Intrathecal Azacitidine and Nivolumab in Patients With Recurrent High-grade Glioma

NCT06896110 | Enrolling By Invitation Phase 1 DMC FDA Drug

• 1 other identifier: 202406429
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Glioblastoma (GBM); Diffuse Midline Glioma (DMG); Astrocytoma, IDH-Mutant, Grade 4; Diffuse Hemispheric Glioma, H3 G34-Mutant; Gliosarcoma of Brain

Outcome Measures

Primary Outcomes (3)

• Incidence of adverse events

  Adverse events will be graded by the Common Terminology Criteria for Adverse Events version 5.0.

  24 months

• Maximum tolerated dose (MTD) of intrathecal azacitidine in combination with intrathecal nivolumab

  The MTD will be established using a 3+3 design.

  24 months

• Overall Response Rate (Expansion Cohort)

  The primary objective of the expansion cohort is to obtain a preliminary estimate of the overall response rate (ORR). ORR will be defined as the proportion of patients with a complete response (CR) or partial response (PR) according to Response Assessment in Neuro-Oncology (RANO) 2.0 criteria

  24 months

Secondary Outcomes (4)

• To estiamte the duration of response (DOR)

  24 months

• To estimate progression-free survival

  24 months

• To estimate overall survival

  24 months

• To assess biomarkers for immunologic and epigenetic effects of therapy

  24 months

Study Arms (1)

Treatment (IT nivolumab + IT azacitidine)

EXPERIMENTAL

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…).

Drug: Nivolumab; Drug: Azacitidine (AZA); Procedure: lumbar puncture; Diagnostic Test: MRI Contrast

Interventions

Nivolumab DRUG

Intrathecal nivolumab will be given at a flat dose of 40 mg

Treatment (IT nivolumab + IT azacitidine)

Azacitidine (AZA) DRUG

Intrathecal azacitidine will be dose-escalated with 4 dose levels (5, 10, 20, 40 mg) using a 3+3 design.

Treatment (IT nivolumab + IT azacitidine)

lumbar puncture PROCEDURE

Lumbar puncture for intrathecal delivery and collection of CSF

Treatment (IT nivolumab + IT azacitidine)

MRI Contrast DIAGNOSTIC_TEST

MRI Brain and full Spine (with and without contrast) will be performed prior to enrollment. During trial therapy, MRI Brain (with and without contrast) will be performed after cycle 1 and after that every 8 weeks (e.g. after cycle 3, cycle 5, etc…)

Treatment (IT nivolumab + IT azacitidine)

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• For patients age ≥ 18: Able and willing to provide written informed consent
• For patients aged 13-17: Parent/guardian of adolescent patient must have the ability to provide written informed consent. Adolescent patients must have the ability to provide written informed assent.
• Stated willingness to comply with all trial procedures and availability for the duration of the trial
• Histologically confirmed diagnosis of World Health Organization Grade IV high-grade glioma. Eligible diagnoses include: Glioblastoma (IDH-wildtype), Gliosarcoma, Diffuse Midline Glioma (H3 K27-altered), diffuse hemispheric glioma (H3 G34-mutant), diffuse pediatric-type high-grade glioma (H3 and IDH-wildtype), Astrocytoma IDH-mutant (Grade 4)
• Previous first-line treatment with at least radiotherapy (and temozolomide in the case of glioblastoma or astrocytoma IDH-mutant (grade 4))
• Documented recurrence by diagnostic biopsy or contrast-enhanced magnetic resonance imaging (MRI) per RANO 2.0 criteria
• At least one measurable lesion per RANO 2.0 meeting the following criteria: Contrast-enhancing or non-enhancing lesions with clearly defined margins by MRI Scan, with both perpendicular diameters on a single slice of at least 10 mm, visible on two or more slices that are preferably, at most, 3 mm apart with 0-mm interslice gap.
• Age ≥ 13
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (age ≥ 16) or Lansky of ≥ 60 (age \<16)
• Disease status confirmed with baseline imaging performed within 28 days of Day 1 of trial treatment. Patients with extracranial metastatic or leptomeningeal disease will be excluded (see Section 5.2)
• Subjects must be on a stable or decreasing dose of corticosteroids for at least 7 days before enrollment
• Patients must have organ and marrow function as defined below:
• Eligibility Guidelines of Organ and Marrow Function Hematologic Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Hemoglobin ≥ 9.0 g/dL Platelets ≥ 75 x 109/L PT/INR and PTT ≤ 1.5 X ULN Hepatic Total bilirubin ≤ 1.5 X ULN (except subjects with known Gilbert syndrome, who can have total bilirubin \< 3.0 mg/dL AST and ALT ≤ 3.0 X ULN Renal Creatinine OR Calculated creatinine clearance OR 24-hour urine creatinine clearance ≤ 2 X ULN
• mL/min
• ml/min

You may not qualify if:

• Presence of extracranial metastatic or leptomeningeal disease
• Patients with diffuse intrinsic pontine glioma, defined as tumors with a pontine epicenter and diffuse involvement of the pons
• Patients must not have active autoimmune disease that has required systemic treatment in the past 2 years (e.g. use of disease modifying agents, corticosteroids, or immunosuppressive drugs)
• Prior azacitidine for the treatment of cancer (prior administration of nivolumab or other immune checkpoint inhibitor is allowed)
• Subjects with major medical, neurologic, or psychiatric condition who are judged to be unable to fully comply with trial therapy or assessments
• Positive test for hepatitis B or C virus indicating acute or chronic infection, given the risk of reactivation with checkpoint inhibition
• Known history of testing positive for HIV or known acquired immunodeficiency syndrome (AIDS), due to the unknown effects of HIV on the immune response to intrathecal azacitidine and nivolumab
• Patients with a history of pneumonitis
• Evidence of active infection requiring treatment with IV antibiotics ≤ 7 days prior to initiation of trial therapy.
• History of allergy to trial drug components
• Prisoners or subjects involuntarily incarcerated
• Patients of all genders, races, and ethnicities are invited to participate.

Sponsors & Collaborators

• Andrew P. Groves: lead

Study Sites (1)

Holden Comprehensive Cancer Center

Iowa City, Iowa, 52242, United States

Location

MeSH Terms

Conditions

Glioblastoma; Astrocytoma

Interventions

Nivolumab; Azacitidine; Spinal Puncture

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Biopsy; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Neurological; Punctures; Therapeutics; Surgical Procedures, Operative; Investigative Techniques

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Assistant Professor

Study Record Dates

• First Submitted: March 19, 2025
• First Posted: March 26, 2025
• Study Start: June 5, 2025
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027
• Last Updated: June 26, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF

Locations

US (1)