Obinutuzumab for Glomerulonephritis

Overseen By Corbyn Bendtsen

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Cyclophosphamide, ACTH, Mycophenolate, Prednisone

Disqualifiers: Hepatitis, HIV, Pregnancy, Infection, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

20 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research is to learn if Obinutuzumab is effective and safe in treating patients with fibrillary glomerulonephritis (FGN).

Will I have to stop taking my current medications?

The trial requires that you have not taken certain medications recently, such as cyclophosphamide in the last 6 months, ACTH or mycophenolate mofetil in the last 30 days, and prednisone at a dose greater than 10 mg/day in the last 15 days. If you are on these medications, you may need to stop them before participating.

What data supports the effectiveness of the drug Obinutuzumab for treating glomerulonephritis?

Obinutuzumab has been shown to effectively deplete certain B-cell types in patients with end-stage kidney disease, which suggests it might help in conditions like glomerulonephritis that involve the immune system. Additionally, it has been effective in treating other conditions like chronic lymphocytic leukemia and follicular lymphoma, indicating its potential in managing immune-related diseases. ^{1 2 3 4 5}

Is Obinutuzumab (Gazyva) generally safe for humans?

Obinutuzumab, also known as Gazyva, has been studied for safety in humans, primarily for conditions like chronic lymphocytic leukemia and follicular lymphoma. Common side effects include infusion-related reactions, low blood cell counts, and infections, but it is generally considered safe when monitored by healthcare professionals. ^{6 7 8 9 10}

How is the drug Obinutuzumab unique in treating glomerulonephritis?

Obinutuzumab is unique because it is a type II anti-CD20 monoclonal antibody that targets B-cells, which are part of the immune system, and induces their death. This mechanism is different from other treatments for glomerulonephritis, as it specifically enhances immune-mediated cell death, potentially offering a novel approach for patients with this condition. ^{1 2 3 5 11}

Research Team

Ladan Zand

Principal Investigator

Mayo Clinic

Fernando Fervenza, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

Adults over 18 with fibrillary glomerulonephritis (FGN), protein in urine, and a minimum kidney function can join. Excluded are those with hepatitis B/C, HIV, pregnant or breastfeeding women, other kidney diseases on biopsy, active infections, low platelet count or anemia. Participants must agree to use effective contraception.

Inclusion Criteria

Proteinuria > 1.0 g/24hrs prior to initiation of immunosuppressive therapy

eGFR ≥ 20 ml/min/BSA

My kidney disease was confirmed by a biopsy.

Exclusion Criteria

Hepatitis B, C or HIV positive

Pregnant or breast-feeding

My biopsy shows I have another disease besides my main condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Obinutuzumab for the treatment of fibrillary glomerulonephritis

12 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Obinutuzumab

Trial Overview The trial is testing if Obinutuzumab is safe and works for treating FGN. It's given to see if it helps reduce the disease's effects on the kidneys by targeting specific immune cells.

Participant Groups

Group I: Obinutuzumab in Treatment of Fibrillary Glomerulonephritis Experimental Treatment 1 Intervention

Patients with biopsy proven fibrillary GN who have \>1 gram/24 hour of proteinuria and eGFR ≥ 20 ml/min/BSA will be treated with Obinutuzumab.

Obinutuzumab is already approved in United States, European Union for the following indications:

Approved in United States as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Approved in European Union as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Findings from Research

Obinutuzumab is an effective treatment for B-cell malignancies, specifically approved in the US for chronic lymphocytic leukaemia (CLL) in combination with chlorambucil, showcasing its efficacy in targeting cancer cells.

Utilizing GlycoMAb® technology, obinutuzumab enhances immune-mediated cell death through increased antibody-dependent cellular cytotoxicity, making it a promising option in ongoing phase III trials for various B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: first global approval. Cameron, F., McCormack, PL.[2021]

Obinutuzumab, an anti-CD20 antibody, effectively induces a rapid loss of various B-cell subsets in patients with end-stage renal disease, demonstrating its potential to target B cells in the immune system.

The treatment was associated with increased levels of B cell-activating factor and decreased CXCL13, suggesting a significant impact on B-cell activity that could enhance its efficacy in conditions like lupus, where traditional B-cell therapies face challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab Effectively Depletes Key B-cell Subsets in Blood and Tissue in End-stage Renal Disease Patients. Looney, CM., Schroeder, A., Tavares, E., et al.[2023]

Obinutuzumab, combined with bendamustine, significantly prolonged progression-free survival (PFS) in patients with indolent non-Hodgkin's lymphoma, particularly benefiting those with follicular lymphoma, as shown in the phase III GADOLIN study.

The treatment was generally well-tolerated, with mild to moderate infusion-related reactions being the most common side effects, while neutropenia was the most frequent severe adverse event, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma. Dhillon, S.[2018]

In a multinational phase III study, obinutuzumab combined with chlorambucil significantly improved progression-free survival and event-free survival in adults with previously untreated chronic lymphocytic leukaemia (CLL) compared to chlorambucil alone and rituximab plus chlorambucil.

Obinutuzumab plus chlorambucil had a manageable safety profile, with neutropenia and infusion-related reactions being the most common serious side effects, primarily occurring during the first infusion and generally manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia. Hoy, SM.[2018]

Obinutuzumab (OBZ) was used to treat a patient with refractory cryoglobulinaemic vasculitis (CV) who was immunized against rituximab (RTX), and no cross-reactivity between anti-RTX antibodies and OBZ was found, suggesting OBZ can be a viable alternative.

The patient experienced a flare of CV after OBZ infusion, which may be linked to the release of immune complexes due to B cell lysis, indicating that the use of OBZ in patients with mixed CV should be approached with caution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flare of a mixed cryoglobulinaemic vasculitis after obinutuzumab infusion. Martin de Fremont, G., Chiron, A., Krzysiek, R., et al.[2022]

A 28-year-old woman developed acute renal failure after receiving Alemtuzumab for multiple sclerosis, highlighting a potential risk associated with this treatment.

Despite early diagnosis and immunosuppressive therapy for anti-glomerular basement membrane disease, the patient progressed to end-stage kidney failure, emphasizing the need for vigilance in monitoring renal function in patients treated with Alemtuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glomerulonephritis With Positive Anti-Glomerular Basement Membrane Antibodies Following Alemtuzumab Treatment. White, E., Watson, A., Holian, J., et al.[2021]

Cetuximab, an EGFR inhibitor used in cancer treatment, is associated with a very rare risk of nephrotoxicity, as demonstrated in a case of a 65-year-old woman who developed severe crescentic glomerulonephritis after treatment.

This case highlights the need for careful monitoring of renal function in patients receiving cetuximab, as it may trigger or worsen kidney injury, leading to serious complications such as acute renal failure and the need for hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab-Associated Crescentic Diffuse Proliferative Glomerulonephritis. Manthri, S., Bandaru, S., Chang, A., et al.[2020]

Rituximab, a monoclonal antibody targeting CD20 on B-cells, has shown promise as a safer and effective alternative to traditional cytotoxic immunosuppressants and corticosteroids for treating glomerular immune-mediated diseases.

Originally approved for non-Hodgkin's lymphoma, Rituximab has been successfully used off-label for various conditions like membranous nephropathy and lupus nephritis, demonstrating a favorable safety and efficacy profile, including FDA approval for ANCA-associated vasculitis in 2011.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[An innovative approach to the treatment of immune-mediated glomerular diseases]. Roccatello, D.[2013]

A 60-year-old woman developed severe acute kidney injury after receiving pembrolizumab, an immune checkpoint inhibitor, for squamous cell carcinoma, highlighting a potential link between this treatment and anti-GBM glomerulonephritis.

The patient's kidney biopsy confirmed crescentic glomerulonephritis, and despite treatment with plasmapheresis and steroids, she progressed to kidney failure requiring dialysis, suggesting the need for increased awareness of this rare but serious side effect in patients undergoing immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-Induced Anti-GBM Glomerulonephritis: A Case Report. El Yamani, N., Cote, G., Riopel, J., et al.[2023]

In a study of 16 children with steroid-resistant or steroid-dependent nephrotic syndrome, rituximab treatment led to remission in 7 patients, indicating its potential efficacy as a nonstandard immunosuppressive therapy.

The treatment was well-tolerated, with no significant side effects or changes in leukocyte counts observed, suggesting that rituximab could be a safe alternative for patients not responding to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of rituximab treatment in children with primary glomerulonephritis. Zachwieja, J., Silska, M., Ostalska-Nowicka, D., et al.[2015]

In preclinical studies involving cynomolgus monkeys, obinutuzumab caused expected B-cell depletion but also led to hypersensitivity reactions, indicating potential safety concerns that were observed at all doses.

Despite these reactions in monkeys, clinical evidence suggests that hypersensitivity to obinutuzumab is rare in humans, highlighting that animal studies may not always predict human responses to immunogenicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypersensitivity Reactions to Obinutuzumab in Cynomolgus Monkeys and Relevance to Humans. Husar, E., Solonets, M., Kuhlmann, O., et al.[2018]

References

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

Obinutuzumab: first global approval. [2021]

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

Obinutuzumab Effectively Depletes Key B-cell Subsets in Blood and Tissue in End-stage Renal Disease Patients. [2023]

3. France pubmed.ncbi.nlm.nih.gov

Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma. [2018]

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

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia. [2018]

5. Italy pubmed.ncbi.nlm.nih.gov

Flare of a mixed cryoglobulinaemic vasculitis after obinutuzumab infusion. [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

Glomerulonephritis With Positive Anti-Glomerular Basement Membrane Antibodies Following Alemtuzumab Treatment. [2021]

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

Cetuximab-Associated Crescentic Diffuse Proliferative Glomerulonephritis. [2020]

8. Italy pubmed.ncbi.nlm.nih.gov

[An innovative approach to the treatment of immune-mediated glomerular diseases]. [2013]

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

Pembrolizumab-Induced Anti-GBM Glomerulonephritis: A Case Report. [2023]

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

Efficacy and safety of rituximab treatment in children with primary glomerulonephritis. [2015]

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

Hypersensitivity Reactions to Obinutuzumab in Cynomolgus Monkeys and Relevance to Humans. [2018]