Glofitamab + Obinutuzumab for Central Nervous System Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Immunotherapeutics, Chemotherapy, Radiotherapy, others

Disqualifiers: Organ transplant, Unstable cardiac, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 20

Duration: 36 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, glofitamab and obinutuzumab, to determine their safety and effectiveness in treating central nervous system (CNS) lymphoma, a cancer affecting the brain and spinal cord. Glofitamab is a specialized antibody that targets lymphoma cells and aids the immune system in fighting them, while obinutuzumab enhances the safety and effectiveness of glofitamab. This study may suit individuals with CNS lymphoma that has not responded to other treatments, such as methotrexate, and who do not have rapidly worsening brain issues. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, certain prior treatments like systemic chemotherapy, radiotherapy, and some immunotherapies must be stopped a few weeks before starting the trial. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the combination of glofitamab and obinutuzumab has been studied for safety in treating different types of lymphoma. Glofitamab is a unique antibody that can attach to two targets simultaneously, while obinutuzumab specifically targets cancer cells.

This treatment combination has been tested in patients with aggressive B-cell lymphomas. In these studies, most patients tolerated the treatment well, although some experienced side effects. Common side effects included low blood cell counts and reactions similar to allergies during or after treatment.

The combination has received approval for other conditions, indicating it is considered safe in those cases, though side effects can still occur. Since this clinical trial is in an early phase, the main goal is to ensure the treatment's safety and determine the right dose. This phase is crucial for understanding how patients tolerate the treatment. Typically, early-phase trials involve fewer participants, and researchers closely monitor the treatments for any negative effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Glofitamab is unique because it targets CD20 and CD3 proteins, which helps the immune system attack cancer cells more effectively. Unlike standard treatments for central nervous system lymphoma that often rely on traditional chemotherapy or radiation, glofitamab offers a more precise immunotherapy approach. Researchers are excited about this treatment because it has the potential to offer a more targeted and potentially less toxic option for patients, addressing a critical need in managing this challenging condition.

What evidence suggests that glofitamab and obinutuzumab might be effective for CNS lymphoma?

This trial will evaluate the combination of glofitamab and obinutuzumab for treating central nervous system lymphoma. Research has shown that using these two drugs together may help treat certain types of lymphomas. In one study, glofitamab alone helped more than half of the patients, with 30% experiencing complete disappearance of cancer signs. Many patients, therefore, experienced some improvement. Evidence also indicates that symptoms improved in cases where lymphoma had spread to the brain and spinal cord. Combining these medications might enhance their effectiveness, as obinutuzumab can make glofitamab safer and easier to handle. While these results are promising, further research is needed to confirm their effectiveness specifically for lymphoma in the brain and spinal cord. ^{1 2 3 4 6}

Who Is on the Research Team?

James Godfrey

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with central nervous system lymphoma. Participants should be eligible for lumbar punctures and imaging tests like PET, CT, and MRI scans. The study aims to test a new treatment approach using the drugs glofitamab and obinutuzumab.

Inclusion Criteria

Documented informed consent of the participant and/or legally authorized representative

Assent, when appropriate, will be obtained per institutional guidelines

Agreement to allow the use of archival tissue from diagnostic tumor biopsies

Exclusion Criteria

Any other condition that would contraindicate the patient's participation in the clinical study

Any investigational therapy for the purposes of treating cancer within specified timeframe

History or presence of an abnormal electrocardiogram (ECG)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive obinutuzumab IV on day 1 of cycle 1 and glofitamab IV on days 8 and 15 of cycle 1 and on day 1 of subsequent cycles. Cycles repeat every 21 days for up to 12 cycles.

36 weeks

12 cycles, multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion at 30 days and at 3, 6, 9, 12, 18, and 24 months.

24 months

7 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Glofitamab
• Obinutuzumab

Trial Overview The safety, side effects, and effectiveness of glofitamab following obinutuzumab pre-treatment are being tested in this phase Ib trial. Glofitamab is a bispecific antibody targeting cancer cells, while obinutuzumab is a monoclonal antibody used as pre-treatment.

How Is the Trial Designed?

Group I: Treatment (obinutuzumab, glofitamab) Experimental Treatment 7 Interventions

Patients receive obinutuzumab IV on day 1 of cycle 1 and glofitamab IV over 2-4 hours on days 8 and 15 of cycle 1 and on day 1 of subsequent cycles. Cycles repeat every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or PET/CT at screening and CSF and blood sample collection, brain MRI throughout the study. Patients with secondary CNS lymphoma also undergo CT or PET/CT throughout the study. Additionally, patients with baseline CSF involvement, may undergo lumbar puncture throughout the study.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Glofitamab, a bispecific antibody targeting CD20 and CD3, demonstrated clinical activity in patients with relapsed/refractory B-cell non-Hodgkin lymphoma during a phase 1 trial, showing T-cell activation and tumor cell killing.

The study identified that tumor intrinsic factors, such as TP53 signaling, may contribute to resistance against glofitamab, indicating that these factors could serve as important biomarkers for predicting treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma. Bröske, AE., Korfi, K., Belousov, A., et al.[2022]

Ibrutinib, a Bruton's tyrosine kinase inhibitor, shows promise in treating primary central nervous system lymphoma by blocking signals that activate tumor growth, making it a key focus in ongoing clinical studies.

Immunomodulatory agents like lenalidomide and pomalidomide, along with immune checkpoint inhibitors targeting the PD-1 pathway, are being explored as potential new therapies to enhance the body's immune response against this rare brain tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Therapies and Immune Checkpoint Inhibitors in Primary CNS Lymphoma. Wirsching, HG., Weller, M., Balabanov, S., et al.[2021]

Glofitamab is a novel bispecific T-cell recruiting antibody that targets both CD20 on B-cells and CD3 on T-cells, showing over 50% complete response rates in heavily treated patients with aggressive and indolent B-cell lymphoma during Phase 1 trials.

The unique 2:1 configuration of glofitamab allows for an extended half-life and superior binding to CD20, making it a promising option for patients with limited treatment choices, with ongoing trials evaluating its efficacy in combination therapies and earlier treatment lines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glofitamab CD20-TCB bispecific antibody. Minson, A., Dickinson, M.[2022]

In a study of 56 patients with relapsed/refractory follicular lymphoma, obinutuzumab combined with chemotherapy (either G-CHOP or G-FC) resulted in high response rates of 93% to 96%, indicating strong efficacy for this treatment approach.

The safety profile was acceptable, with most adverse events being mild infusion-related reactions; however, G-FC was associated with more adverse events compared to G-CHOP, suggesting that while both regimens are effective, G-CHOP may be better tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Radford, J., Davies, A., Cartron, G., et al.[2022]

Glofitamab, a bispecific monoclonal antibody targeting CD20 and CD3, was conditionally approved in Canada on March 25, 2023, for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have undergone multiple prior therapies and are ineligible for CAR T-cell therapy.

The drug is currently under regulatory review in the EU and USA, with ongoing clinical development as both a standalone treatment and in combination with other therapies for non-Hodgkin lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glofitamab: First Approval. Shirley, M.[2023]

A combination treatment of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the BTK inhibitor ibrutinib showed promising responses in patients with primary central nervous system lymphoma.

However, this treatment regimen was linked to significant toxicity, including serious infections like pulmonary and cerebral aspergillosis, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. Grommes, C., Younes, A.[2018]

In a retrospective study of 120 patients with aggressive B cell central nervous system lymphoma, the addition of rituximab to high-dose methotrexate-based chemotherapy was associated with improved overall survival, suggesting it may enhance treatment efficacy.

Key factors predicting better survival included younger age (≤60 years), good performance status, normal lactate dehydrogenase levels, and receiving treatment after 2004, highlighting the importance of these variables in patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. Gregory, G., Arumugaswamy, A., Leung, T., et al.[2022]

Glofitamab, a bispecific antibody, demonstrated a 53.8% overall response rate in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, with a complete response rate of 36.8%, indicating its efficacy in a heavily pretreated population.

The treatment had a manageable safety profile, with cytokine release syndrome occurring in 50.3% of patients but mostly at lower grades, and only 2.9% of patients withdrew due to adverse events, suggesting that glofitamab can be safely administered with prior obinutuzumab pretreatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. Hutchings, M., Morschhauser, F., Iacoboni, G., et al.[2023]

In a study of 81 patients with newly diagnosed primary CNS lymphomas, the addition of rituximab to high-dose methotrexate (HD-MTX) significantly increased the complete response (CR) rate from 36% to 73%.

Patients receiving the combination treatment of HD-MTX and rituximab also experienced a median progression-free survival of 26.7 months, compared to just 4.5 months for those on HD-MTX alone, indicating a substantial improvement in treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Holdhoff, M., Ambady, P., Abdelaziz, A., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06922604

NCT06922604 | Glofitamab With Obinutuzumab Pre- ... This phase Ib trial tests the safety and side effects of glofitamab after pre-treatment with obinutuzumab and how well they work in treating patients with ...

2. ashpublications.org ashpublications.org/blood/article/146/18/2177/546196/Real-world-outcomes-of-patients-with-aggressive-B

Real-world outcomes of patients with aggressive B-cell ... The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12313487/

Glofitamab treatment of Richter transformation with isolated ... In summary, we reported a rare case of CLL transforming into isolated CNS-involved DLBCL via RT. The patient's clinical symptoms improved after ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2206913

Glofitamab for Relapsed or Refractory Diffuse Large B-Cell ... Glofitamab therapy was effective for DLBCL. More than half the patients had an adverse event of grade 3 or 4.

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2023/761309Orig1s000MultidisciplineR.pdf

761309Orig1s000 - accessdata.fda.gov nervous system lymphoma. Reference ID: 5192035. Page 34 ... preliminary anti-tumor activity of glofitamab in combination with obinutuzumab, following Gpt.

6. library.ehaweb.org library.ehaweb.org/eha/2025/eha2025-congress/4160375/zhiyong.zeng.real-world.analysis.of.glofitamab.in.relapsed.refractory.primary.html

REAL-WORLD ANALYSIS OF GLOFITAMAB IN RELAPSED ... Background: The prognosis of relapsed/refractory primary central nervous system lymphoma (PCNSL) is very poor, with a median survival of only 2.1 months.