Bispecific Antibody-Based Holding/Bridging Therapy Before CAR-T in Aggressive B-Cell Lymphomas

• Glofitamab (Drug): Glofitamab administered according to the protocol-specified step-up dosing schedule, followed by two full doses in combination with either polatuzumab vedotin or GemOx.
• Epcoritamab (Drug): Epcoritamab administered according to the protocol-specified step-up dosing schedule, followed by two full doses in combination with either polatuzumab vedotin or GemOx.
• Polatuzumab Vedotin (Drug): Polatuzumab vedotin 1.8 mg/kg administered intravenously once per cycle for two cycles in combination with the protocol-specified CD20xCD3 bispecific antibody.
• Gemcitabine & oxaliplatin (Drug): Gemcitabine 1000 mg/m² and oxaliplatin 100 mg/m² administered intravenously once every 21 days for two cycles in combination with the protocol-specified CD20xCD3 bispecific antibody.
• Obinutuzumab (Drug): Obinutuzumab 1000 mg administered intravenously as protocol-specified pretreatment before initiation of glofitamab step-up dosing.

Primary outcomes

• Objective Response Rate After Two Cycles of Holding/Bridging Therapy [14 to 21 days after completion of the second 21-day combination cycle, before leukapheresis in the holding pathway or before lymphodepletion in the bridging pathway.]: Proportion of participants achieving a complete or partial metabolic response according to Lugano 2014 criteria using the Deauville 5-point scale.

Secondary outcomes

• Proportion of Participants Receiving CAR T-Cell Infusion [Assessed at the time of planned CAR T-cell infusion, following completion of holding/bridging therapy.]: Number and proportion of enrolled participants who receive the planned CAR T-cell infusion.
• Incidence and Severity of Adverse Events During Holding/Bridging Therapy [From the first dose of study treatment through the start of lymphodepletion, up to approximately 12 weeks]: Number and proportion of participants with adverse events (AEs), Grade 3 or higher AEs, serious adverse events (SAEs), cytokine release syndrome (CRS), ICANS, infections, cytopenias, peripheral neuropathy, treatment delays, treatment discontinuations, and deaths. AEs will be graded according to CTCAE v6.0; CRS and ICANS will be graded according to ASTCT 2019 criteria.
• Safety of CAR T-Cell Therapy After Bispecific Antibody-Based Holding/Bridging Therapy [From CAR T-cell infusion through Day +90; primary safety assessment through Day +28 with additional assessment through Day +90.]: Number and proportion of participants experiencing cytokine release syndrome (CRS), ICANS, IEC-HS, cytopenias, infections, Grade 3 or higher adverse events, and serious adverse events after CAR T-cell infusion. CRS, ICANS, and IEC-HS will be assessed according to ASTCT criteria, and adverse events will be graded according to CTCAE v6.0.
• Objective Response Rate After CAR T-Cell Therapy [Day +28 and Day +90 after CAR T-cell infusion]: Proportion of participants achieving a complete or partial metabolic response according to Lugano 2014 criteria.
• Event-Free Survival [Up to 12 months after CAR T-cell infusion]: Time from CAR T-cell infusion to the first occurrence of disease progression, relapse, or death from any cause, whichever occurs first.
• Overall Survival [Up to 12 months after CAR T-cell infusion]: Time from CAR T-cell infusion to death from any cause.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age 18 years or older.
* Ability to understand the study requirements and provide written informed consent.
* Histologically confirmed relapsed or refractory aggressive mature B-cell non-Hodgkin lymphoma.
* Failure of at least one prior line of systemic anticancer therapy.
* Documented CD19 expression on tumor cells by immunohistochemistry and/or flow cytometry/immunophenotyping of current disease.
* Considered eligible for CD19-directed CAR T-cell therapy by the treating multidisciplinary team, with no absolute contraindication to CAR T-cell therapy at the time of enrollment.
* At least one measurable FDG-avid lesion according to Lugano 2014 criteria.
* Baseline PET/CT performed within 28 days before enrollment.
* ECOG performance status 0-2.
* Life expectancy of at least 12 weeks.
* No severe uncontrolled comorbid condition that would preclude protocol therapy.
* Women of childbearing potential must have a negative pregnancy test before study treatment and agree to use highly effective contraception; male participants must agree to follow protocol-specified contraceptive requirements.

Exclusion Criteria:

* Prior treatment with a CD20×CD3 bispecific antibody.
* Absence of confirmed CD19 expression on tumor cells.
* No indication for, or any contraindication to, CD19-directed CAR T-cell therapy.
* ECOG performance status ≥3.
* Uncontrolled bacterial, viral, fungal, or opportunistic infection, including sepsis.
* Active hepatitis B or C infection, HIV infection, or syphilis.
* Concurrent active malignancy not in remission.
* Active autoimmune disease requiring systemic immunosuppressive therapy.
* Ongoing systemic corticosteroid therapy at a dose equivalent to >10 mg/day of prednisone, except physiologic replacement therapy or protocol-required premedication.
* Clinically significant uncontrolled cardiovascular, pulmonary, neurologic, or psychiatric disease.
* Grade ≥2 peripheral sensory or motor neuropathy according to CTCAE.
* Known hypersensitivity to any study drug or its components.
* Pregnancy or breastfeeding.
* Any other condition that, in the investigator's judgment, would place the participant at unacceptable risk or interfere with study treatment or required study procedures.

• Elena Parovichnikova, MD, DSc, Principal investigator, National Research Center for Hematology