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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of combining two drugs, azacitidine and nivolumab, to treat high-grade glioma, a type of brain cancer. The study aims to determine the optimal dose of these drugs when administered directly into the fluid around the brain and spine. It seeks participants whose brain cancer has returned after initial treatments like radiation or chemotherapy. Those diagnosed with specific high-grade gliomas and who have experienced a recurrence are suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this potentially groundbreaking therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that injecting azacitidine directly into the spinal fluid is being tested for treating brain cancer. However, limited information exists about its safety in humans. This trial is in phase 1, focusing primarily on assessing the treatment's safety. This phase typically involves small groups of patients to evaluate their tolerance and identify any side effects.

For intrathecal nivolumab, some studies have shown it is generally safe for patients with conditions like melanoma and cancer in the brain and spinal cord linings. In these studies, most serious side effects were not linked to the spinal fluid treatment, suggesting it might be well-tolerated.

In summary, while evidence suggests nivolumab is safe in similar conditions, this trial will help determine the safety of both azacitidine and nivolumab for brain cancer. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for brain cancer?

Unlike the standard treatments for brain cancer, which typically involve surgery, radiation, and chemotherapy, the combination of azacitidine and nivolumab stands out for its novel approach. Researchers are excited about these treatments because they are administered intrathecally, directly into the cerebrospinal fluid, allowing for more targeted action against cancer cells in the brain. Additionally, azacitidine is being dose-escalated, meaning its dosage is adjusted to find the optimal level for maximum effectiveness. Nivolumab, an immunotherapy drug, helps the immune system recognize and attack cancer cells, offering a promising new mechanism of action compared to traditional therapies.

What evidence suggests that azacitidine and nivolumab might be an effective treatment for brain cancer?

Research has shown that Nivolumab is somewhat effective in treating cancer that has spread to the brain. This suggests it might also help with recurring aggressive brain tumors, though more evidence is needed. In this trial, participants will receive a combination of intrathecal azacitidine and intrathecal nivolumab to determine their combined effectiveness. The goal is to find out if this combination can help control the tumor by boosting the body's immune response. Although the data remains early, these drugs are being tested for their potential to improve outcomes in brain cancer. ^{1 4 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

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]

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]

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]

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]

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 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]

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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06896110

Intrathecal Azacitidine and Nivolumab in Patients With ... This is a single-arm open-label phase 1 dose escalation/expansion trial assessing the safety and efficacy of concurrent intrathecal azacitidine and intrathecal ...

2. clinicaltrials.uihealthcare.org clinicaltrials.uihealthcare.org/studies/phase-1-trial-intrathecal-azacitidine-and-nivolumab-patients-recurrent-high-grade-glioma

Phase 1 trial of intrathecal azacitidine and nivolumab in ... PRIMARY OUTCOME Phase I To determine the safety and maximum tolerated dose (MTD) of intrathecal (IT) azacitidine in combination with IT nivolumab in ...

3. withpower.com withpower.com/trial/phase-1-glioblastoma-4-2025-94423

Azacitidine + 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 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11674442/

Immune Checkpoint Inhibitors in Glioblastoma IDHwt Treatment Conclusions: ICI for the treatment of GBM has not demonstrated clear evidence of efficacy thus far. This review serves as a quick reference of ...

5. braintumor.org braintumor.org/news/new-brain-tumor-clinical-trials-april-october-2024/

New Brain Tumor Clinical Trials: April – October 2024 This phase II trial tests how well the combination of WP1066 and radiation therapy works in treating newly diagnosed glioblastoma. Anti ...

6. trials.braintumor.org trials.braintumor.org/trials/NCT06896110

Intrathecal Azacitidine and Nivolumab in Patients With ... This is a single-arm open-label phase 1 dose escalation/expansion trial assessing the safety and efficacy of concurrent intrathecal azacitidine and intrathecal ...

7. trial.medpath.com trial.medpath.com/clinical-trial/9c480c9e31b22c21/nct06896110-intrathecal-azacitidine-nivolumab-glioma

Intrathecal Azacitidine and Nivolumab in Patients ... - MedPath This is a single-arm open-label phase 1 dose escalation/expansion trial assessing the safety and efficacy of concurrent intrathecal azacitidine and intrathecal ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7594550/

5-Azacitidine in patients with IDH1/2-mutant recurrent glioma In addition, data from AML patients showed that 5-azacitidine is less efficient in rapidly proliferative diseases and that a subset of ...