Roflumilast and Standard Chemoimmunotherapy in Treating Patients with Stage II-IV High-Risk Diffuse Large B-Cell Lymphoma

Inclusion Criteria

• Pathologically proven diffuse large B-cell lymphoma
• Non-GCB of origin by standard immunohistochemical classification
• No prior systemic therapy for lymphoma
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Life expectancy of >= 3 months
• Ann Arbor stage II-IV, stage I bulky disease may be included if lesion > 7.5 cm
• Measurable disease, meaning at least 1 lymph node or other lymphomatous lesion with a long axis of >= 1.5 cm by computed tomography (CT) imaging, and at least one fluorodeoxyglucose (FDG)-avid lesion by FDG-positron emission tomography (PET) scan
• Left ventricular ejection fraction of at least 45% by either echocardiography or radionucleotide angiography
• Ability to swallow oral tablets without difficulty
• All subjects with preserved reproductive potential must agree to practice abstinence or employ contraceptive measures for the duration of treatment and for 4 weeks following final dosing. All male subjects are considered to have reproductive potential. Female subjects of reproductive potential are those who: 1) are not at least 50 years old and have no menses for 24 consecutive months; or 2) have not been rendered surgically sterile (having undergone hysterectomy and/or bilateral salpingo-oophorectomy). Female subjects of reproductive potential must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 7 days of first day of drug dosing
• Creatinine clearance >= 30 ml/min by Cockcroft-Gault formula
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless indirect bilirubin is elevated due to Gilbert's syndrome or hemolysis)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN
• Platelet count >= 50,000/uL, with or without transfusion support
• Absolute neutrophil count (ANC) >= 1000/uL, with or without chronic granulocyte growth factor support
• Hemoglobin >= 8 g/dL, with or without transfusion support

Exclusion Criteria

• Allergy or intolerance to roflumilast
• Any active malignancy other than DLBCL
• Prior allogeneic bone marrow transplant within 12 months of screening date
• Prior autologous stem cell transplant within 6 months of screening date
• Immunotherapy, chemotherapy, radiotherapy, or investigational therapy within 6 months prior to drug dosing
• Active central nervous system (CNS) involvement by lymphoma, including untreated symptomatic epidural disease
• Active uncontrolled infection
• History of poorly controlled clinical depression prior to cancer diagnosis
• Uncontrolled illness including but not limited to: symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV heart failure), unstable angina pectoris, uncontrolled cardiac arrhythmia, and psychiatric illness that would limit compliance with study requirements
• History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty and/or stent placement within 6 months prior to study drug dosing
• History of another active cancer within 2 years prior to study drug dosing, excluding adequately treated basal cell or squamous cell carcinoma of the skin, cervical cancer in situ, or other adequately treated in situ carcinoma
• History of major surgery within 3 weeks or minor surgery within 1 week of roflumilast administration; major surgery includes, for example, any open or laparoscopic entry into a body cavity, or operative repair of fracture; minor surgery includes, for example, open surgical biopsy of palpable/superficial lymph node, or placement of vascular access device
• Other medical or psychiatric illness or organ dysfunction, which in the opinion of the investigator, would either compromise the subject's safety or interfere with the evaluation of the safety of the study agent
• Corrected QT interval (QTc) prolongation (defined as a QTc > 450 ms for males and > 470 ms for females [Fridericia's correction]) or other clinically significant electrocardiogram (ECG) abnormalities as assessed by the investigator
• Baseline serum troponin above the upper limit of normal
• Baseline serum B-type natriuretic peptide (BNP) above the age-adjusted upper limit of normal
• Baseline amylase above the upper limit of normal
• Patients known to be human immunodeficiency (HIV)-positive must not have multi-drug resistant HIV infection, CD4 counts < 150/ul or other concurrent acquired immunodeficiency syndrome (AIDS)-defining conditions; serologic screening for HIV is required within the 6 months prior to study enrollment
• Patients positive for hepatitis B surface antigen (HBsAg) or hepatitis C-virus ribonucleic acid (HCV RNA), unless both AST and ALT =< 1.25 x ULN and there is no known history of chronic active hepatitis; serologic screening for hepatitis B and C testing is required within the 6 months prior to study enrollment
• Patients with moderate or severe liver impairment, as defined by a Child-Pugh class of B or C
• Women who are pregnant or breastfeeding
• Concurrent use of known interacting medications with roflumilast such as: boceprevir, carbamazepine, ciprofloxacin, cobicistat, conivaptan, enzalutamide, fluvoxamine, itraconazole, ketoconazole, mitotane, phenytoin, posaconazole, rifampin, ritonavir, St. John’s wort, telaprevir, voriconazole, zafirlukast, non-nucleoside reverse transcriptase inhibitors (NNRTI), or use of any strong CYP3A4 inhibitors or inducers