Determining Dose of Regadenoson Most Likely to Transiently Alter the Integrity of the Blood-Brain Barrier in Patients With High Grade Gliomas

NCT ID: NCT03971734

Last Updated: 2023-10-06

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-12-06
• Study Completion Date: 2023-10-02

Brief Summary

enroll patients with histologically confirmed high-grade gliomas to evaluate the ability of regadenoson to transiently disrupt a relatively intact blood-brain barrier (BBB). determine the best dose of regadenoson to disrupt the BBB and allow for enhanced penetration of gadolinium during MRI.

Detailed Description

PRIMARY OBJECTIVE:

To determine if there is a dose of regadenoson, in the range shown to be safe for clinical administration, that can increase gadolinium Ktrans by more than 10 times the values reported in the literature within normal-appearing brain parenchyma with a previously documented intact blood-brain barrier in patients with high grade gliomas.

SECONDARY OBJECTIVE To determine if there is a dose of regadenoson, in the range shown to be safe for clinical administration, that can substantially alter the normalized, contrast enhanced MRI signal intensity in normal-appearing tissues and in: A) Brain adjacent to tumor (i.e. T2 hyperintense, but without contrast enhancement before regadenoson) and B) Contrast enhancing tumor (with contrast enhancement before regadenoson).

Part I Treatment Plan

Part I of the protocol is designed to identify the best regadenoson dose(s) to transiently disrupt the blood-brain barrier as measured by DCE-MRI and contrast enhancement on T1-weighted images corresponding to an increase in the accumulation of MRI contrast (gadolinium) into normal appearing brain contralateral to the brain tumor.

Patients who are at low risk of having complications with a standard regadenoson cardiac stress test (young with no known cardiac disease) and who have had stable MRI scans for at least 2 months prior to enrollment will be asked to undergo a research MRI within two weeks after their most recent previous MRI.

Part II Treatment Plan

Part II will be initiated if the first portion of the study identifies one or more doses of regadenoson that meets the desired endpoint of a Ktrans value >0.04 min-1 within contralateral normal-appearing brain following regadenoson administration. Part II patients will undergo more extensive imaging prior to regadenoson administration to confirm that regadenoson has a significant effect on the BBB using a more comprehensive imaging approach.

Five additional patients who are at low risk to have complications of a standard chemical cardiac stress test (young with no known significant cardiac disease) will be sequentially enrolled at each regadenoson dose meeting the desired endpoint in Part I. In these cohorts, the full research imaging protocol will be utilized in both the pre- and post-regadenoson MRI scans which will allow a direct comparison of all imaging parameters in both the pre-regadenoson and post-regadenoson settings to be directly compared.

Conditions

High Grade Glioma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Glioblastoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1 regadenoson 0.05mg

Approximately 10 minutes prior to undergoing the research MRI, patients will be administered a single dose of regadenoson at their assigned dose level, under the supervision of a cardiologist.

The research MRI scan will be performed immediately following administration of regadenoson and appropriate monitoring of vital signs and 12-lead electrocardiography on a similar machine as the pre-enrollment eligibility MRI scan, using the same administered dose of gadolinium and acquisition parameters.

The research MRI will consist of DCE perfusion MRI for estimation of Ktrans and will be performed with co-administration of standard doses of gadolinium following regadenoson dose.

Regadenoson 0.05mg

Group Type: EXPERIMENTAL

Regadenoson 0.05mg

Intervention Type: DRUG

Regadensoson 0.05mg administered prior to MRI

Arm 2 regadenoson 0.1mg

Approximately 10 minutes prior to undergoing the research MRI, patients will be administered a single dose of regadenoson at their assigned dose level, under the supervision of a cardiologist.

The research MRI scan will be performed immediately following administration of regadenoson and appropriate monitoring of vital signs and 12-lead electrocardiography on a similar machine as the pre-enrollment eligibility MRI scan, using the same administered dose of gadolinium and acquisition parameters.

The research MRI will consist of DCE perfusion MRI for estimation of Ktrans and will be performed with co-administration of standard doses of gadolinium following regadenoson dose.

Group Type: EXPERIMENTAL

Regadensoson 0.1mg

Intervention Type: DRUG

Regadensoson 0.1mg administered prior to MRI

Arm 3 regadenoson 0.2mg

Approximately 10 minutes prior to undergoing the research MRI, patients will be administered a single dose of regadenoson at their assigned dose level, under the supervision of a cardiologist.

The research MRI scan will be performed immediately following administration of regadenoson and appropriate monitoring of vital signs and 12-lead electrocardiography on a similar machine as the pre-enrollment eligibility MRI scan, using the same administered dose of gadolinium and acquisition parameters.

The research MRI will consist of DCE perfusion MRI for estimation of Ktrans and will be performed with co-administration of standard doses of gadolinium following regadenoson dose.

Group Type: EXPERIMENTAL

Regadensoson 0.2mg

Intervention Type: DRUG

Regadensoson 0.2mg administered prior to MRI

Arm 4 regadenoson 0.4mg

Approximately 10 minutes prior to undergoing the research MRI, patients will be administered a single dose of regadenoson at their assigned dose level, under the supervision of a cardiologist.

The research MRI scan will be performed immediately following administration of regadenoson and appropriate monitoring of vital signs and 12-lead electrocardiography on a similar machine as the pre-enrollment eligibility MRI scan, using the same administered dose of gadolinium and acquisition parameters.

The research MRI will consist of DCE perfusion MRI for estimation of Ktrans and will be performed with co-administration of standard doses of gadolinium following regadenoson dose.

Group Type: EXPERIMENTAL

Regadensoson 0.4mg

Intervention Type: DRUG

Regadensoson 0.4mg administered prior to MRI

Arm 5 regadenoson 0.7mg

Approximately 10 minutes prior to undergoing the research MRI, patients will be administered a single dose of regadenoson at their assigned dose level, under the supervision of a cardiologist.

The research MRI scan will be performed immediately following administration of regadenoson and appropriate monitoring of vital signs and 12-lead electrocardiography on a similar machine as the pre-enrollment eligibility MRI scan, using the same administered dose of gadolinium and acquisition parameters.

The research MRI will consist of DCE perfusion MRI for estimation of Ktrans and will be performed with co-administration of standard doses of gadolinium following regadenoson dose.

Group Type: EXPERIMENTAL

Regadensoson 0.7mg

Intervention Type: DRUG

Regadensoson 0.7mg administered prior to MRI

Arm 6 regadenoson 1.0mg

Approximately 10 minutes prior to undergoing the research MRI, patients will be administered a single dose of regadenoson at their assigned dose level, under the supervision of a cardiologist.

The research MRI scan will be performed immediately following administration of regadenoson and appropriate monitoring of vital signs and 12-lead electrocardiography on a similar machine as the pre-enrollment eligibility MRI scan, using the same administered dose of gadolinium and acquisition parameters.

The research MRI will consist of DCE perfusion MRI for estimation of Ktrans and will be performed with co-administration of standard doses of gadolinium following regadenoson dose.

Group Type: EXPERIMENTAL

Regadensoson 1.0mg

Intervention Type: DRUG

Regadensoson 1.0mg administered prior to MRI

Arm 7 regadenoson 1.4mg

Approximately 10 minutes prior to undergoing the research MRI, patients will be administered a single dose of regadenoson at their assigned dose level, under the supervision of a cardiologist.

The research MRI scan will be performed immediately following administration of regadenoson and appropriate monitoring of vital signs and 12-lead electrocardiography on a similar machine as the pre-enrollment eligibility MRI scan, using the same administered dose of gadolinium and acquisition parameters.

The research MRI will consist of DCE perfusion MRI for estimation of Ktrans and will be performed with co-administration of standard doses of gadolinium following regadenoson dose.

Group Type: EXPERIMENTAL

Regadensoson 1.4mg

Intervention Type: DRUG

Regadensoson 1.4mg administered prior to MRI

Interventions

Regadenoson 0.05mg

Regadensoson 0.05mg administered prior to MRI

Intervention Type: DRUG

Regadensoson 0.1mg

Regadensoson 0.1mg administered prior to MRI

Intervention Type: DRUG

Regadensoson 0.2mg

Regadensoson 0.2mg administered prior to MRI

Intervention Type: DRUG

Regadensoson 0.4mg

Regadensoson 0.4mg administered prior to MRI

Intervention Type: DRUG

Regadensoson 0.7mg

Regadensoson 0.7mg administered prior to MRI

Intervention Type: DRUG

Regadensoson 1.0mg

Regadensoson 1.0mg administered prior to MRI

Intervention Type: DRUG

Regadensoson 1.4mg

Regadensoson 1.4mg administered prior to MRI

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Patients must have histologically confirmed high grade glioma (including but not limited to glioblastoma (GBM), anaplastic astrocytoma (AA), gliosarcoma, and anaplastic oligodendroglioma). Patients with previous low-grade glioma who progressed after RT/chemotherapy and are biopsied and found to have GBM/GS are eligible.

2. Patients must have measurable contrast-enhancing disease by MRI imaging within 7-14 days of starting treatment (defined by at least 1 cm x 1 cm). Patient must be able to tolerate MRIs with contrast.

3. Patients must have stable MRI (no progression of disease) for the past 2 months or more.

4. Patients may have an unlimited number of prior relapses.

5. The following intervals from previous treatments are required to be eligible:

• 12 weeks from the completion of radiation.
• 16 weeks from an anti-VEGF therapy
• 6 weeks from a nitrosourea chemotherapy
• 3 weeks from a non-nitrosourea chemotherapy
• 2 weeks or 5 half-lives from any investigational (not FDA-approved) agents
• 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.)

6. Age ≥18 years and ≤ 45 years.

7. Karnofsky Performance (KPS) Status 80% (see Appendix A).

8. Patients must have adequate organ and marrow function as defined below:

• Creatinine ≤ 1.5 mg/Dl or eGFR ≥30 mL/min/1.73 m2

9. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

10. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of regadenoson are eligible for this trial.

11. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

1. Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.

2. Patients who are receiving any other investigational agents.

3. History of hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to regadenoson.

4. Patients with any history, current symptoms, or signs of cardiovascular disease including:

• any ischemic cardiac event (myocardial infarction, coronary revascularization, stable or unstable angina)
• Ischemic or nonischemic cardiomyopathy and/or congestive heart failure
• Supraventricular tachycardia, atrial fibrillation, and/or atrial flutter
• Ventricular tachyarrhythmias
• Severe sinus bradycardia defined as a resting heart rate <40 bpm
• Symptomatic bradycardia, sick sinus syndrome, greater than first-degree AV block, left bundle branch block, and/or presence of a cardiac pacemaker
• Stenotic valvular heart disease

5. Patients who have uncontrolled hypo- or hypertension defined as a systolic blood pressure <90 mmHg or >180 mmHg, respectively.

6. Patients who have uncontrolled asthma or seizures.

7. Patients taking potential neurotoxic medications - see eligibility criteria of protocol for specific list of medications

8. Patients with uncontrolled concurrent illness.

9. Patients with psychiatric illness/social situations that would limit compliance with study requirements.

10. Pregnant women will be excluded from this study.

11. Because of the potential risk of serious cardiac reactions in the breastfed infant, advise the nursing mother to pump and discard breast milk for 10 hours after administration of regadenoson

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stuart A Grossman, MD

Role: STUDY_CHAIR

ABTC

Locations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Wake Forest University Comprehensive Cancer Center

Winston-Salem, North Carolina, United States

Countries

United States

References

Grossman SA, Romo CG, Ye X, Kral B, Strowd RE, Lesser G, Raymond C, Iacoboni M, Desideri S, Fisher J, Danda N, Ellingson BM. Assessing the dose of regadenoson required to transiently alter blood-brain barrier integrity in patients with infiltrating gliomas. Neurooncol Adv. 2025 Feb 15;7(1):vdaf041. doi: 10.1093/noajnl/vdaf041. eCollection 2025 Jan-Dec.

Reference Type: DERIVED

PMID: 40225909 (View on PubMed)

Other Identifiers

UM1CA137443

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ABTC 1804

Identifier Type: -

Identifier Source: org_study_id