A Study Evaluating Efficacy and Safety of Mosunetuzumab in Combination With Polatuzumab Vedotin Compared to Rituximab in Combination With Gemcitabine Plus Oxaliplatin in Participants With Relapsed or Refractory Aggressive B-Cell Non-Hodgkin's Lymphoma

This study will assess the efficacy and safety of mosunetuzumab in combination with polatuzumab vedotin (M+P) in participants with relapsed or refractory (R/R) diffuse-large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, transformed follicular lymphoma (trFL) and FL Grade 3B (FL3B) in comparison with a commonly used regimen in this participant population, rituximab, gemcitabine and oxaliplatin (R-GemOx).


Eligibility Criteria:
Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
* CD20+ aggressive lymphoma as determined by the local hemopathology laboratory from the following diagnoses by 2016 World Health Organization classification of lymphoid neoplasms: DLBCL, not otherwise specified (NOS); high-grade B-cell lymphoma (NOS or double/triple hit); transformed follicular lymphoma; follicular lymphoma Grade 3b
* Have disease relapsed or refractory to at least one prior systemic therapy for aggressive non-Hodgkin's lymphoma (aNHL)
* Participants who have received only one prior line of therapy must be ineligible for autologous stem cell transplant (ASCT)
* Measurable disease
* Adequate hepatic, hematologic, and renal function
* Estimated creatinine clearance (CrCl) ≥ 30 mL/min by Cockroft-Gault method or other institutional standard methods
* Negative HIV test at screening. Participants with a positive HIV test at screening are eligible provided that, prior to enrollment, they are stable on anti-retroviral therapy for at least 4 weeks, have a CD4 count of at least 200 microliters, have an undetectable viral load, and have not had a history of opportunistic infection attributable to AIDS within the last 12 months

Exclusion Criteria:

* Pregnant or breast feeding, or intending to become pregnant during the study or within 3 months after the final dose of mosunetuzumab, 9 months after the final dose of polatuzumab vedotin, 12 months after the final dose of rituximab, 6 months after the final dose of gemcitabine, 9 months after the final dose of oxaliplatin, and 3 months after the final dose of tocilizumab, as applicable
* Inability to comply with protocol-mandated activity restrictions
* Prior treatment with mosunetuzumab or other CD-20-directed bispecific antibodies, or R-GemOx or Gem-Ox
* Prior treatment with polatuzumab vedotin, with the following exceptions: participants who have a documented response (partial response or complete response) to polatuzumab vedotin and an absence of PD within 12 months from the last dose of polatuzumab vedotin; participants who received up to 2 doses of a polatuzumab vedotin-containing regimen as bridging to CAR-T therapy, and either has a documented disease control (stable disease, partial response, or complete response), or were not assessed for response following treatment with polatuzumab vedotin
* Contraindication to any component of the study treatment
* Grade \> 1 peripheral neuropathy
* Participants with Grade \> 1 persistent toxicity related to prior anti-lymphoma treatment (except for alopecia and anorexia, or other toxicities not considered a safety risk for the participant per investigator's judgment)
* Received anti-lymphoma treatments with monoclonal antibodies, radio-immunoconjugates or antibody-drug conjugates (ADCs) within 4 weeks before the first dose of study treatment
* Treatment with any chemotherapeutic agent, or treatment with any other anti-lymphoma agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to the first dose of study treatment
* Treatment with radiotherapy within 2 weeks prior to the first dose of study treatment
* ASCT within 100 days prior to the first study treatment administration
* Prior treatment with chimeric antigen receptor (CAR) T cell therapy within 30 days before the first study treatment administration
* Prior allogenic stem cell transplant (SCT)
* Have had a solid organ transplantation
* Known or suspected history of hemophagocytic lymphohistiocytosis (HLH)
* History of confirmed progressive multifocal leukoencephalopathy
* History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombination antibody-related fusion proteins)
* History of other malignancy that could affect compliance with the protocol or interpretation of results, with the exception of malignancies with a negligible risk of metastasis or death
* Currently have or have had a past history of central nervous system (CNS) involvement of lymphoma
* Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits as judged by the investigator, or with a history of epilepsy who have had no seizures in the past 2 years while not receiving any anti-epileptic medications, are allowed
* 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
* Significant active pulmonary disease
* Participants with active symptoms of interstitial lung disease and/or pneumonitis, or those with a history of interstitial lung disease and/or pneumonitis within 6 months prior to the first dose of study treatment
* Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of the nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 2 weeks prior to the first study treatment administration
* Known or suspected chronic active Epstein-Barr virus (EBV) infection
* Recent major surgery within 4 weeks prior to the first study treatment administration
* Positive test results for chronic hepatitis B infection
* Acute or chronic hepatitis C virus (HCV) infection
* Have been administered a live, attenuated vaccine within 4 weeks before the first dose of study treatment administration or anticipation that such a live, attenuated vaccine will be required during the study
* Participants who have positive SARS-CoV-2 test within 7 days prior to enrollment (rapid antigen test result is acceptable)
* History of autoimmune disease
* Received investigational therapy, whether or not intended for lymphoma treatment, within 7 days prior to initiation of study treatment
* Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis