Inclusion Criteria:
\- To be eligible to participate in this trial, an individual must meet all of the following criteria:
1. Provision of signed and dated informed consent form (ICF) ) by the patient/impartial witness/legal representative before any trial related procedures.
2. Male or female aged between 18 and 65 years.
3. Ability and willingness to comply with the study protocol.
4. Histologically confirmed diagnosis of primary refractory or relapsed DLBCL (all subtypes including primary mediastinal B cell lymphoma, high grade B cell lymphoma, large B cell lymphoma etc) or transformed low grade B cell lymphoma planned for salvage Rituximab-chemotherapy regimens followed by ASCT.
5. Patients with a life expectancy of at least 6 months.
6. All patients must be stable without any signs of active infection, systemic (oral or parenteral) corticosteroid or anticonvulsant therapy for at least 2 weeks prior to study treatment. Inhaled non-absorbable and topical corticosteroid use are permitted as indicated.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks.
8. Women of child-bearing potential and male subjects shall agree to take medically acceptable contraception measures while on study treatment and for 3 months following completion of study treatment. All women of child-bearing potential must have a negative blood pregnancy test at screening.
Women must remain abstinent or use contraceptive methods with a failure rate of ≤1% per year during the study treatment period and for 2 months after the final dose of glofitamab, 3 months after the final dose of tocilizumab (if applicable), 12 months after rituximab or chemotherapy, or 18 months after the final dose of obinutuzumab. Women must refrain from donating eggs during this same period. A woman is considered of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (i.e., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of contraceptive methods with a failure rate of ≤1% per year include bilateral tubal ligation, male sterilization, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method. 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 individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. For men who are not surgically sterile (or with azoospermia for other reasons): Investigators will discuss sperm conservation prior to initiation of study treatment for male participants. Participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agree to refrain from donating sperm, as defined below: With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of ≤1% per year during the study treatment period and for 2 months after the final dose of glofitamab, 3 months after the final dose of tocilizumab (if applicable), 6 months after rituximab, ICE (ifosfamide, carboplatin, and etoposide) or obinutuzumab. 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 individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
9. Patients with at least one bi-dimensionally measurable (≥1.5 cm) nodal lesion, or one bi-dimensionally measurable (≥1 cm) extranodal lesion, as measured on CT scan.
10. Adequate hematologic function (unless attributable to the underlying disease, as established by extensive bone marrow involvement or associated with hypersplenism secondary to the involvement of the spleen by DLBCL per the investigator), defined as follows:
\- ANC ≥1.0 x109/L ( ≥1000/μL) Participants with a history of benign ethnic neutropenia may be included with ANC ≥0.75x109/L (≥750/μL).
\- Platelet count ≥50x109/L (≥50,000/μL) without a transfusion in the week prior to starting study treatment.
11. Adequate renal function, defined as an estimated CrCl ≥ 45 mL/min.
12. Participants who have a negative HIV test at screening, with the following exception: Individuals with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy for at least 4 weeks, have a CD4 count ≥200/μL, have an undetectable viral load, and have not had a history of opportunistic infection attributable to AIDS within the last 12 months.
Exclusion Criteria:
* An individual, who meets ANY of the following criteria, will be excluded from participation in this trial:
1. Patients receiving any investigational drug, biological, immunological therapy within the previous 21 days before enrollment.
2. Presence of any severe or uncontrolled systemic disease or condition, including serious cardiac, pulmonary or renal conditions; any type of bacterial, viral, fungal or other infection that would pose a significant risk to the patient in the opinion of the investigator; or active Hepatitis B or positive HCV antibodies.
3. Any unresolved toxicities from prior therapy, greater than CTCAE-version 5 grade 2 at the time of starting study treatment, with exception of alopecia.
4. Patients with a significant cardiovascular disease or condition, including any of the following:
1. Congestive heart failure (CHF) currently requiring therapy and patients with New York Heart Association Class III/IV CHF
2. LVEF \< 50%
3. Need for antiarrhythmic medical therapy for a ventricular arrhythmia or patients with uncontrolled or unstable cardiac arrhythmias
4. Severe conduction disturbance (e.g., second- or third-degree AV block)
5. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
1. Absolute neutrophil count \< 1 x 109/L (or \< 0.75 x 109/L in case of ethnic neutropenia due to excess margination)
2. Platelet count \< 50 x 109/L (Transfusion-dependent patients are excluded)
6. Severe hepatic and/or renal impairment as demonstrated by any of the following:
a. Alanine aminotransferase \> 2.5 times the upper limit of normal (ULN) b. Aspartate aminotransferase \> 2.5 times ULN c. Total bilirubin \> 1.5 times ULN (Total bilirubin \>3 times the ULN in patients with documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) d. Creatinine clearance \< 45 mL/min (measured or calculated by Cockcroft and Gault equation). Confirmation of creatinine clearance is only required when creatinine is \>1.5 times ULN
7. Judgement by the investigator that the patient should not participate in the study if the patient is unlikely to comply with all study procedures and treatment.
8. Significant medical or psychiatric illness that would interfere with compliance and ability to tolerate treatment as outlined in the protocol.
9. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products.
10. The presence of any contraindication to: Obinutuzumab, rituximab, or tocilizumab.
11. Prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3.
10\. Peripheral neuropathy assessed to be Grade \>1 according to National Cancer Institute (NCI) CTCAE) v5.0 at Enrollment.
11\. Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, o neurodegenerative disease (note: Participants with a history of stroke who have not experienced a stroke or transient ischemic attack within the past 2 years and have no residual neurologic deficits, as judged by the investigator, are allowed).
12\. 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 (as evaluated by the investigator) within 2 weeks prior to the first study treatment. 13. History of other malignancy that could affect compliance with the protocol or interpretation of results, with the following exceptions:
Note:
* Participants with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix at any time prior to enrollment are allowed.
* Participants 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 enrollment are allowed.
* Participants with any other malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment are eligible.
* Participants receiving adjuvant endocrine therapy for non-metastatic, hormone receptor positive breast cancer for ≥2 years prior to enrollment are eligible.
14\. Contraindications to treatment with rituximab, Obinutuzumab or tocilizumab.
