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

Inclusion Criteria:

1. Men and women 18 years of age or older.

2. Pathologically proven diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS).

• Patients with Diffuse large B-cell lymphoma/ high grade B-cell lymphoma withMYC and BCL2 rearrangements are allowed.

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 inthe 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 witha long axis of ≥1.5 cm by CT imaging, and at least one FDG-avid lesion by FDG-PETscan.

11. Left ventricular ejection fraction of at least 45% by either echocardiography orradionucleotide angiography.

12. Ability to swallow oral tablets without difficulty.

13. All subjects with preserved reproductive potential must agree to practice abstinenceor employ contraceptive measures for the duration of treatment and for 10 months (iffemale) or 7 months (if male) following final dosing. All male subjects areconsidered to have reproductive potential. Female subjects of reproductive potential are those who: i) are not at least 50 years old and have no menses for 24 consecutive months; orii) have not been rendered surgically sterile (having undergone hysterectomy and/orbilateral 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.

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 bilirubinis 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.

Exclusion Criteria:

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 6months prior to drug dosing.

8. Active central nervous system (CNS) involvement by lymphoma, including untreatedsymptomatic epidural disease.

9. Active uncontrolled infection.

10. Poorly controlled depressive symptoms and/ or currently under management fordepression that is poorly controlled.

11. Significant disease or medical conditions, as assessed by the Investigator andSponsor, that would substantially increase the riskbenefit ratio of participating inthe study. This includes, but is not limited to, acute myocardial nfarction withinthe last 6 months, unstable angina, uncontrolled diabetes mellitus, significantactive infections, and congestive heart failure New York Heart Association ClassIII-IV.

12. Second malignancy, except treated basal cell or localized squamous skin carcinomas,localized prostate cancer, or other malignancies for which subjects are not onactive anti-cancer therapies and have had no evidence of active malignancy for atleast 1 year.

13. History of major surgery within 3 weeks or minor surgery within 1 week ofroflumilast administration. Major surgery includes, for example, any open orlaparoscopic entry into a body cavity, or operative repair of fracture; minorsurgery includes, for example, open surgical biopsy of palpable/superficial lymphnode, or placement of vascular access device.

14. Other medical or psychiatric illnesses or organ dysfunction, which in the opinion ofthe investigator, would either compromise the subject's safety or interfere with theevaluation 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 ECGabnormalities 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. Serologicscreening for HIV is required within the 6 months prior to study enrollment.

20. Subjects positive for Hepatitis B surface antigen (HBsAg) or Hepatitis C-virusribonucleic acid (HCV RNA), unless both AST and ALT≤1.25 x ULN and there is no knownhistory of chronic active hepatitis. Serologic screening for hepatitis B and C testing is required within the 6 monthsprior to study enrollment.

21. Subjects with moderate or severe liver impairment, as defined by a Child-Pugh classof 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'sWort, telaprevir, voriconazole, or zafirlukast.

24. Current use of non-nucleoside reverse transcriptase inhibitors (NNRTI) includingefavirenz, rilpivirine, etravirine, delavirdine, nevirapine, and lersivirine.