POLA+BR for Relapsed or Refractory DLBCL

Inclusion Criteria:

1. Signed ICF
2. Age ≥ 18 years
3. Able to comply with the study protocol, in the investigator's judgment
4. Histologically confirmed DLBCL (Obtaining pathology samples is not required prior to enrollment, but confirmation of availability is required prior to enrollment)
5. Must have received at least one prior rituximab containing chemotherapy therapy for DLBCL.
6. Patients must be transplant-eligible and have either relapsed or have become refractory to a prior regimen.
7. The following DLBCL histologies would be considered eligible for study entry:

   o DLBCL, not otherwise specified (NOS) (including both GCB type and ABC type)
   * T-cell/histiocyte-rich large B-cell lymphoma
   * High-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements
   * High grade B-cell lymphoma, NOS
   * Primary mediastinal (thymic) large B-cell lymphoma
   * Epstein Barr virus positive DLBCL, NOS
   * HHV8-positive DLBCL, NOS
   * HIV positive DLBCL
8. At least one bi-dimensionally measurable lesion on imaging scan defined as \> 1.5 cm in its longest dimension
9. Life expectancy of at least 24 weeks
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
11. Adequate hematologic function unless inadequate function is due to underlying disease, such as extensive bone marrow involvement or hypersplenism secondary to the involvement of the spleen by lymphoma per the investigator. Adequate hematologic function is defined as follows:

    o Hemoglobin ≥ 9 g/dL

    o ANC ≥ 1.0 x 10g/L

    o Platelet count ≥ 75 x 10g/L
12. For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea and age \> 45 years) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or to use single highly effective or combined contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for ≥ 12 months after the last dose of rituximab.

    * Abstinence is only acceptable if it is in line with 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.
    * Examples of highly effective contraceptive methods with a failure rate of \< 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of \< 1% per year. Barrier methods must always be supplemented with the use of a spermicide.
13. For women of childbearing potential, a negative serum pregnancy test result within 7 days prior to commencement of dosing. Women who are considered not to be of childbearing potential are not required to have a pregnancy test.
14. For men, agreement to remain abstinent or to use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for at least 6 months after the last dose of study drug and agreement to refrain from donating sperm during this same period.

    * Men with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy.
    * Abstinence is only acceptable if it is in line with 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.
    * Male patients considering preservation of fertility should bank sperm before treatment with polatuzumab vedotin.

Exclusion Criteria:

1. History of severe allergic or anaphylactic reactions to humanized or murine MAbs (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products
2. Contraindication to bendamustine or rituximab.
3. History of sensitivity to mannitol (mannitol is an excipient in bendamustine).
4. Prior use of any monoclonal antibody (MAb), radioimmunoconjugate, or antibody drug conjugate (ADC) within 5 half-lives or 4 weeks, whichever is longer, before Cycle 1 Day 1.
5. Treatment with chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to Cycle 1 Day 1. Radiotherapy for palliative relief of symptoms is allowed.
6. All acute, clinically significant treatment-related toxicity from prior therapy, except for alopecia, must have resolved to Grade ≤ 2 prior to Cycle 1 Day 1.
7. Ongoing corticosteroid use \> 30 mg/day prednisone or equivalent, for purposes other than lymphoma symptom control. Patients receiving corticosteroid treatment ≤ 30 mg/day prednisone or equivalent must be documented to be on a stable dose prior to study enrollment and initiation of therapy (Cycle 1 Day 1).
8. Ineligibility for ASCT (determined by investigator per local institutional practice)
9. Prior ASCT
10. History of transformation of indolent disease to DLBCL
11. Active CNS lymphoma. (Previously treated CNS disease is allowed)
12. Current Grade \> 1 peripheral neuropathy
13. History of other malignancy that could affect compliance with the protocol or interpretation of results. Exceptions include, but are not limited to:

    • Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix or ductal carcinoma in situ of the breast at any time prior to the study are eligible.

    • A patient with any other malignancy that has been treated with curative intent and the malignancy has been in remission without treatment for \> 3 years prior to enrollment is eligible.

    • Patients with low-grade, early-stage prostate cancer with no requirement for systemic therapy at any time prior to study are eligible.
14. 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 significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm).
15. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection requiring treatment with intravenous (IV) antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1.
16. Patients with suspected or latent tuberculosis. • Latent tuberculosis should be confirmed according to local testing requirements.
17. Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen \[HBsAg\] serology).

    • Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody \[HBcAb\]) may be included if HBV DNA is undetectable, provided that they are willing to undergo DNA testing on day 1 of every cycle and monthly for at least 12 months after the last cycle of study treatment and are willing to get prophylaxis with lamuvidine or entecavir for 6 months post immunosuppressive therapy. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible.
18. Patients who are positive for Hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.
19. Positive test results for uncontrolled HIV infection.

    • For patients with controlled HIV status (Positive HIV antibody, on Antiretroviral therapy with stable HIV viral load) are eligible.
20. Known infection human T-cell leukemia virus 1 (HTLV-1) virus. 21. Vaccination with a live vaccine within 28 days prior to treatment.

22\. Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis.

23\. Women who are pregnant or lactating or who intend to become pregnant within a year of the last dose of study treatment in the rituximab cohorts or within 18 months of the last dose of study treatment in the obinutuzumab cohort

24\. Any of the following abnormal laboratory values, unless abnormal laboratory values are due to underlying lymphoma per the investigator:

* Creatinine \> 1.5 x upper limit of normal (ULN) or a measured creatinine clearance \< 40 mL/min • AST or ALT \> 2.5 x ULN
* Total bilirubin ≥ 1.5 x ULN. Patients with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3 x ULN
* INR or PT \> 1.5 x ULN in the absence of therapeutic anticoagulation
* PTT or aPTT \> 1.5 x ULN in the absence of a lupus anticoagulant

  25\. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications