Loncastuximab and Roflumilast Added to R-CHOP (Lo-RR-CHOP) for Naïve High-Risk Diffuse Large B-cell Lymphoma (DLBCL)

Eligibility Criteria

• 1. Men and women 18 years of age or older.
• 2. Pathologically proven diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS).
• 3. No prior systemic therapy for lymphoma.
• 4. Subject has provided informed consent.
• 5. Subject is willing and able to comply with clinic visits and procedure outlined in the study protocol.
• 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• 7. Life expectancy of ≥3 months.
• 8. Ann Arbor stage II-IV
• 9. National Comprehensive Cancer Network - International Prognostic Index (NCCN-IPI) risk score of ≥ 2
• 10. Measurable disease, meaning at least 1 lymph node or other lymphomatous lesion with a long axis of ≥1.5 cm by CT imaging, and at least one FDG-avid lesion by FDG-PET scan.
• 11. Left ventricular ejection fraction of at least 45% by either echocardiography or radionucleotide angiography.
• 12. Ability to swallow oral tablets without difficulty.
• 13. All subjects with preserved reproductive potential must agree to practice abstinence or employ contraceptive measures for the duration of treatment and for 10 months (if female) or 7 months (if male) following final dosing. All male subjects are considered to have reproductive potential.
• 14. Meet the following clinical laboratory requirements:
• * Creatinine clearance ≥30 ml/min by Cockcroft-Gault formula;
• * Total bilirubin ≤ 1.5 × 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 × ULN;
• * Platelet count ≥ 50,000/µL, with or without transfusion support;
• * ANC ≥ 1000/µL, with or without chronic granulocyte growth factor support;
• * Hemoglobin ≥8 g/dL, with or without transfusion support.
• 1. Allergy or intolerance to roflumilast.
• 2. Allergy or intolerance to loncastuximab
• 3. Any active malignancy other than DLBCL
• 4. Current participation in another interventional clinical study
• 5. Prior allogeneic bone marrow transplant within 12 months of screening date.
• 6. Prior autologous stem cell transplant within 6 months of screening date.
• 7. Immunotherapy, chemotherapy, radiotherapy, or investigational therapy within 6 months prior to drug dosing.
• 8. Active central nervous system (CNS) involvement by lymphoma, including untreated symptomatic epidural disease.
• 9. Active uncontrolled infection.
• 10. Poorly controlled depressive symptoms and/ or currently under management for depression that is poorly controlled.
• 11. Significant disease or medical conditions, as assessed by the Investigator and Sponsor, that would substantially increase the riskbenefit ratio of participating in the study. This includes, but is not limited to, acute myocardial nfarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III-IV.
• 12. Second malignancy, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, or other malignancies for which subjects are not on active anti-cancer therapies and have had no evidence of active malignancy for at least 1 year.
• 13. 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.
• 14. Other medical or psychiatric illnesses 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.
• 15. 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 ECG abnormalities as assessed by the investigator.
• 16. Baseline serum troponin above the upper limit of normal.
• 17. Baseline serum BNP above the age-adjusted upper limit of normal.
• 18. Baseline amylase above the upper limit of normal.
• 19. Subjects known to be HIV-positive must not have multi-drug resistant HIV infection, CD4 counts \< 150/µl or other concurrent AIDS-defining conditions. Serologic screening for HIV is required within the 6 months prior to study enrollment.
• 20. Subjects 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.
• 21. Subjects with moderate or severe liver impairment, as defined by a Child-Pugh class of B or C.
• 22. Women who are pregnant or breastfeeding.
• 23. Current use of any of the following medications: boceprevir, carbamazepine, ciprofloxacin, cobicistat, conivaptan, enzalutamide, fluvoxamine, itraconazole, ketoconazole, mitotane, phenytoin, posaconazole, rifampin, ritonavir, St. John's Wort, telaprevir, voriconazole, or zafirlukast.
• 24. Current use of non-nucleoside reverse transcriptase inhibitors (NNRTI) including efavirenz, rilpivirine, etravirine, delavirdine, nevirapine, and lersivirine.