Polatuzumab Vedotin and Combination Chemotherapy for the Treatment of Untreated Aggressive Large B-cell Lymphoma

Inclusion Criteria:

Untreated aggressive B-cell large-B cell lymphoma (non-Hodgkin lymphoma) with adverse features that may predict sub-optimal response to rituximab-cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), prednisone (R-CHOP) and in the opinion of the investigator would be treated with DA-EPOCH-R as standard of care. Subjects must be planned to receive full course (6 cycles) chemoimmunotherapy as per clinical standard of care. Composite lymphomas are not excluded provided that the subject has not receive prior systemic therapy for the indolent component and would receive DA-EPOCH-R as the standard of care regimen for the aggressive component. Eligible histologies based on 2016 World Health Organization (WHO) classification include:

High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocations
High grade B-cell lymphoma, not otherwise specified (NOS)
Diffuse large B-cell lymphoma (DLBCL) NOS
Primary mediastinal B-cell lymphoma
T-cell/histiocyte-rich large-B-cell lymphoma
Epstein-Barr virus (EBV) + DLBCL, NOS
ALK+ large B-cell lymphoma
B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
Be willing and able to provide written informed consent for the trial
Be >= 18 years of age on day of signing informed consent
Have measurable disease, including at least 1 nodal site measuring 1.5 cm or 1 extranodal site measuring 1.0 cm in longest dimension on computed tomography (CT) or fluorodeoxyglucose-positron emission tomography (FDG-PET)
Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) performance scale (PS)
Left ventricular ejection fraction (LVEF) >= 50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)
Absolute neutrophil count (ANC) >= 1,000/uL except in cases of marrow infiltration by lymphoma
Platelets >= 75,000 / mcL except in cases of marrow infiltration by lymphoma or hypersplenism
Hemoglobin >= 8 g/dL except in cases of marrow infiltration by lymphoma without red blood cell (RBC) transfusion within 14 days of first treatment

Measured or calculated creatinine clearance (Glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 40 mL/min.

* Creatinine clearance should be calculated per institutional standard

Serum total bilirubin =< 1.5 X upper limit of normal (ULN) (Patients with documented Gilbert disease may be enrolled if total bilirubin =< 3.0 x ULN)
Direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver involvement
International Normalized Ratio (INR) or Prothrombin Time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants, or subject is shown to have an antiphospholipid antibody on workup
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of =< 1% per year during the treatment period and for at least 12 months after the last dose of study treatment. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (=<12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. Examples of contraceptive methods with a failure rate of =<1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception
For women of childbearing potential, a negative serum pregnancy test result during screening period. Women who are considered not to be of childbearing potential are not required to have a pregnancy test
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the last treatment. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of preventing drug exposure. Male patients considering preservation of fertility should bank sperm before study treatment

Exclusion Criteria:

Contraindication to any of the individual components of EPCH-R, including prior receipt of anthracyclines, or history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, or known sensitivity or allergy to murine products
Prior systemic treatment for lymphoma with the exception of corticosteroids. Prior radiotherapy is allowed provided that this site is not used as a measurable site to assess response.
Richter's transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma is not allowed. Transformation from follicular lymphoma is allowed provided that the subject has not received prior systemic therapy for their lymphoma and the aggressive component meets one of the criteria listed in inclusion criterion 1
Diagnosis of Burkitt lymphoma
Prior organ transplantation
Current Grade > 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease
Prior systemic therapy for indolent lymphoma
Prior use of any monoclonal antibody within 3 months of the start of cycle 1; any investigational therapy within 28 days prior to the start of cycle 1; vaccination with live vaccines within 28 days prior the start of cycle 1
Prior therapy for large B-cell lymphoma except for patients who require lymphoma symptom control during screening may receive steroids in the following manner: Up to 30 mg/day of prednisone or equivalent may be used for lymphoma symptom control during screening, including prior to finalization of staging (not included as part of pre-phase treatment) If glucocorticoid treatment is urgently required at higher doses for lymphoma symptom control prior to the start of study treatment, tumor assessments must be completed prior to initiation of > 30-100 mg/day of prednisone or equivalent. Prednisone > 30-100 mg/day or equivalent may be given for a maximum of 7 days as a pre-phase treatment. If patients exceed the allowed dosing of corticosteroids, patients may still be eligible for the study provided that baseline imaging is performed (or repeated) after completion of the course of higher dose of steroids. Allowed corticosteroid dosing resets from the point of imaging forward and patients who do not exceed the allowed corticosteroid dosing from the point of imaging until initiation of study treatment may enroll

History of other malignancy that could affect compliance with the protocol or interpretation of results except with permission of the principal investigator. The following are eligible without a specific waiver:

Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible
Patients with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for >= 2 years prior to enrollment are eligible
Patients with low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time prior to study are eligible
Evidence of significant, uncontrolled, concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
Recent major surgery (within 4 weeks prior to the start of cycle 1), other than for diagnosis
History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree heart block, or evidence of prior myocardial infarction
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) which requires systemic treatment. Patients may proceed with screening during treatment for infection, but systemic treatment must be completed by cycle 1 day 1

Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HBsAg] serology):

* Patients with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. These patients must be willing to undergo monthly DNA testing and appropriate antiviral therapy as indicated by institutional standard

Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)

* Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

History of uncontrolled human immunodeficiency virus (HIV)

* Patients with known diagnosis of HIV must have undetectable viral load and be on anti-retroviral therapy

Patients with a history of progressive multifocal leukoencephalopathy
Pregnancy or lactation or intending to become pregnant during study