Pembrolizumab and Combination Chemotherapy (R-CHOP) for the Treatment of Non-germinal Center Diffuse Large B Cell Lymphoma or High-Grade B Cell Lymphoma
- Participants 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)
- 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 or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137)
- 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 * 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. 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
I. To determine the progression-free survival at 24 months (PFS24) of patients with previously untreated, high-risk, non-germinal center (GC) diffuse large B cell lymphoma (DLBCL) or high-grade B cell lymphoma (HGBCL) treated with pembrolizumab, rituximab (PR)-cyclophosphamide-doxorubicin hydrochloride (hydroxydaunorubicin)-vincristine sulfate (Oncovin)-prednisone (CHOP) followed by pembrolizumab (P), and to compare PFS24 associated with PR-CHOP followed by P therapy to that of historical controls treated with R-CHOP alone.
I. To determine the rate of complete response (CR) in patients with previously untreated, high risk, non-GC DLBCL or HGBCL following 6 cycles of PR-CHOP therapy, and compare to that of historical controls treated with R-CHOP.
II. To determine event-free survival at 24 months (EFS24) associated with PR-CHOP treatment of patients with previously untreated non-GC DLBCL or HGBCL.
III. To determine the overall survival (OS) of previously untreated patients with non-GC DLBCL or HGBCL following treatment with PR-CHOP followed by P, and compare OS after PR-CHOP and P therapy with that of historical controls treated with R-CHOP.
IV. To determine the tolerability of PR-CHOP followed by P therapy in patients with non-GC DLBCL or HGBCL.
I. Determine the degree to which PD-L1 copy number alterations (CNA) predict for best overall response (BOR) and PFS24 in patients with non-GC DLBCL or HGBCL following PR-CHOP and P continuation therapy.
II. Determine the degree to which PD-L1 protein expression on lymphoma cells (using Dako PD-L1 [immunohistochemistry] IHC 22C3 pharmDx) predicts for BOR and PFS24 in patients with non-GC DLBCL or HGBCL following PR-CHOP and P continuation therapy.
III. Identify mechanisms of relapse following PR-CHOP and P continuation therapy in patients with non-GC DLBCL or HGBCL.
IV. Elucidate the impact of PR-CHOP and P continuation on plasma cell-free tumor (ct) deoxyribonucleic acid (DNA) level, and assess the effect of this therapy on clonal evolution as measured by the mutational landscape of ctDNA over time, including at relapse.
V. Archive patient samples for future translational research investigation.
Patients receive pembrolizumab intravenously (IV) over 30 minutes, rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1. Patients also receive prednisone orally (PO) on days 1-5. Treatments repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pembrolizumab IV over 30 minutes on day 1. Treatments repeat every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 8-12 weeks for up to 2 years.
Trial Phase Phase II
Trial Type Treatment
University of Chicago Comprehensive Cancer Center
Justin Paul Kline
- Primary ID IRB19-0072
- Secondary IDs NCI-2019-06776
- Clinicaltrials.gov ID NCT03995147