Pembrolizumab and Intensity-Modulated Pleural Radiation Therapy for the Treatment of Unresectable Malignant Pleural Mesothelioma

Inclusion Criteria

• Pathologically confirmed diagnosis of malignant pleural mesothelioma
• Unresectable per thoracic surgeon assessment
• At least one prior line of systemic therapy. Note: Patients who were on prior immunotherapy are eligible
• Eastern Cooperative Oncology Group (ECOG) 0-1
• Carbon monoxide diffusing capability (DLCO) > 40% predicted
• Forced expiratory volume in 1 second (FEV1) > 50% predicted
• Male/female participants who are at least 18 years of age on the day of signing informed consent
• Disease outside the ipsilateral thorax allowed as long as it has either been treated definitively and been stable for 6 months
• A male participant must agree to use a contraception as detailed in Appendix 1 of this protocol during the treatment period and for at least 30 days, corresponding to time needed to eliminate any study treatment(s) (pembrolizumab and or any active comparator/combination) plus an additional 120 days (a spermatogenesis cycle) for study treatments with evidence of genotoxicity at any dose after the last dose of study treatment and refrain from donating sperm during this period
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days (corresponding to time needed to eliminate any study treatment(s) (pembrolizumab and or any active comparator/combination) plus 30 days (a menstruation cycle) for study treatments with risk of genotoxicity after the last dose of study treatment
• The participant (or legally authorized representative if applicable) provides written informed consent for the trial
• Have a ECOG performance status of 0 to 1. Evaluation of ECOG is to be performed within 30 days prior to the date of allocation
• Absolute neutrophil count (ANC) >= 1.5 K/mcL (specimens must be collected within 45 days prior to the start of study treatment)
• Platelets >= 100 K/mcL (specimens must be collected within 45 days prior to the start of study treatment)
• Hemoglobin >= 9.0 g/dL (specimens must be collected within 45 days prior to the start of study treatment)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (specimens must be collected within 45 days prior to the start of study treatment) * Creatinine clearance (CrCl) should be calculated per institutional standard
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (specimens must be collected within 45 days prior to the start of study treatment)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (specimens must be collected within 45 days prior to the start of study treatment)

Exclusion Criteria

• Newly diagnosed malignant pleural mesothelioma (MPM)
• Prior thoracic radiation therapy, immunotherapy or intrapleural therapy
• Bulky disease in the fissure preventing IMPRINT
• Serious infection, concurrent active malignancies, or other serious medical illness
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137) within 4 weeks prior to study day 1 or has not recovered (i.e. >= grade 1 at baseline) from adverse events due to a previously administered agent
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist) are live attenuated vaccines and are not allowed
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. * Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Low grade malignancies not requiring active treatment are not excluded
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment
• Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has a known history of human immunodeficiency virus (HIV)
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection
• Has a known history of active TB (Bacillus tuberculosis)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has 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 study, starting with the screening visit through 120 days after the last dose of trial treatment
• Has undergone major surgery < 4 weeks from starting pembrolizumab