Azacitidine + Nivolumab for Brain Cancer

Overseen By Andrew Groves, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Andrew P. Groves

Must not be taking: Azacitidine, Corticosteroids, Immunosuppressives, others

Disqualifiers: Metastatic disease, Autoimmune disease, HIV, others

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

Compensation: Varies

Number of Visits: 1

Duration: 24 months

34 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be on a stable or decreasing dose of corticosteroids for at least 7 days before enrollment.

What data supports the effectiveness of the drug combination Azacitidine and Nivolumab for brain cancer?

Research shows that Nivolumab, part of the drug combination, has shown some effectiveness in treating brain metastases (cancer spread to the brain) in patients with non-small cell lung cancer, with some patients experiencing a reduction in brain tumors. This suggests potential for Nivolumab's effectiveness in brain cancer treatment. ^{1 2 3 4 5}

Is the combination of Azacitidine and Nivolumab safe for humans?

Nivolumab, used in combination with other drugs, has shown some safety concerns, including immune-related side effects like fatigue, nausea, and more serious neurological effects such as encephalitis (brain inflammation). However, these effects are often reversible with appropriate treatment, and the drug has been used safely in various cancer treatments. ^{1 3 6 7 8}

How is the drug combination of Azacitidine and Nivolumab unique for brain cancer treatment?

The combination of Azacitidine and Nivolumab for brain cancer is unique because Nivolumab is an immune checkpoint inhibitor that helps the immune system attack cancer cells, and it has shown potential intracranial activity in other cancers like melanoma and lung cancer. This approach is novel as it leverages the immune system to target brain cancer, which is challenging due to the blood-brain barrier that typically limits drug delivery. ^{1 5 9 10 11}

What is the purpose of this trial?

This is a single-arm open-label phase 1 dose escalation/expansion trial assessing the safety and efficacy of concurrent intrathecal azacitidine and intrathecal nivolumab in recurrent high-grade glioma.

Eligibility Criteria

This trial is for patients with recurrent high-grade glioma, a type of brain cancer. Participants must have specific forms of this condition, such as Glioblastoma or Diffuse Midline Glioma. Detailed inclusion and exclusion criteria are not provided but would typically involve health status and prior treatments.

Inclusion Criteria

At least one measurable lesion per RANO 2.0 meeting specific criteria

Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours of starting therapy

WOCBP must agree to follow instructions for methods of contraception

Exclusion Criteria

Subjects with major medical, neurologic, or psychiatric condition who are judged to be unable to fully comply with trial therapy or assessments

Patients with a history of pneumonitis

History of allergy to trial drug components

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intrathecal azacitidine and nivolumab with dose escalation and monitoring for safety and efficacy

24 months

Visits on days 1, 8, and 22 of cycle 1; days 1 and 15 of subsequent cycles; MRI every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Azacitidine
• Intrathecal Administration
• Nivolumab

Trial Overview The study tests the safety and effectiveness of azacitidine (AZA) and nivolumab delivered directly into the spinal fluid via lumbar puncture in treating recurrent high-grade gliomas. It's an early-phase trial where everyone gets both drugs to see how well they work together.

Participant Groups

Group I: Treatment (IT nivolumab + IT azacitidine) Experimental Treatment 4 Interventions

Patients will receive intrathecal azacitidine on day 1, 8, and 22 of cycle 1 (34 day cycle). Intrathecal nivolumab will be given at a flat dose of 40 mg on day 8 and 22. Each subsequent cycle will be 28 days with intrathecal azacitidine and intrathecal nivolumab given on days 1 and 15. Intrathecal azacitidine will be dose-escalated with 4 dose levels (5, 10, 20, 40 mg) using a 3+3 design. Patients may continue on study in the absence of disease progression or unacceptable toxicity. Patients will have CSF and blood specimen collection on days 1 and 8 of cycle 1, and then day 1 of every-other cycle starting with cycle 2. Patients will undergo MRI at baseline, then every 8 weeks (e.g. after cycle 3, cycle 5, etc...).

Who Is Running the Clinical Trial?

Andrew P. Groves

Lead Sponsor

Trials

1

Recruited

30+

Findings from Research

In a retrospective study of five patients with advanced non-small cell lung cancer (NSCLC) and new or progressing brain metastases, nivolumab showed promising intracranial activity, with one complete and one partial response observed, and stabilization of leptomeningeal carcinomatosis in another patient.

Nivolumab was well-tolerated, with no severe treatment-related adverse events reported, suggesting a favorable safety profile for patients with CNS metastases from NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. Dudnik, E., Yust-Katz, S., Nechushtan, H., et al.[2022]

In a study of 66 patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab, those with a poor performance status (PS ≥2) had a significantly shorter median overall survival of 3.04 months compared to 10.23 months for those with better performance status (PS ≤1).

Despite similar rates of treatment-related adverse events between the two groups, the findings suggest that performance status is a crucial factor in predicting survival outcomes and should be considered when selecting immunotherapy treatments for lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience of nivolumab in the treatment of poor performance status patients with advanced non-small cell lung cancer. Abbas, MN., Klevansky, M., Koczwara, B., et al.[2022]

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 study of 119 patients with melanoma brain metastases, those who were asymptomatic showed a significant clinical benefit from the combination of nivolumab and ipilimumab, with a 36-month overall survival rate of 71.9%.

Symptomatic patients had much lower efficacy, with only 36.6% overall survival at 36 months, highlighting the challenges in treating symptomatic melanoma brain metastases with this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Tawbi, HA., Forsyth, PA., Hodi, FS., et al.[2022]

In a study of 380 patients with melanoma brain metastasis (MBM), treatment with nivolumab plus ipilimumab, especially when combined with local therapies like stereotactic radiosurgery or surgery, significantly improved overall survival (OS) rates, with 2-year and 3-year OS rates at 41% and 30%, respectively.

The study found that the timing of immunotherapy (first-line or later) did not affect OS, and factors such as elevated serum lactate dehydrogenase levels and the number of brain metastases were significant prognostic indicators for survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients. Amaral, T., Kiecker, F., Schaefer, S., et al.[2021]

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]

Recent phase 2 clinical trials have shown that immune checkpoint inhibitors can lead to durable responses in patients with brain metastases, particularly in melanoma, improving median survival beyond the historical average of months.

However, these therapies can also increase the risk of neurologic toxicities, such as symptomatic edema and radiation necrosis, highlighting the need for careful management and a multidisciplinary approach in treating these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications associated with immunotherapy for brain metastases. Tran, TT., Jilaveanu, LB., Omuro, A., et al.[2023]

In a review of 3,763 patients with advanced melanoma treated with nivolumab and ipilimumab, 0.93% experienced serious neurologic immune-related adverse events (irAEs), including encephalitis, with a median onset time of 45 days.

Most neurologic irAEs resolved (75% of cases), but awareness and prompt management of these rare but serious events are crucial for oncologists and neurologists to prevent complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. Larkin, J., Chmielowski, B., Lao, CD., et al.[2018]

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]

Nivolumab and ipilimumab show significant intracranial activity in patients with melanoma brain metastases, with response rates of 46% and 57% in two phase II studies, respectively.

Nivolumab can penetrate the cerebrospinal fluid (CSF), achieving concentrations that are effective for therapeutic action, challenging the belief that large molecules like monoclonal antibodies cannot affect the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review. van Bussel, MTJ., Beijnen, JH., Brandsma, D.[2020]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases. [2022]

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

Real-world experience of nivolumab in the treatment of poor performance status patients with advanced non-small cell lung cancer. [2022]

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

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

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

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. [2022]

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

Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients. [2021]

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

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

7. England pubmed.ncbi.nlm.nih.gov

Complications associated with immunotherapy for brain metastases. [2023]

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

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. [2018]

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

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

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

Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review. [2020]