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

Trial Summary

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 the combination of Glofitamab and Obinutuzumab safe for humans?

Glofitamab and Obinutuzumab have been studied in people with certain types of lymphoma, and the most common side effects were mild to moderate infusion-related reactions (like fever or chills) and low white blood cell counts. Serious reactions were rare, and the treatments generally had an acceptable safety profile. ^{1 2 3 4 5}

How is the drug Glofitamab + Obinutuzumab unique for treating central nervous system lymphoma?

Glofitamab + Obinutuzumab is unique because it combines two monoclonal antibodies that target specific proteins on B-cells, potentially offering a novel approach compared to traditional chemotherapy or other targeted therapies like ibrutinib, which have been associated with significant side effects. ^{6 7 8 9 10}

What is the purpose of this trial?

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 central nervous system (CNS) lymphoma. Glofitamab is a bispecific antibody that can bind to two different antigens (substances that cause the body to make a specific immune response) at the same time. Glofitamab binds to CD20 on lymphoma cells, and CD3 on T-cells (a type of white blood cell) and may interfere with the ability of cancer cells to grow and spread. Obinutuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Obinutuzumab can also be administered as a pre-treatment to make glofitamab safer and more tolerable. Giving glofitamab with obinutuzumab pre-treatment may be safe, tolerable, and/or effective in treating patients with CNS lymphoma.

Research Team

James Godfrey

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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]

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]

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 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]

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]

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]

References

1. United States 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. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma. [2022]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Glofitamab: First Approval. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Glofitamab CD20-TCB bispecific antibody. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Targeted Therapies and Immune Checkpoint Inhibitors in Primary CNS Lymphoma. [2021]

10. Italy pubmed.ncbi.nlm.nih.gov

Intraventricular treatment of relapsed central nervous system lymphoma with the anti-CD20 antibody rituximab. [2015]