Pembrolizumab and Combination Chemotherapy (R-CHOP) for the Treatment of Non-germinal Center Diffuse Large B Cell Lymphoma or High-Grade B Cell Lymphoma

Inclusion Criteria

• Male/female participants who are at least 18 years of age on the day of signing informed consent with a histologically confirmed diagnosis of diffuse large B cell lymphoma or high-grade B cell lymphoma not otherwise specified (NOS) of a non-germinal center phenotype according to Hans criteria are eligible for enrollment in this study
• International prognostic index (IPI) score of >= 3, or an age-adjusted (aa) IPI score of >= 2
• A male participant must agree to use a contraception during the treatment period and for at least 120 days after the final 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 after the last dose of study treatment
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
• Have measurable disease with one or more measurable lymphoma lesions (> 1.5 cm in the long axis and > 1.0 cm in the short axis).
• Patients must be able to provide an archived tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue * Note: If submitting unstained cut slides, newly cut slides should be submitted within 14 days from the date slides are cut
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation
• Absolute neutrophil count (ANC) >= 1000/uL (specimens must be collected within 14 days prior to treatment allocation) * Lower hematological values may be allowable, provided that they are due to involvement of the bone marrow by lymphoma (after discussion with the principal investigator)
• Platelets >= 100 000/uL (specimens must be collected within 14 days prior to treatment allocation) * Lower hematological values may be allowable, provided that they are due to involvement of the bone marrow by lymphoma (after discussion with the principal investigator)
• Hemoglobin >= 8.0 g/dL (specimens must be collected within 14 days prior to treatment allocation) * Lower hematological values may be allowable, provided that they are due to involvement of the bone marrow by lymphoma (after discussion with the principal investigator)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR measured/calculated creatinine clearance (CrCl) >= 30 mL/min for participants with creatinine levels > 1.5 x ULN (specimens must be collected within 14 days prior to treatment allocation) * 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 14 days prior to treatment allocation)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver involvement) (specimens must be collected within 14 days prior to treatment allocation)

Exclusion Criteria

• A WOCBP who has a positive urine pregnancy test within 72 hours prior to the initiation of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * Note: In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent
• Has received prior anti-lymphoma therapy, including radiation therapy, chemotherapy, targeted therapy, or immunotherapy * Note: Prior corticosteroid treatment (< 10 days in duration) to alleviate lymphoma-related symptoms is permitted * One cycle of prior R-CHOP or R-CHOP-like chemotherapy is also allowed * Note: If participant received major surgery, he or she must have recovered adequately from complications from the intervention prior to starting study treatment
• 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 (e.g., 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
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent, with the exception of short-term corticosteroid use to control lymphoma-related symptoms as outlined above) 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. Other exceptions may be permitted after discussion with the principal investigator
• Has known active central nervous system (CNS) involvement by lymphoma
• Has a diagnosis of high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 gene rearrangements (double hit lymphoma), primary mediastinal lymphoma, gray zone lymphoma, composite lymphoma, or previously untreated low-grade lymphoma with disease transformation to DLBCL
• 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 (e.g., 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 an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive, hepatitis B core [HBc] antibody total reactive, or HBV virus detected) or known active hepatitis C virus infection (defined as HCV ribonucleic acid [RNA] is detected). Note: All patients will be screened for prior hepatitis B exposure prior to starting therapy. Patients with positive HBc antibody but negative HBV deoxyribonucleic acid (DNA) are eligible provided they have initiated therapy with appropriate anti-viral prophylaxis (entecavir or lamivudine) prior to receiving treatment Hepatitis C testing is not required
• Has a known history of, or active infection with tuberculosis
• Has a history of solid organ transplantation
• Has a left ventricular ejection fraction < 45%, myocardial infarction within 6 months of initiating study treatment, New York Heart Association class III/IV heart failure, or any uncontrolled cardiovascular conditions
• 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