab + Olaparib for Breast Cancer?

Research suggests that combining radiation with pembrolizumab (an immunotherapy drug) can enhance immune responses against cancer, as seen in studies with breast cancer and other types like lung cancer. Additionally, early clinical trials have shown promising results when combining radiation and immunotherapy in breast cancer, indicating potential benefits of this treatment approach. ^{1 2 3 4 5}

Is the combination of radiation, pembrolizumab, and olaparib safe for humans?

There are reports of potential safety concerns when combining radiation with pembrolizumab, such as immune-related adverse events and skin reactions. These effects suggest that caution is needed when using this combination, as it may increase the risk of side effects. ^{3 5 6 7 8}

How is the treatment of Radiation + Pembrolizumab + Olaparib for breast cancer different from other treatments?

This treatment is unique because it combines radiation therapy, which can enhance the immune response against tumors, with pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells, and olaparib, a drug that targets cancer cell DNA repair mechanisms. This combination aims to improve both local and systemic cancer control by leveraging different mechanisms to fight breast cancer. ^{1 2 3 4 5}

Research Team

Atif Khan, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for women at least 18 years old with metastatic or recurrent triple-negative or hormone-receptor positive/Her2 negative breast cancer. Participants must not be pregnant, breastfeeding, and should follow contraceptive guidance. They need to have stable organ function and performance status (ECOG) of 0-1. Those with HIV, active TB or hepatitis, severe allergies to study drugs, certain previous treatments or conditions that could affect the study's outcome are excluded.

Inclusion Criteria

My organs are functioning well according to the test results.

I can swallow and keep down pills.

Participant must agree not to breastfeed during the study or for 180 days after the last dose of study treatment

Exclusion Criteria

Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements

Previous enrollment in the present study

I am not taking strong or moderate CYP3A inhibitors.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab with or without olaparib in combination with standard radiation therapy

8 weeks

Regular visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Olaparib
• Pembrolizumab
• Radiation

Trial Overview The trial tests if adding pembrolizumab (an immunotherapy drug), with or without olaparib (a targeted therapy drug), to standard radiation therapy is more effective for treating metastatic breast cancer than radiation alone. The safety and effectiveness of these combinations are being compared.

Participant Groups

Group I: Arm C (activate new arm) Experimental Treatment 3 Interventions

Participants will have metastatic ER+ breast cancer (ER+ MBC) Treatment will be pembro/SBRT/Olaparib)

Group II: Arm B (the study is amended to pause Arm B) Experimental Treatment 2 Interventions

Participants will have triple negative breast cancer diagnosis Treatment will be pembro + RT only

Group III: Arm A Experimental Treatment 3 Interventions

Participants will have triple negative breast cancer diagnosis Treatment will be pembro + RT + olaparib

Radiation is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in United States as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in Canada as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in Japan as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in China as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in Switzerland as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

In a pooled analysis of 148 patients with metastatic non-small-cell lung cancer, adding radiotherapy to pembrolizumab significantly improved the best out-of-field response rate (41.7% vs 19.7%) and best disease control rate (65.3% vs 43.4%), indicating enhanced efficacy of the combination treatment.

Patients receiving the combination therapy also experienced longer median progression-free survival (9.0 months vs 4.4 months) and overall survival (19.2 months vs 8.7 months) compared to those receiving pembrolizumab alone, with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Theelen, WSME., Chen, D., Verma, V., et al.[2021]

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]

The KEYLYNK-012 study is a phase III clinical trial evaluating the effectiveness of pembrolizumab combined with chemoradiotherapy in patients with stage III non-small-cell lung cancer (NSCLC), involving participants aged 18 and older with unresectable disease.

This study aims to determine if the addition of pembrolizumab, with or without olaparib, improves progression-free survival and overall survival compared to standard concurrent chemoradiotherapy, with enrollment ongoing at around 190 sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. Jabbour, SK., Cho, BC., Bria, E., et al.[2022]

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]

In a phase 2 clinical trial involving 17 patients with metastatic triple-negative breast cancer, the combination of pembrolizumab and radiotherapy showed an overall response rate of 17.6%, with three patients achieving complete responses that lasted up to 108 weeks.

The treatment was found to be safe, with the most common side effects being mild dermatitis, and no treatment-related deaths or severe adverse events reported, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer. Ho, AY., Barker, CA., Arnold, BB., et al.[2020]

Combining ionizing radiation therapy (RT) with PD-1/PD-L1 inhibitors has shown promise in enhancing the immune response against tumors, making it a compelling treatment strategy for various cancers.

The review discusses both preclinical and clinical data supporting the safety and efficacy of this combination, emphasizing the need for careful clinical trial design to optimize outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. Gong, J., Le, TQ., Massarelli, E., et al.[2023]

The combination of localized radiotherapy and immune checkpoint inhibitors, like pembrolizumab, may enhance the immune response against tumors, particularly in metastatic melanoma, but clinical data on this combination is limited.

A case report indicates that pembrolizumab may cause acute skin radiosensitization when used with radiation therapy, suggesting a rapid interaction that warrants caution in prescribing this combination for advanced cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute skin reaction suggestive of pembrolizumab-induced radiosensitization. Sibaud, V., David, I., Lamant, L., et al.[2015]

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]

References

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

Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. [2021]

2. 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]

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

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. [2022]

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

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

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

A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. [2023]

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

Acute skin reaction suggestive of pembrolizumab-induced radiosensitization. [2015]

8. 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]