Pembrolizumab + Radiation for Mesothelioma

Overseen By Melenda Jeter, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must be taking: Platinum, Pemetrexed

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

Disqualifiers: Immunodeficiency, Active TB, CNS metastases, others

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

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

Compensation: Varies

Number of Visits: 30

Duration: Up to 2 years

24 Participants Needed

Trial Summary

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 patients should not receive steroids during pembrolizumab administration, and there are restrictions on recent chemotherapy, targeted therapy, or radiation therapy. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Pembrolizumab + Radiation for Mesothelioma?

Research shows that combining pembrolizumab (an immunotherapy drug) with radiotherapy can enhance the body's immune response against tumors, as seen in studies with other cancers like lung cancer. Additionally, advanced radiotherapy techniques have been effective in treating challenging cases of mesothelioma, providing a progression-free period without significant side effects. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and Radiation Therapy safe for humans?

Research on stereotactic radiotherapy (a precise form of radiation therapy) combined with immunotherapy (like Pembrolizumab) for brain metastases shows that the timing between treatments can affect safety, but it is generally used as a standard treatment. This suggests that while there may be some risks, the combination is considered safe enough to be used in clinical settings. ^{6 7 8 9 10}

How is the treatment of Pembrolizumab combined with Radiation Therapy unique for mesothelioma?

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 for mesothelioma, a cancer with limited options after standard chemotherapy. ^{1 4 11 12 13}

What is the purpose of this trial?

This phase I trial studies the side effects and best way to give pembrolizumab after radiation therapy in treating patients with pleural malignant mesothelioma. Radiation therapy uses high energy radiation to kill tumor cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab after radiation therapy may kill more tumor cells.

Research Team

Matthew S. Ning

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with pleural malignant mesothelioma who've had certain treatments. They must have acceptable blood and organ function, not be pregnant or breastfeeding, agree to use contraception, and have no severe medical conditions or recent live vaccines. Cohort 1 can't have metastatic disease outside the chest except lymph nodes; Cohort 2 can have any number of prior therapies.

Inclusion Criteria

I am not pregnant and agree to use birth control.

I have had any number of treatments before, including immunotherapy.

You need to have specific blood and chemical levels within a certain range.

Exclusion Criteria

I have been treated with a drug targeting PD-1, PD-L1, or PD-L2 before.

I have a genetic condition like ataxia-telangiectasia or Nijmegen breakage syndrome.

I haven't had any infectious diseases or live vaccines in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation Therapy

Patients undergo either hemithoracic or palliative radiation therapy

1-3 weeks

Treatment

Patients receive pembrolizumab IV every 3 weeks for up to 2 years

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Follow-up at 30 days, every 6 weeks for 48 weeks, then every 12 weeks

Treatment Details

Interventions

• Palliative Radiation Therapy
• Pembrolizumab
• Radiation Therapy

Trial Overview The study tests pembrolizumab's effectiveness when given after radiation therapy in mesothelioma patients. Pembrolizumab is an immunotherapy drug that may boost the immune system's cancer-fighting abilities post-radiation, which aims to shrink tumors by killing cancer cells.

Participant Groups

Group I: Cohort 2 (palliative radiation therapy, pembrolizumab) Experimental Treatment 3 Interventions

Patients undergo palliative radiation therapy over 1-3 weeks to only the region of palliation (a region that does not include the entire side of the chest or thorax). After radiation therapy, patients receive pembrolizumab IV over about 30 minutes on day 1. Courses repeat every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

Group II: Cohort 1 (hemithoracic radiation therapy, pembrolizumab) Experimental Treatment 3 Interventions

Patients undergo hemithoracic radiation therapy. After radiation therapy, patients receive pembrolizumab IV over about 30 minutes on day 1. Courses repeat every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

Radiation Therapy 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
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in United States as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Canada as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Japan as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in China as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Switzerland as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 68 patients with advanced solid tumors, the combination of stereotactic body radiotherapy (SBRT) followed by pembrolizumab showed a high one-year treated metastasis control rate of 89.5%, indicating effective tumor response regardless of whether the tumors received complete or partial radiation coverage.

The study found that treated metastasis control (TMC) was significantly associated with improved overall survival, and SBRT altered tumor gene expression by increasing immune-related genes while decreasing those related to cell cycle and DNA repair, suggesting a mechanism for enhanced immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. Luke, JJ., Onderdonk, BE., Bhave, SR., et al.[2021]

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 phase I trial involving 38 patients with extensive-stage small cell lung cancer, the combination of pembrolizumab and thoracic radiotherapy was found to be safe, with no dose-limiting toxicities observed in the first 35 days of treatment.

The median progression-free survival was 6.1 months and overall survival was 8.4 months, suggesting that while the safety profile is promising, further studies are needed to fully understand the efficacy of this combined treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer. Welsh, JW., Heymach, JV., Chen, D., et al.[2023]

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]

In a study of 289 prostate cancer patients, hypofractionated proton beam therapy (PBT) showed no significant differences in acute adverse event rates or quality of life, as measured by the International Prostate Symptom Score (IPSS), compared to conventionally fractionated PBT.

The study evaluated patients treated with different doses (2.0, 2.5, and 3.0 Gy RBE per fraction) and found that factors like diabetes, age, and androgen deprivation therapy did not influence the IPSS outcomes, suggesting that hypofractionated PBT is a safe option without increased toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute toxicity and patient-reported symptom score after conventional versus moderately hypofractionated proton therapy for prostate cancer. Iizumi, T., Ishikawa, H., Sekino, Y., et al.[2022]

In a study of 59 patients with brain metastases from non-small-cell lung cancer and melanoma, the timing between immunotherapy and stereotactic radiotherapy (SRT) did not significantly affect the local control of tumors or the incidence of severe toxicities.

The main predictor of toxicity was tumor volume, with only 5.1% of patients experiencing grade 3 or higher toxicities, indicating that SRT combined with immunotherapy is generally safe regardless of the timing of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and time lapse between immunotherapy and stereotactic radiotherapy of brain metastases. Cabanie, C., Biau, J., Durando, X., et al.[2021]

Patients with localized prostate cancer treated with 3D conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) reported significant declines in bowel quality of life (QOL) shortly after treatment, while those receiving proton beam therapy (PBT) did not show this decline.

At 12 months, patients treated with PBT experienced significant urinary irritation/obstruction issues, unlike those treated with IMRT or 3DCRT, indicating that different radiation therapies have distinct toxicity profiles affecting patient QOL over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Gray, PJ., Paly, JJ., Yeap, BY., et al.[2022]

Patients with localized prostate cancer treated with 3D conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) reported significant declines in bowel quality of life (QOL) shortly after treatment, while those treated with proton beam therapy (PBT) did not experience this immediate decline.

At 12 months, patients receiving PBT reported significant urinary irritation/obstruction issues, which were not seen in the 3DCRT or IMRT groups, indicating that different radiation therapies have distinct toxicity profiles affecting patient QOL over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Commentary on "Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer." Gray PJ, Paly JJ, Yeap BY, Sanda MG, Sandler HM, Michalski JM, Talcott JA, Coen JJ, Hamstra DA, Shipley WU, Hahn SM, Zietman AL, Bekelman JE, Efstathiou JA. Harvard Radiation Oncology Program, Boston, MA.: Cancer 2013;119(9):1729-35. doi: 10.1002/cncr.27956. [Epub 2013 Feb 22]. Gottschalk, A.[2018]

In a study involving 25 patients with PD-L1-positive malignant pleural mesothelioma, pembrolizumab demonstrated a 20% objective response rate, indicating potential anti-tumor activity in this aggressive cancer.

The treatment was generally well tolerated, with 64% of patients experiencing treatment-related adverse events, but no treatment-related deaths occurred, suggesting a favorable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Alley, EW., Lopez, J., Santoro, A., et al.[2022]

The combination of the anti-PD-L1 antibody avelumab with stereotactic body radiation therapy (SBRT) was found to be tolerable in patients with malignant pleural mesothelioma, with no severe (grade 4 or 5) adverse events reported during the study.

Out of 13 patients, the most common side effects included mild to moderate reactions such as infusion-related allergic reactions and fatigue, indicating that while there are some adverse effects, they are manageable and do not pose significant safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 Safety Study of Avelumab Plus Stereotactic Body Radiation Therapy in Malignant Pleural Mesothelioma. Rimner, A., Adusumilli, PS., Offin, MD., et al.[2023]

Pembrolizumab, an anti-PD-1 antibody used for treating malignant pleural mesothelioma, can cause serious side effects such as minimal change disease (MCD), which was identified in a 62-year-old patient who developed nephrotic syndrome and acute renal failure after treatment.

The patient's symptoms improved significantly after discontinuing pembrolizumab and starting steroid treatment, highlighting the importance of monitoring renal function and recognizing potential autoimmune reactions in patients receiving this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma. Bickel, A., Koneth, I., Enzler-Tschudy, A., et al.[2022]

References

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

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. [2021]

2. 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]

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

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer. [2023]

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiotherapy for relapsed malignant pleural mesothelioma. [2020]

6. Germany pubmed.ncbi.nlm.nih.gov

Adjuvant intensity-modulated proton therapy in malignant pleural mesothelioma. A comparison with intensity-modulated radiotherapy and a spot size variation assessment. [2021]

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

Acute toxicity and patient-reported symptom score after conventional versus moderately hypofractionated proton therapy for prostate cancer. [2022]

8. France pubmed.ncbi.nlm.nih.gov

Toxicity and time lapse between immunotherapy and stereotactic radiotherapy of brain metastases. [2021]

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

Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. [2022]

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

Commentary on "Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer." Gray PJ, Paly JJ, Yeap BY, Sanda MG, Sandler HM, Michalski JM, Talcott JA, Coen JJ, Hamstra DA, Shipley WU, Hahn SM, Zietman AL, Bekelman JE, Efstathiou JA. Harvard Radiation Oncology Program, Boston, MA.: Cancer 2013;119(9):1729-35. doi: 10.1002/cncr.27956. [Epub 2013 Feb 22]. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. [2022]

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

A Phase 1 Safety Study of Avelumab Plus Stereotactic Body Radiation Therapy in Malignant Pleural Mesothelioma. [2023]

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

Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma. [2022]