The goal of this clinical trial is to see if a new combination of standard of care radiotherapy treatment prior to administering the study drugs obinutuzumab and glofitamab in relapsed/refractory Diffuse Large B Cell Lymphoma patients is effective. The main question it aims to answer is:

If you are able to tolerate the study treatments, and whether your cancer responds to the study treatment, compared with other reported studies of standard care treatments.

Participants will have three parts they need to complete over a 5 year period.

• Screening period over a 28 day period
• Treatment period - Radiotherapy followed by 12 treatment cycles every three weeks (total time approx. 37 weeks)
• Follow up, up to 4 years. Additional PET imaging studies will be performed in a cohort of patients (up to 6) who are willing to undergo infusions of 89Zr-Df-Crefmirlimab and 18F-Granzyme B for evaluation of the impact of radiotherapy plus glofitamab with relapsed diffuse large B-cell lymphoma.

Clinical trial looking at Radiotherapy in combination with glofitimab in relapsed/refractory Diffuse Large B Cell lymphoma. Where Relapsed/refractory diffuse large B-cell lymphoma after ≥ 2 therapies OR after 1 line AND transplant or CAR-T ineligible. The primary end points is to see what proportion of patients who achieve a complete metabolic response in the absence of prohibitive toxicity following radiotherapy (25Gy in 5 fractions) plus 12 cycles of glofitamab therapy with each cycle delivered every 3 weeks. The secondary endpoints are to assess overall toxicity, to evaluate overall response rates, duration of Response (DOR), time to treatment failure, progression free survival, overall survival, patient report outcome measure - Using EORTC QLD-C30, EORTC IL46 and PRO-CTCAE.

Additional PET imaging studies will be performed in a cohort of patients (up to 6) who are willing to undergo infusions of 89Zr-Df-Crefmirlimab and for evaluation of the impact of radiotherapy plus glofitamab on CD8+ T cell biodistribution in the body and in relapsed diffuse large B-cell lymphoma.

Additional PET imaging studies will be performed in a cohort of patients (up to 6) who are willing to undergo infusions of 18F-Granzyme B to image active immune responses to treatment with radiotherapy plus glofitamab in patients with relapsed diffuse large B-cell lymphoma.

Inclusion Criteria:

1. Age 18 years.

2. Histologically proven relapsed/refractory CD20+ve DLBCL or a recognised subtype, including follicular large B-cell lymphoma and high grade B-cell lymphoma.

3. Prior systemic treatment: ≥2 lines OR after 1 line AND autologous stem cell transplant/CAR-T ineligible

4. Eastern Collaborative Oncology Group (ECOG) performance status 0 to 2.

5. Measurable FDG avid disease on baseline PET/CT scan

6. At least one site of active, PET positive disease that can be safely irradiated. Patients with disease only in previously irradiated sites that cannot be safely irradiated again due to tissue tolerance will be excluded.

7. Adequate bone marrow function including:

   • Haemoglobin >8.0 g/dL
   • White cell count (WCC) ≥2000/μL
   • Neutrophils >1.0 x 109/L
   • Platelets >75 x 109/L at the time of study entry, unless attributed to lymphoma. Red cell transfusion is permitted.

8. Adequate renal function with serum creatinine ≤1.5 x ULN or creatinine clearance (CrCl) ≥ 45mL/min (using Cockcroft-Gault formula, Modification of Diet in Renal Disease Study Equation, 24hr urine collection, eGFR or a formal nuclear medicine technique) unless attributed to lymphoma (e.g. ureteric obstruction).

9. Adequate hepatic function with AST/ALT ≤3x ULN and total bilirubin ≤1.5 x ULN (except subjects with Gilbert syndrome, who can have a total bilirubin ≤3 mg/dL or ≤51.3 μmol/L) unless attributed to lymphoma (e.g. liver infiltration or biliary obstruction).

10. Adequate left ventricular ejection fraction of >40% as demonstrated on a Gated Cardiac Blood Pool Scan or echocardiogram.

11. Life expectancy > 3 months.

12. Patients of childbearing potential willing to adhere to the following contraceptive precautions:

    For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs, as defined below:

    Women must remain abstinent or use contraceptive methods with a failure rate of <1% per year during the treatment period and for at least 6 months after the final dose of obinutuzumab and 2 months after the final dose of glofitamab. Women must refrain from donating eggs during this same period.

    A woman is considered to be of childbearing potential if she is postmenarcheal, 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 (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements.

    Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

    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 patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized acceptable methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

    For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:

    With a female partner of childbearing potential or pregnant female partners, 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 treatment period and for at least 6 months after obinutuzumab, and 2 months after the final dose of glofitamab or tocilizumab to avoid exposing the embryo. 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 patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

13. Written, informed consent.

Exclusion Criteria:

1. Patient has failed only one prior line of therapy and is a candidate for stem cell
2. Transplantation or CAR-T cell therapy
3. Excessively bulky or rapidly progressive disease that, in the opinion of the investigator, requires rapid debulking or is unsafe to be irradiated
4. Richter's transformation from CLL. Transformation from other low-grade histology (e.g. Follicular lymphoma, Marginal zone lymphoma etc) is permitted
5. Refractory to prior therapy with glofitamab or other anti-CD3/CD20 bispecific antibodies, defined as progression during or within 3 months of cessation.
6. Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 4 weeks or 5 half-lives (whichever is shorter) prior to first study treatment.
7. Current central nervous system, meningeal involvement or spinal cord compression by lymphoma. Previous involvement is permitted if there is currently no active CNS disease.
8. Patients with active, known or suspected autoimmune disease. Patients with well controlled type I diabetes mellitus, coeliac disease, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, vitiligo or psoriasis not requiring systemic treatment, or other conditions not expected to recur in the absence of an external trigger are permitted to enrol.
9. Subjects with a condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration without prior discussion with the medical monitor. Inhaled or topical steroids, and adrenal replacement therapy are permitted in the absence of active autoimmune disease.
10. Prior solid organ transplantation or allogeneic bone marrow transplantation within 6 months.
11. Prior malignancy active within the previous 2 years except for those treated with curative intent and with a <20% chance of relapse. Low-grade prostate cancer under observation or well controlled on hormone therapy is permitted. Resected or locally treated non-melanoma skin cancer is permitted.
12. Uncontrolled or severe cardiovascular disease (NYHA class III or IV heart failure; myocardial infarction within the last 6 months of study entry); unstable angina; unstable cardiac arrhythmias; clinically significant pericardial disease.
13. Any other serious active disease or infection that in the opinion of the investigator takes precedence over the DLBCL, or will impact on the ability to deliver study treatment.
14. Any positive test result for hepatitis B or hepatitis C virus during screening indicating acute or chronic infection. Latent hepatitis B with undetectable viral load by PCR is allowable provided appropriate anti-viral prophylaxis is given as per institutional guidelines.
15. Any positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) unless the viral load is fully suppressed for >2 years with a CD4 count of >350x106/L and compliant with antiretroviral therapy.
16. Any history of severe hypersensitivity reactions to other monoclonal antibodies.
17. A history of allergy or intolerance (unacceptable AEs) to study drug components.
18. Patients incarcerated or without Medicare
19. Medical or psychiatric conditions that compromise the patient's ability to give informed consent.

Data sharing to occur at publication.