Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis

Glioma Clinical Trial

Official title: Feasibility of Evaluating Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis

Status Recruiting

Clinical Trial Summary

Background:

Diffuse midline gliomas are the most aggressive brain tumors of childhood and young adults. Most people with these tumors survive less than 2 years. Researchers want to see if an anticancer drug (abemaciclib) can help.

Objective:

To see if researchers can measure how much abemaciclib is in a person's brain tumor and brain fluid after they take the drug for a few days.

Eligibility:

People aged 18 to 39 with recurrent high-grade glioma or diffuse midline glioma.

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Tests of heart function

Imaging scans of the brain, with a contrast agent

Screening tests will be repeated during the study. Participants will also have chest X-rays.

Participants will take abemaciclib by mouth twice a day for 4 and a half days.

Participants will undergo surgery. They will have either a tumor biopsy (a needle will be inserted to remove a small piece of tissue) or a surgical resection (part or all of the tumor will be removed). A small tube (catheter) will be placed in their brain for 48 hours to collect fluid samples. They will have a neurological exam every few hours while the tube is in place. Two days later, the tube will be removed without surgery. Participants will stay in the hospital for about 4 days for treatment.

Based on the results of abemaciclib levels in the brain, participants may keep taking abemaciclib and another drug (temozolomide) by mouth until their cancer gets worse or they have bad side effects. While taking these two drugs, participants will come back to the clinic for follow-up routinely. They will be followed by the study for life.

Clinical Trial Description

Background

Diffuse midline gliomas are the most aggressive brain tumors of childhood and young adults, with documented 2 year survival rates of <10%. These tumors are infiltrative midline high-grade gliomas. Treatment failure is due in part to the presence of the blood-brain barrier (BBB), which limits permeability of varied agents.

Efforts to evaluate drug delivery across the BBB in midline gliomas have been restricted to post biopsy specimens. In comparison, intracerebral microdialysis sampling of cortical tissue has been shown to be a highly effective tool in determining cortical neuropharmacokinetics (brain extracellular fluid penetration, accumulation and excretion) intratumorally and peritumorally in adult brain tumor participants. Microdialysis is underutilized in the adult brain tumor setting to evaluate chemotherapy or targeted therapy permeability.

Within the US, midline gliomas are not routinely biopsied. However, in the last several years, using modern surgical techniques, biopsy at the time of diagnosis has been performed with acceptable risks (4% mortality rate), with a feasible means to molecularly characterize the tumors; in order to identify potentially druggable targets.

One of the main attributes of disease progression/proliferation in midline gliomas is associated with dysregulation of the cell cycle. CDKN2A is the primary inhibitory brake on CDK4/6 driven signaling and is commonly deleted in glioblastoma, pancreas, bladder, breast and prostate cancer. The specific CDK4/6 inhibitor, abemaciclib, has FDA approval for the treatment of metastatic breast cancer.

This is a safety and feasibility study to evaluate pharmacokinetic and pharmacodynamic effects post abemaciclib administration in recurrent high grade glioma participants (cortical and midline tumors). We propose a trial using clinical microdialysis, placed in diffuse midline glioma tissue post biopsy, as an experimental research tool, to assess CNS drug entry and targeted inhibition with abemaciclib. These studies are focused with the overall intent to inform future clinical therapies and preclinical modeling.

Objectives:

To evaluate safety and feasibility of intratumoral microdialysis placement post high grade glioma resection or midline glioma biopsy

To evaluate safety and feasibility of brain interstitial dialysate sampling in glioma participants post abemaciclib administration

To measure intratumoral vs. systemic concentrations of abemaciclib in glioma participants post abemaciclib administration

Eligibility:

Participants must have recurrent high grade glioma or diffuse midline glioma based on clinical and/or radiologic findings

Participants with cortical high grade gliomas must have previous intra-operative pathology confirming disease

Participants must be >18 and <= 39 years of age, at time of enrollment

Ability to swallow tablets/pills

Must have adequate organ function as per laboratory testing parameters

Abemaciclib administration must be able to begin no later than 14 days after the date of radiographic diagnosis (by T2 or FLAIR imaging)

Design:

This is a safety and feasibility study to evaluate tumor pharmacokinetics (PK) and pharmacodynamics (PD) of abemaciclib in recurrent high grade glioma and midline glioma participants in need of surgical resection or biopsy respectively.

All participants will take abemaciclib pre-operatively for 4.5 days (9 total doses of abemaciclib) at twice daily dosing.

A maximally safe surgical resection for cortical high grade glioma or stereotactic needle biopsy for midline glioma will be performed in the OR. Microdialysis insertion (based on participant safety and surgical feasibility) will be performed post-biopsy in the OR and placement will be verified by brain CT.

Continuous microdialysis sampling will be obtained over the course of the next 48 hours, with subsequent removal of the catheter at the bedside.

After discharge from NIH inpatient, PK and PD findings will assist in determination of whether the participant will continue to receive abemaciclib therapy. If intratumoral or PK brain dialysate sampling concentrations are >10nmol/L, or PD findings suggest CDK inhibition (decreased expression of Rb and/or topoII ), then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy post resection or biopsy.

Maintenance therapy will be abemaciclib 150mg po BID together with temozolomide 200mg/m2 po daily x 5 days in 28 day cycles (temozolomide 150mg/m2 po daily x 5 days for cycle 1). After every 3 cycles, repeat brain MRI s will be obtained to evaluate treatment response and disease progression.

If a participant starts to exhibit signs of clinical deterioration or radiographic progression, the participant will discontinue maintenance therapy, with ongoing contact for survival approximately every 6 months (+/- 14 days) until death.

Results of the PK measurements and molecular testing will be provided to the participant s home oncologist to provide for assistance with directed therapy decisions (outside of this investigational trial).

We propose to evaluate 5 participants. The accrual ceiling will be set at 7 participants. ;

Related Conditions & MeSH terms

• Glioma

• NCT number: NCT05413304
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Sadhana Jackson, M.D.
• Phone: (240) 760-6018
• Email: sadhana.jackson@nih.gov
• Status: Recruiting
• Phase: Phase 1
• Start date: April 7, 2023
• Completion date: August 31, 2026