Intravenous and Intrathecal Nivolumab for Leptomeningeal Disease

Overseen By Isabella Glitza, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, Active infections, HIV, others

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

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 13

Duration: Up to 2 years

70 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial allows patients to continue certain medications, like approved targeted therapies and chemotherapy for lung cancer, without a break. However, if you're on other systemic therapies, you might need to stop them for a specific period before starting the trial. It's best to discuss your current medications with the trial team to understand any necessary changes.

What data supports the effectiveness of the drug Nivolumab for treating leptomeningeal disease?

In a study, patients with melanoma and leptomeningeal disease who received Nivolumab had a median survival of 4.9 months, which is longer than the historical average of about 6 weeks with traditional treatments like radiation and chemotherapy. Additionally, a case report showed complete remission of leptomeningeal metastasis in a kidney cancer patient treated with Nivolumab, suggesting potential effectiveness. ^{1 2 3 4 5}

Is nivolumab safe for treating leptomeningeal disease?

Nivolumab, used alone or with other drugs, has shown an acceptable safety profile in treating leptomeningeal disease, with some patients experiencing side effects like fatigue, nausea, and rash. In one study, no dose-limiting toxicities were found, and another reported rare but serious neurological effects that were reversible with treatment. ^{1 2 4 5 6}

How is the drug nivolumab unique for treating leptomeningeal disease?

Nivolumab is unique for treating leptomeningeal disease because it is administered both intravenously (through a vein) and intrathecally (directly into the spinal fluid), which allows it to target cancer cells in the brain and spinal cord more effectively. This dual administration method is different from traditional treatments like radiation and chemotherapy, which have limited effectiveness for this condition. ^{1 2 3 4 5}

What is the purpose of this trial?

This phase I/Ib trial studies the side effects and best dose of intrathecal nivolumab, and how well it works in combination with intravenous nivolumab in treating patients with leptomeningeal disease. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Research Team

Isabella C. Glitza, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with leptomeningeal disease from melanoma or non-small cell lung cancer. Participants can have had prior treatments but must meet specific conditions, such as not having severe allergies to monoclonal antibodies, no active autoimmune diseases requiring treatment in the past 2 years, and no ongoing serious side effects from previous immunotherapy.

Inclusion Criteria

My tests show cancer cells in my brain or spinal fluid.

I last received biologic therapy for my condition over 2 weeks ago.

I last received immunotherapy at least 7 days before starting this treatment.

Exclusion Criteria

I haven't needed treatment for an autoimmune disease in the last 2 years.

I am experiencing significant side effects from my immunotherapy.

I have not had any infections in the last week.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive intrathecal nivolumab on day 1 of every cycle, and intravenous nivolumab starting from cycle 2. Cycles repeat every 14 days for 18 cycles and then every 28 days.

Up to 2 years

Visits on days 1, 2, 8 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks initially, then every 12 weeks

Follow-up visits every 12 weeks

Treatment Details

Interventions

• Nivolumab

Trial Overview The trial tests intrathecal (into the spinal canal) and intravenous Nivolumab to see how well it works against leptomeningeal disease. It aims to find the best dose and assess side effects when using this form of immunotherapy that helps the immune system fight cancer.

Participant Groups

Group I: Treatment (nivolumab) Experimental Treatment 6 Interventions

Patients receive nivolumab IT over 5 minutes on day 1 of every cycle. Beginning in cycle 2, patients also receive nivolumab IV over 30 minutes on day 1 (4 hours after the IT dose). Cycles repeat every 14 days for 18 cycles and then every 28 days (cycles 19 and beyond) in the absence of disease progression or unacceptable toxicity. Patients will have CSF and blood specimen collection on days 1, 2, 8 of each cycle and end of treatment. Patients undergo CT or PET at baseline, cycle 5 and then every 8 weeks. Patients undergo MRI at baseline, cycles 3, 5, and then every 8 weeks.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The ongoing phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in 25 patients with melanoma and leptomeningeal disease shows that the treatment is safe, with no dose-limiting toxicities observed at any tested dose levels.

The recommended IT dose of nivolumab is 50 mg, and the median overall survival for patients was 4.9 months, indicating potential efficacy, especially in patients who had previously undergone anti-PD1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results. Glitza Oliva, IC., Ferguson, SD., Bassett, R., et al.[2023]

In a phase I trial, patients with melanoma and leptomeningeal disease treated with intrathecal and intravenous nivolumab had a median overall survival of 4.9 months, significantly longer than the historical average of about 6 weeks with traditional treatments like radiation and chemotherapy.

The treatment was well-tolerated, with no dose-limiting toxicities reported, suggesting that nivolumab may be a safer alternative for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 Inhibitors Prolong Survival in Leptomeningeal Disease. [2023]

Intraventricular administration of (131)I-3F8, a targeted antibody therapy, successfully detected leptomeningeal (LM) tumors in four out of five patients, indicating its potential for diagnosing GD2-positive cancers.

The treatment resulted in a favorable cerebrospinal fluid (CSF) to blood radiation dose ratio, suggesting that (131)I-3F8 could be effective for both diagnosis and radioimmunotherapy of LM cancers with manageable side effects like fever and headache.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted radioimmunotherapy for leptomeningeal cancer using (131)I-3F8. Kramer, K., Cheung, NK., Humm, JL., et al.[2019]

In a Phase II study involving 18 patients with leptomeningeal disease, the combination of ipilimumab and nivolumab showed promising efficacy, with 44% of patients alive at three months, surpassing the expected 18%.

The treatment had an acceptable safety profile, although one-third of patients experienced significant adverse events, including two cases leading to treatment discontinuation due to hepatitis and colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. Brastianos, PK., Strickland, MR., Lee, EQ., et al.[2021]

A 60-year-old man with renal cell carcinoma and leptomeningeal metastasis achieved complete remission after being treated with nivolumab, marking the first report of its efficacy in this specific type of metastasis.

The patient experienced rapid improvement in symptoms and increased bone mineral density without any drug-related toxicity, suggesting that nivolumab is a safe and effective treatment option for this rare condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab efficacy in leptomeningeal metastasis of renal cell carcinoma: a case report. Bonomi, L., Bettini, AC., Arnoldi, E., et al.[2022]

A case study of a 59-year-old woman with treatment-resistant laryngeal cancer revealed that nivolumab, an immunotherapy drug, can cause severe central nervous system (CNS) toxicities, specifically acute demyelinating encephalitis, which is rarely reported in the literature.

The patient's symptoms improved significantly after discontinuing nivolumab and receiving high-dose steroids and immunoglobulin therapy, suggesting that CNS toxicity from immune checkpoint inhibitors may be reversible with prompt treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-Associated Acute Demyelinating Encephalitis: A Case Report and Literature Review. Zafar, Z., Vogler, C., Hudali, T., et al.[2020]

References

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

Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results. [2023]

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

PD-1 Inhibitors Prolong Survival in Leptomeningeal Disease. [2023]

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

Targeted radioimmunotherapy for leptomeningeal cancer using (131)I-3F8. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. [2021]

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

Nivolumab efficacy in leptomeningeal metastasis of renal cell carcinoma: a case report. [2022]

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

Nivolumab-Associated Acute Demyelinating Encephalitis: A Case Report and Literature Review. [2020]