Loncastuximab Tesirine in Combination with DA-EPOCH-R in Patients with Previously Untreated Aggressive B-cell Lymphoid Malignancies

Inclusion Criteria:

1. Age ≥ 18 years.

2. Adult patients with B-cell lymphoma, specifically one of the following: high-gradeB-cell lymphoma with MYC and B-cell lymphoma 2 (BCL2) and/or B cell lymphoma 6 (BCL6) rearrangements; high-grade B-cell lymphoma, not otherwise specified, primarymediastinal diffuse large B-cell lymphoma; Burkitt lymphoma; diffuse large B-celllymphoma with MYC rearrangement; or Cluster of Differentiation 19 (CD19) -positiveplasmablastic lymphoma.

3. Patients must not have received prior multiagent chemotherapy for their lymphoma.Limited palliative radiation is allowed. Corticosteroid therapy in symptomaticpatients will be permitted and does not require a washout period. Prephase treatmentwith cyclophosphamide and corticosteroids or vincristine and corticosteroids isallowed in symptomatic patients.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status criteria of 0-3.

5. Adequate hematological function, defined as absolute neutrophil count (ANC) ≥1 × 103/μL and platelet count ≥50 x 10^3/μL.

• These requirements do not apply to patients with bone marrow involvement oflymphoma.

6. Adequate hepatic function: aspartate aminotransferase (AST) / alanineaminotransferase (ALT) / gamma-glutamyl transferase (GGT) ≤ 3 x institutional upperlimit of normal (ULN) and bilirubin < 1.5 x ULN, unless due to hepatic involvementwith lymphoma or Gilbert's syndrome.

• Exceptions can be granted from principal investigator for primarily indirectbilirubinemia if due to recent transfusion and/or hemolysis.

7. Creatinine clearance ≥ 30 ml/min calculated using the Cockroft-Gault formula.

8. Left ventricular ejection fraction (LVEF) of ≥50%, assessed by echocardiography orcardiac multi-gated acquisition (MUGA) scan.

9. Patients with marrow-only disease will be eligible.

10. Patients rendered no evidence of disease via surgery will be eligible.

11. Central nervous system (CNS) involvement is not considered contraindication forpatients with Burkitt lymphoma.

12. Known HIV-positive patients compliant with antiretroviral therapy and withundetectable viral loads will be permitted.

13. Pregnancy It is not known what effects this treatment has on human pregnancy ordevelopment of the embryo or fetus. Therefore, female patients participating in thisstudy should avoid becoming pregnant, and male patients should avoid impregnating afemale partner. Non-sterilized female patients of reproductive age and male patientsshould use effective methods of contraception through defined periods during andafter study treatment as specified below.

• Female patients of childbearing potential must use a highly effective method ofcontraception during the entire study treatment period and through nine monthsafter the last dose of loncastuximab tesirine.

• Male patients, even if surgically sterilized (i.e., status postvasectomy), withfemale partners who are of childbearing potential should use a condom whensexually active during the entire study treatment period and through six monthsafter the last dose of loncastuximab tesirine.

14. Ability to understand a written informed consent document, and the willingness tosign it.

Exclusion Criteria:

1. Presence of clinically significant pericardial or pleural effusions, or third spacefluid accumulations (i.e., ascites requiring drainage or pleural effusion that iseither requiring drainage or associated with shortness of breath).

2. Known history of hypersensitivity to CD19 antibody, components of study medication,or DA-EPOCH-R.

3. Serologic evidence of chronic hepatitis B virus (HBV) infection and unable orunwilling to receive standard prophylactic antiviral therapy. These subjects MUSTHAVE undetectable HBV viral load to be considered for this protocol.

4. Serologic evidence of hepatitis C virus (HCV) infection without completion ofcurative treatment or with detectable HCV viral load.

5. Breastfeeding or pregnant.

6. Active systemic bacterial, viral, fungal, or other infection requiring systemictreatment at time of screening.

7. Congenital long QT syndrome or a corrected QT measure (QTc) interval of >480 ms atscreening (unless secondary to pacemaker or bundle branch block).

8. Patients diagnosed with another malignancy within three years or with any evidenceof residual prior malignant disease (except nonmelanoma skin cancer, non-metastaticprostate cancer, in situ cervical cancer, or ductal or lobular carcinoma in situ).Patients meeting this exclusion criteria may be enrolled after approval from studyPI.

9. Significant medical comorbidities such as New York Heart Association class ≥IIIheart failure, unstable angina, uncontrolled arrhythmias, or severe chronicpulmonary disease.

10. Lymphoma with active CNS involvement at time of screening unless the patient hasBurkitt lymphoma.

11. Patient with known intraparenchymal CNS involvement (including those with Burkittlymphoma).

12. Patients with known Child Pugh Class C hepatic impairment.