Brain Interstitium Temozolomide Concentration Pre and Post Regadenoson Administration

NCT02389738 | Completed Early Phase 1 Results DMC

• 2 other identifiers: J14155IRB00045837
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

The blood-brain barrier (BBB) is an intricate barrier composed of a variety of efflux pumps, a luminal negative charge, a basal lamina and three distinct cell types: brain endothelial cells, pericytes, and astrocyte foot processes. Specifically, the BBB integrity and degree of permeability is regulated by the capillary endothelial cells in response to astrocytic signals. The strength of intercellular junctions (ex. tight junctions, adherins) amongst endothelial cells also plays a major role in permeability. Therefore, modulation of all these paracellular properties may decrease BBB integrity and thus improve drug penetration to the tumor bed. Previous studies utilizing the vasoactive peptide, Regadenoson, demonstrated transient increase in BBB permeability, allowing a 70kD dextran molecule to enter the brain of rodents. Thus, the investigators propose to evaluate brain interstitium concentrations of temozolomide pre and post Regadenoson using brain microdialysis. If Regadenoson successfully demonstrates effectiveness in disrupting the BBB, it could be of major importance in improving the outcome of patients with a variety of brain tumors and other neurologic illnesses.

Conditions

Blood Brain Barrier Defect

Outcome Measures

Primary Outcomes (1)

• Change in AUC0-18 of the Temozolomide Concentration (AUC-T) in Brain Interstitium Before and After Regadenoson Infusion

  The AUC-T for each day will be estimated by the trapezoid rule, based on the number of time points available for the particular evaluable patient. The PK variables will be tabulated and descriptive statistics calculated pre and post Regadenoson. The difference of AUCs will be summarized by mean and standard deviation or median and range if there is large variation from patient to patient. Means and standard deviation or mean and range will be presented for Cmax and AUC(inf) for each group. Graphic method will be used to display the difference for individual patient and all five patients.

  18 hours post temozolomide administration

Secondary Outcomes (1)

• Evaluation of Relationaship Between Cognitive/Mood Disorders and Expression of Biochemical Markers Post-op Day 1

  24 hours post-op

Study Arms (1)

BBB disruption with regadenoson

EXPERIMENTAL

This is an exploratory (pilot) study to assess whether Regadenoson can disrupt the BBB, change the barrier permeability, to enhance the temozolomide delivery to brain. Five evaluable patients will be studied in this trial. The sample size justification is not based on statistical rationale but clinical affordability. If the investigators detect ≥ 50% increase in temozolomide brain interstitium concentrations after Regadenoson, then the investigators will consider future studies evaluating additional patients.

Drug: Regadenoson; Drug: Temozolomide; Device: Microdialysis catheter

Interventions

Regadenoson DRUG

Regadenoson administration on post-op day 2 after temozolomide administration. Temozolomide plasma and dialysate concentrations will be obtained over 18 hours post temozolomde administration.

Also known as: Lexiscan

BBB disruption with regadenoson

Temozolomide DRUG

Temozolomide administration on post-op day 1 and 2. Temozolomide plasma and dialysate concentrations will be obtained over 18 hours post temozolomde administration.

Also known as: Temodar

BBB disruption with regadenoson

Microdialysis catheter DEVICE

Microdialysis catheter placement post surgical resection and removed at the bedside after completion of obtaining all dialysate collections.

BBB disruption with regadenoson

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18
• Diagnosis of recurrent high grade glioma confirmed by frozen pathology intra-operatively
• Patients with planned surgical debulking or biopsy
• Karnofsky performance status (KPS) ≥ 60%
• Mini Mental Status Exam ≥ 15
• Adequate hepatic function
• Total bilirubin ≤ 1.8 mg/dL
• Serum levels of aspartate aminotransferase ≤ 3x the institutional upper limit of normal
• Adequate renal function
• Serum creatinine ≤ 1.5mg/dL
• Adequate bone marrow function
• ANC ≥ 1500 cells/mm3
• Platelet count ≥ 100,000 cells/mm3

You may not qualify if:

• Currently receiving chemotherapy, or radiation therapy
• Allergic to temozolomide
• Pregnant or breast-feeding
• Have a serious medical or psychiatric illness or social situation that could interfere with catheter placement or monitoring
• Prior use of VEGF or VEGFR-targeted therapy
• Use of medications: Vincristine, Vinblastine, Rifampin, Opioid's, Antidepressants within the past 24 hours
• Use of investigational agents within the past 4 weeks
• NCI CTC Grade 3 or greater baseline neurologic symptoms
• History of cardiac disease:
• Atrial fibrillation or uncontrolled tachyarrhythmia, or advanced atrioventricular block (second or third degree heart block)
• History of sinus node dysfunction
• History of symptomatic sinus bradycardia or recorded (heart rate \<40/minute)
• Use of dipyridamole, dipyridamole-containing medications
• Any history of coronary heart disease defined by prior myocardial infarction or ischemia on cardiac stress testing or coronary stenosis ≥50% severity
• Moderate or severe aortic stenosis

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead

Study Sites (1)

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

MeSH Terms

Interventions

regadenoson; Temozolomide

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Principal Investigator
• Organization: Johns Hopkins/NIH

sjacks78@jhmi.edu

4109558837

Study Officials

• Stuart Grossman, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 4, 2015
• First Posted: March 17, 2015
• Study Start: February 1, 2015
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2018
• Last Updated: November 20, 2018
• Results First Posted: November 20, 2018

Record last verified: 2018-11

Locations

US (1)