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

Phase 1

Not yet recruiting

• Conditions: Glioblastoma (GBM); Diffuse Midline Glioma (DMG); Astrocytoma, IDH-Mutant, Grade 4; Diffuse Hemispheric Glioma, H3 G34-Mutant; Gliosarcoma of Brain
• Interventions: Drug: Nivolumab; Drug: Azacitidine (AZA); Procedure: lumbar puncture; Diagnostic Test: MRI Contrast

• Registration Number: NCT06896110
• Lead Sponsor: Andrew P. Groves

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.

Detailed Description

PRIMARY OUTCOME Phase I To determine the safety and maximum tolerated dose (MTD) of intrathecal (IT) azacitidine in combination with IT nivolumab in patients with recurrent high-grade glioma

Expansion Cohort To estimate the overall response rate (ORR)

SECONDARY OUTCOMES

To estimate:

1. Duration of response (DOR)

2. Progression-free survival (PFS)

3. Overall survival (OS)

EXPLORATORY OUTCOMES Changes in immune profiling (flow cytometry, cytokine/chemokine analysis) and circulating tumor DNA (ctDNA) biomarkers (quantification, DNA methylation)

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-19
• Study First Submitted QC: 2025-03-19
• Last Update Submitted: 2025-03-25
• Study First Posted: 2025-03-26
• Last Update Posted: 2025-03-30
• Study Start: 2025-05
• Primary Completion: 2027-03
• Study Completion: 2027-03

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 34

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (IT nivolumab + IT azacitidine)	Nivolumab	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...).
Treatment (IT nivolumab + IT azacitidine)	Azacitidine (AZA)	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...).
Treatment (IT nivolumab + IT azacitidine)	lumbar puncture	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...).
Treatment (IT nivolumab + IT azacitidine)	MRI Contrast	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...).

Primary Outcome Measures

Name	Time	Method
Incidence of adverse events	24 months	Adverse events will be graded by the Common Terminology Criteria for Adverse Events version 5.0.
Maximum tolerated dose (MTD) of intrathecal azacitidine in combination with intrathecal nivolumab	24 months	The MTD will be established using a 3+3 design.
Overall Response Rate (Expansion Cohort)	24 months	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

Secondary Outcome Measures

Name	Time	Method
To estiamte the duration of response (DOR)	24 months	DOR will be defined as the time from first documented complete response (CR) or partial response (PR) to progressive disease (PD) according to RANO 2.0 criteria
To estimate progression-free survival	24 months	PFS will be defined as the time from trial treatment initiation to first documented progression or death due to any cause.
To estimate overall survival	24 months	OS will be defined as the time from trial treatment initiation to death due to any cause.
To assess biomarkers for immunologic and epigenetic effects of therapy	24 months	Changes in CSF and blood immunological profiling by flow cytometry, cytokine/chemokine analysis. Changes in circulating tumor DNA (ctDNA) analysis in CSF

Trial Locations

Locations (1)

Holden Comprehensive Cancer Center; 🇺🇸 Iowa City, Iowa, United States