Immunotherapy and Combination Chemotherapy for the Treatment of Relapsed or Refractory Diffuse Large B-cell Lymphoma

Inclusion Criteria

• Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act authorization for release of personal health information.
• Biopsy proven DLBCL in first relapse (biopsy can be from initial diagnosis). The study will allow high-grade B cell lymphoma, but not including Burkitt’s lymphoma. Per the 2016 World Health Organization criteria, the following histologies are eligible to participate in this study: * Diffuse large B-cell lymphoma (DLBCL), NOS * Germinal center B-cell type * Activated B-cell type * T-cell/histiocyte-rich large B-cell lymphoma * Epstein-Barr Virus Positive DLBCL, NOS * DLBCL associated with chronic inflammation * Primary mediastinal (thymic) large B-cell lymphoma * Intravascular large B-cell lymphoma * ALK positive large B-cell lymphoma * Human Herpesvirus 8 positive DLBCL, NOS * High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements * High-grade B-cell lymphoma, NOS * B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
• Age >= 18 at the time of consent.
• Radiologic evidence of active disease per Lugano criteria within 42 days of starting trial therapy.
• Subject must have at least one prior line of therapy.
• Prior cancer treatment or other investigational treatment must be completed at least 21 days or 5 half-lives (whichever is longer) prior to start of treatment and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 at start of treatment.
• Subjects with a history of prior or concurrent second primary malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the study drugs are eligible for enrollment in the trial. This includes localized prostate cancer, bladder cancer, in situ breast cancer and non-melanoma skin cancers.
• Subjects may be eligible or ineligible for autologous stem cell transplant. * NOTE: The reason for transplant ineligibility should be recorded on the eCRF
• Subjects with Human Immunodeficiency virus (HIV) will be allowed to participate in the trial if they have controlled HIV (CD4+ counts >200 cells/uL). Subjects must be tested within 28 days of starting trial therapy.
• If positive for Hepatitis B virus (HBV) core antibody or surface antigen, subjects will be allowed to participate in the trial with HBV prophylaxis. If positive for Hepatitis C virus (HCV) exposure or active infection, the subject will be allowed to participate in the trial with pharmacotherapy and monitoring for liver function abnormalities. Tests for HBV and HCV within 1 year of starting study treatment are acceptable.
• Must have a minimum level of pulmonary reserve defined as =< Grade 1 dyspnea and pulse oxygenation > 91% on room air.
• Prior therapy with polatuzumab is allowed.
• Absolute Neutrophil Count (ANC) >= 1 x 10^9/L (obtained within 7 days prior to initiating study treatment) NOTE: Hematology and other lab parameters that are =< grade 1 BUT still meet criteria for study entry are allowed.
• Platelets >= 75 × 10^9/L (obtained within 7 days prior to initiating study treatment) * NOTE: Hematology and other lab parameters that are =< grade 1 BUT still meet criteria for study entry are allowed.
• Calculated creatinine clearance >= 60 mL/min using the Cockcroft-Gault formula (obtained within 7 days prior to initiating study treatment) * NOTE: Hematology and other lab parameters that are =< grade 1 BUT still meet criteria for study entry are allowed.
• Bilirubin=< 1.5 x upper limit of normal (ULN) (obtained within 7 days prior to initiating study treatment). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level > 1.5 mg/dL if their conjugated bilirubin is < 1.5 x ULN. * NOTE: Hematology and other lab parameters that are =< grade 1 BUT still meet criteria for study entry are allowed.
• Aspartate aminotransferase (AST) =< 2.5 x ULN (obtained within 7 days prior to initiating study treatment). * NOTE: Hematology and other lab parameters that are =< grade 1 BUT still meet criteria for study entry are allowed.
• Alanine aminotransferase (ALT) =< 2.5 x ULN (obtained within 7 days prior to initiating study treatment). * NOTE: Hematology and other lab parameters that are =< grade 1 BUT still meet criteria for study entry are allowed.
• Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to initiation of study treatment. * NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Documentation of postmenopausal status must be provided
• Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 12 months after rituximab discontinuation and 9 months after last dose of polatuzumab vedotin. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets < 1% failure rate for protection from pregnancy in the product label.
• Male subjects with female partners of childbearing potential must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy and 6 months after the last dose of polatuzumab vedotin.
• Subjects are willing and able to comply with study procedures based on the judgement of the investigator or protocol designee.

Exclusion Criteria

• Known severe, active bacterial, viral, fungal, mycobacterial, parasitic, or other infections at study enrollment that may put the subject at undue risk as determined by the investigator.
• Subjective hearing loss interfering with daily activities or born with impaired or loss of hearing.
• Women who are pregnant or breastfeeding or who intend to become pregnant within a year of the last dose of study treatment. * NOTE: breast milk cannot be stored for future use while the mother is being treated on study.
• History of severe allergic or anaphylactic reaction to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine.
• Contraindication to gemcitabine or cisplatin, or dexamethasone or similar corticosteroid.
• Symptomatic cardiac disease including ventricular dysfunction, left ventricular ejection fraction < 40%, symptomatic coronary artery disease or symptomatic arrhythmias.
• Subjects with severe hepatic insufficiency Child-Pugh Score > 6
• Pre-existing >= grade 2 neuropathy.
• Active central nervous system disease.
• Subject is receiving prohibited medications or treatments, such as strong CYP3A inhibitors and inducers that cannot be discontinued/replaced by an alternative therapy.