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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment using nivolumab, an immunotherapy drug, for individuals with leptomeningeal disease, a serious condition where cancer spreads to the membranes surrounding the brain and spinal cord. Researchers aim to determine the optimal dose and evaluate the effectiveness of combining two forms of nivolumab, one administered in the spine and the other intravenously, against the disease. This trial suits those with a confirmed diagnosis of leptomeningeal disease related to melanoma or non-small cell lung cancer, who have completed recent radiation treatments and can manage low-dose steroids for symptoms. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative therapy.

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.

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

Research has shown that administering nivolumab both intravenously (IV) and directly into the spinal fluid (IT) is generally safe and well-tolerated. Studies found that patients receiving this treatment did not experience unexpected side effects. The tested dose, including 50 mg of nivolumab into the spinal fluid, proved manageable.

In earlier studies with melanoma patients, using both IV and IT nivolumab showed promise without causing harmful reactions. Overall, these findings suggest that this treatment can be tolerated by patients and may offer a potential option for addressing leptomeningeal disease. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Nivolumab is unique because it leverages a dual administration route—both intravenous (IV) and intrathecal (IT)—to target leptomeningeal disease more effectively. Unlike traditional treatments that mainly focus on systemic chemotherapy, nivolumab is an immune checkpoint inhibitor that enhances the body's own immune response against cancer cells. Researchers are excited about this approach because the IT administration allows for direct delivery to the cerebrospinal fluid, potentially offering better penetration and effectiveness in the central nervous system, an area often difficult to treat with standard therapies. This method holds promise for improving outcomes in a condition with limited options.

What evidence suggests that nivolumab might be an effective treatment for leptomeningeal disease?

Research has shown that nivolumab, administered both intravenously and directly into the spinal fluid, may help treat leptomeningeal disease, where cancer spreads to the membranes around the brain and spinal cord. One study found that patients receiving this treatment lived for an average of 4.9 months, significantly longer than the usual 6 weeks for this condition. Another study reported an average survival of 7 months, with 66.6% of patients still alive after 3 months. These findings suggest that nivolumab could extend survival and offer benefits for those with this challenging condition. ^{3 5 6 7 8}

Who Is on the Research Team?

Isabella C. Glitza, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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.

History of allergy to study drug components

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

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Concurrent intrathecal and intravenous nivolumab in ... These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, ...

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Safety and preliminary efficacy of intrathecal (IT) and ... At a median follow-up of 4.6 months (mths) (0, 54.8 mths), median OS was 7.0 mths. OS was 66.6% at 3 mths, 53.1% at 6 mths and 34.8% at 12 mths.

3. aacrjournals.org aacrjournals.org/cancerdiscovery/article/13/6/OF9/727015/PD-1-Inhibitors-Prolong-Survival-in-Leptomeningeal

PD-1 Inhibitors Prolong Survival in Leptomeningeal Disease Patients enrolled in the study experienced a median overall survival (OS) of 4.9 months compared with a historical average of about 6 weeks. In ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0169500225004787

Intrathecal nivolumab and IL-2 for treatment of ... The patient experienced marked clinical improvement, including substantial remission of intracranial metastases, neurological symptom relief, ...

5. nature.com nature.com/articles/s41467-021-25859-y

Phase II study of ipilimumab and nivolumab in ... Median survival was 2.9 months (90% CI: 1.6–5.0 months) (Fig. 1). One patient withdrew consent and stopped participation in the study. For CNS ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11607011/

Immunotherapy for leptomeningeal disease from solid tumors Primary outcome is survival at 6 months, with secondary outcomes of safety, OS, and PFS. Estimated completion of this study occurred in 2022, ...

7. nature.com nature.com/articles/s41591-022-02170-x

Concurrent intrathecal and intravenous nivolumab in ... These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD.

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Concurrent intrathecal and intravenous nivolumab ... - PubMed Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe ...