This phase I trial studies the effect of stereotactic body radiation therapy and immunotherapy in treating patients with mesothelioma. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving stereotactic body radiation therapy and immunotherapy may improve the tumors response to the treatment and decrease side-effects.

PRIMARY OBJECTIVE:

I. To determine the feasibility of focal stereotactic body radiation therapy (SBRT) with immune check inhibitors (ICI) for treatment of mesothelioma.

SECONDARY OBJECTIVES:

I. To determine progression free survival in patients treated with SBRT and ICI.

II. To assess acute and late toxicities overall in patients treated with SBRT and ICI.

TERTIARY OBJECTIVES:

I. To demonstrate that pre-treatment circulating tumor deoxyribonucleic acid (ctDNA) levels correlate with tumor burden in patients with solid tumors.

II. To investigate if ctDNA can robustly identify molecular residual disease (MRD) before clinical, radiographic or pathologic progression in patients with solid tumors treated with definitive-intent surgery +/- radiotherapy +/- chemotherapy.

III. To determine whether post-resection ctDNA levels can be used to predict the risk of tumor recurrence and response to adjuvant radiation or adjuvant chemoradiation in patients with solid tumors.

IV. To determine if ctDNA levels can predict disease response and/or disease recurrence before clinical, pathologic or radiographic response/progression is confirmed in patients with solid tumors.

V. To perform methylation sequencing of cell-free DNA to noninvasively determine ctDNA cell- of-origin.

VI. To perform cell-free ribonucleic acid (RNA) analysis to monitor gene expression changes and identify genomic rearrangements.

VII. To perform epigenetic and genetic analyses including methylation sequencing and single cell RNA sequencing on associated tumor and peripheral blood cell samples.

EXPLORATORY OBJECTIVES:

I. To determine overall survival in these patients. II. To estimate the objective response rate (ORR) using immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) 1.1 criteria.

III. To describe patterns of failure. IV. To estimate the quality of life (QOL) in these patients. V. Determine whether T-cell receptor expression changes during and after immunotherapy and SBRT, and whether these changes correlate with outcomes.

VI To evaluate potential predictive and prognostic biomarkers using various assays including flow cytometry assays, qualitative and quantitative analyses of patients' blood to explore associations with all primary and secondary endpoints.

OUTLINE:

Patients undergo 3-5 daily fractions of SBRT in the absence of disease progression or unacceptable toxicity. Patients also receive immunotherapy at the discretion of the treating medical oncologist.

After completion of study treatment, patients are followed up every 6 weeks for 36 weeks or per clinician discretion, then every 3 months for 2 years or until disease progression or study exit, then yearly for up to 10 years.

Inclusion Criteria:

• Age >= 18 years

• Histological confirmation of pleural mesothelioma

• Measurable disease

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2

• Negative pregnancy test done =< 14 days prior to registration, for women of childbearing potential only. NOTE: male/female: Must be willing to use birth control for the entire study and must agree to use one of the following birth control methods listed:

  • Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or implants
  • Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel that kills sperm)
  • Intrauterine device (IUD)
  • Abstinence (no sex)

• Provide written informed consent

• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

• Willing to provide blood samples for correlative research purposes

• Patient has received or is planning to receive ICI for mesothelioma

• Patient is planning to receive SBRT (stereotactic body radiation therapy) for mesothelioma

Exclusion Criteria:

• Any of the following:

  • Pregnant women
  • Nursing women