Nivolumab + Relatlimab for Glioblastoma

(GIANT Trial)

Overseen By Mustafa Khasraw

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Duke University

Must not be taking: Immunotherapy, Anticoagulants, Immunosuppressants

Disqualifiers: CNS bleeding, Autoimmune disease, Active tuberculosis, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: Unknown

92 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that patients cannot be on certain treatments like immunosuppressive medications or anticoagulation therapy close to the trial start. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Nivolumab + Relatlimab for Glioblastoma?

Research shows that nivolumab has been studied for glioblastoma, but with limited benefits. However, the combination of nivolumab and relatlimab has shown better results in treating melanoma, suggesting potential for improved outcomes in other cancers. ^{1 2 3 4 5}

Is Nivolumab + Relatlimab safe for humans?

Nivolumab, used alone or with other drugs, has been generally safe in humans, but it can cause some serious side effects like liver injury and aplastic anemia (a condition where the body stops producing enough new blood cells). Nivolumab combined with Relatlimab has shown a manageable safety profile in patients with melanoma. ^{1 5 6 7 8}

How is the drug Nivolumab + Relatlimab unique for treating glioblastoma?

Nivolumab + Relatlimab is unique because it combines two immune checkpoint inhibitors, which are designed to enhance the body's immune response against cancer cells. This approach is different from traditional treatments as it specifically targets the immune system to fight glioblastoma, a strategy that has shown promise in other types of cancer. ^{4 5 9 10 11}

What is the purpose of this trial?

GIANT is an open-label, multi-center, randomized, perioperative (neoadjuvant followed by adjuvant), phase 2 trial with a safety lead-in phase to investigate the feasibility, safety and tolerability, and establish the biological activity of nivolumab with or without relatlimab in patients with isocitrate dehydrogenase (IDH) wildtype newly diagnosed glioblastoma (ndGBM).

Eligibility Criteria

This trial is for adults with a new diagnosis of glioblastoma, which is an aggressive type of brain cancer. Participants must have a specific genetic feature in their tumor (IDH wildtype). Details on who can't join are not provided here.

Inclusion Criteria

Life expectancy of at least 12 months

Negative human immunodeficiency virus (HIV) test at Screening

Negative hepatitis B surface antigen (HbsAg) test at Screening

Exclusion Criteria

Abnormal troponin levels

Known allergy or sensitivity to specific medications

My tumor cannot be completely removed by surgery.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Patients receive a single dose of nivolumab with or without relatlimab followed by tumor resection

4 weeks

Part 1 Adjuvant Treatment

Patients receive nivolumab and relatlimab with concomitant radiation and TMZ for MGMT methylated patients

6 weeks

Part 2 Adjuvant Treatment

Continuation of nivolumab and relatlimab with TMZ for up to 6 cycles

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Nivolumab
• Relatlimab

Trial Overview The GIANT study tests the combination of Nivolumab and Relatlimab immunotherapies with radiation and TMZ chemotherapy in patients with newly diagnosed glioblastoma. It's designed to see if this treatment is safe and how well it works.

Participant Groups

Group I: Nivolumab and Relatlimab Experimental Treatment 4 Interventions

In Arm 2 and Safety Lead-In phase, patients will receive treatment in 4 stages as below: 1. Neoadjuvant Treatment: Patient will receive a single dose of 480 mg by IV infusion with 480 mg of relatimab on Day 1. 2. Resection 3. Part 1 Adjuvant Treatment: Patient will receive 480 mg of nivolumab and 480 mg of relatimab for up to 12 cycles with concomitant radiation 2Gy/day (60 Gy in total). All MGMT methylated patients under Part 1 Adjuvant Treatment setting will also receive 75 mg/m2 TMZ from Day 1 to Day 42 orally. 4. Part 2 Adjuvant Treatment: Part 1 Adjuvant Treatment will continue without concomitant radiation.

Group II: Nivolumab Experimental Treatment 3 Interventions

4 stages of treatment on Arm 1 are: 1. Neoadjuvant Treatment: Patient will receive a single dose of 480 mg by IV infusion on Day 1. 2. Resection 3. Part 1 Adjuvant Treatment: Patient will receive 480 mg of nivolumab and 380 mg of relatimab for up to 12 cycles with concomitant radiation 2Gy/day (60 Gy in total). All MGMT methylated patients under Part 1 Adjuvant Treatment setting will also receive 75 mg/m2 TMZ from Day 1 to Day 42 orally. 4. Part 2 Adjuvant Treatment: Part 1 Adjuvant Treatment will continue without concomitant radiation.

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Findings from Research

In a study of 31 adult patients with recurrent high-grade gliomas, salvage therapy using PD-1-blocking antibodies nivolumab or pembrolizumab, with or without bevacizumab, showed a median progression-free survival of only 3.2 months, indicating limited efficacy.

The study found no significant survival benefit from these treatments in this patient population, suggesting that PD-1-blocking antibodies should be used cautiously and only in selected cases until further clinical trial results are available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 inhibition has only limited clinical benefit in patients with recurrent high-grade glioma. Kurz, SC., Cabrera, LP., Hastie, D., et al.[2019]

In a study of 129 patients with advanced melanoma treated with nivolumab and relatlimab, those without diabetes had significantly better progression-free survival (PFS) and overall survival (OS) compared to patients with type 2 diabetes, indicating that diabetes negatively impacts treatment efficacy.

Interestingly, patients who developed immune checkpoint inhibitor-induced diabetes (ICI-DM) during treatment had the best outcomes, suggesting that this condition may enhance the effectiveness of the therapy, possibly due to changes in LAG3 expression in tumor tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. Mallardo, D., Woodford, R., Menzies, AM., et al.[2023]

In a study involving 40 newly diagnosed and 86 recurrent glioblastoma patients, PD-L1 blockade with durvalumab did not meet primary efficacy endpoints, indicating it was ineffective in improving outcomes compared to standard treatments.

Recurrent glioblastoma patients exhibited significantly lower levels of circulating immune cell subsets, and the use of dexamethasone was associated with a reduction in these immune cells, suggesting that immune suppression may hinder treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. Nayak, L., Standifer, N., Dietrich, J., et al.[2023]

Nivolumab alone was better tolerated than when combined with ipilimumab, with treatment-related adverse events like fatigue and diarrhea being more common in the combination therapy group.

Despite the safety concerns, some patients showed promising responses, with three achieving partial responses and eight maintaining stable disease for at least 12 weeks, indicating potential efficacy of nivolumab in treating recurrent glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Omuro, A., Vlahovic, G., Lim, M., et al.[2023]

Immune checkpoint inhibitors like nivolumab have revolutionized cancer treatment but can lead to serious autoimmune-like side effects known as immune-related adverse events (irAEs).

This study highlights a specific case of severe liver injury linked to nivolumab in a glioblastoma patient, emphasizing the need for better understanding and management of these potential toxicities to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. Simonelli, M., Di Tommaso, L., Baretti, M., et al.[2018]

The combination of nivolumab and relatlimab shows a manageable safety profile for patients with advanced melanoma who have already undergone treatment.

This combination therapy may offer a new option for patients with pretreated melanoma, suggesting potential efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab Is Safe and Efficacious in Pretreated Melanoma. [2023]

Nivolumab, an immune checkpoint inhibitor, is being investigated as a treatment for pediatric glioblastoma multiforme, a rare and aggressive brain cancer, to improve patient survival.

This report highlights a significant adverse effect of nivolumab, specifically bilateral optic neuritis, in a patient with grade 4 glioblastoma multiforme, indicating the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral Optic Neuritis Secondary to Nivolumab Therapy: A Case Report. Kartal, Ö., Ataş, E.[2019]

Intracerebral administration of ipilimumab (IPI) and nivolumab (NIVO) after maximal safe resection of recurrent glioblastoma (rGB) was found to be feasible and safe, with mild immune-related adverse events and no significant central nervous system toxicity observed.

The treatment resulted in a median overall survival of 38 weeks, which is favorable compared to historical data, suggesting that this approach may improve outcomes for patients with rGB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial. Duerinck, J., Schwarze, JK., Awada, G., et al.[2022]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study. [2022]

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

PD-1 inhibition has only limited clinical benefit in patients with recurrent high-grade glioma. [2019]

3. England pubmed.ncbi.nlm.nih.gov

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. [2023]

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

Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. [2018]

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

Nivolumab Plus Relatlimab Is Safe and Efficacious in Pretreated Melanoma. [2023]

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

Nivolumab-induced aplastic anemia: A case report and literature review. [2022]

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

Bilateral Optic Neuritis Secondary to Nivolumab Therapy: A Case Report. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial. [2022]

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

PD-1 Inhibitors: Do they have a Future in the Treatment of Glioblastoma? [2021]