FUS Etoposide for DMG - A Feasibility Study
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|ClinicalTrials.gov Identifier: NCT05762419|
Recruitment Status : Recruiting
First Posted : March 9, 2023
Last Update Posted : March 9, 2023
The blood brain barrier (BBB) prevents some drugs from successfully reaching the target tumor. Focused Ultrasound (FUS) using microbubbles and neuro-navigator controlled sonication is a non-invasive method of temporarily opening up the blood brain barrier to allow a greater concentration of the drug to reach into the brain tumor. This may improve response and may also reduce system side effects in the patient.
The primary purpose of this study is to evaluate the feasibility of safely opening the blood brain barrier in children with progressive diffuse midline gliomas (DMG) treated with oral etoposide using focused ultrasound with microbubbles and neuro-navigator-controlled sonication.
For the purpose of the study, the investigators will be opening up the blood brain barrier temporarily in one or two locations around the tumor using the non-invasive focused ultrasound technology, and administrating oral etoposide in children with progressive diffuse midline glioma.
|Condition or disease||Intervention/treatment||Phase|
|Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant||Drug: Etoposide; Oral, 50 Mg Device: Focused ultrasound with neuro-navigator-controlled sonication||Phase 1|
Diffuse midline gliomas constitute 10% of all pediatric central nervous system (CNS) tumors. Subjects with Diffuse Intrinsic Pontine Gliomas (DIPG) have a poor prognosis with a median survival that is usually reported to be 9 months, and nearly 90% of children die within 18 months from diagnosis. The mainstay of treatment is radiation to the primary tumor site. Surgical resection does not influence the outcome and is often not feasible in this part of the central nervous system.
Many promising drugs for central nervous system disorders have failed to attain clinical success due to an intact blood brain barrier, limiting their access from the systemic circulation into the brain. Systemic administration of high doses may increase delivery to the brain, but this approach risks significant side effects and systemic toxicities. Direct delivery of the drugs to the brain by injection into the parenchyma bypasses the blood brain barrier; however, drug distribution from the site of injection tends to be limited.
The technique of using focused ultrasound with microbubbles and neuro-navigator-controlled sonication can temporarily open up the blood brain barrier and allow for a greater concentration of drug to reach the tumor, thus potentially improving response in patients.
With the current study, the investigators are planning to evaluate the safety and feasibility of using focused ultrasound and open-space neuronavigator-controlled sonication to open one to two tumor sites. For the purpose of the study, investigators will be administrating oral etoposide in children with progressive diffuse midline glioma. This drug has a known toxicity profile, dose, and well-documented efficacy against many metastatic cancers. Successful opening and closing of the blood brain barrier will be confirmed with periodic magnetic resonance imaging (MRI).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Feasibility Study Examining the Use of Non-Invasive Focused Ultrasound (FUS) With Oral Etoposide Administration in Children With Progressive Diffuse Midline Glioma (DMG)|
|Estimated Study Start Date :||March 2023|
|Estimated Primary Completion Date :||January 2025|
|Estimated Study Completion Date :||January 2027|
Experimental: Focused ultrasound using oral etoposide
All patients enrolled in the study will be treated with oral etoposide after receiving focused ultrasound (FUS) treatment with microbubbles and neuro-navigator-controlled sonication.
Drug: Etoposide; Oral, 50 Mg
Subjects will receive focused ultrasound sonication followed by once daily oral etoposide (50mg/m^2/dose). Oral etoposide will be taken every day for 21 days, followed by one week of rest. For the first cycle, etoposide will be administered immediately following confirming of the blood brain barrier opening through contrast magnetic resonance imaging (MRI) which will occur within 4 hours of the focused ultrasound procedure. For subsequent cycles, etoposide will be administered immediately following the focused ultrasound procedure. Subjects may continue for a maximum of 4 cycles.
Other Name: Etoposide phosphate
Device: Focused ultrasound with neuro-navigator-controlled sonication
Focused ultrasound sonication will be performed a maximum of three times a week for two weeks with two weeks of rest.
- Number of total adverse events [ Time Frame: Up to 90 days after the end of the last focused ultrasound treatment ]This is to evaluate the safety of using focused ultrasound to open the blood brain barrier at one or two sites for administration of etoposide in children with progressive diffuse midline glioma. Safety will be assessed by adverse events as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (including abnormalities from physical and neurologic examinations, laboratory values, and radiographic results).
- Number of patients with successful opening of the blood brain barrier [ Time Frame: Treatment will consist of up to 4 cycles, each lasting 28 days. During the first 2 weeks of each cycle, subjects will receive FUS therapy for a maximum of 3 times per week, concurrent with etoposide. ]This is to evaluate the feasibility of using FUS to open the blood brain barrier at one or two sites for administration of etoposide in children with progressive diffuse midline glioma. The study defines feasibility as successful opening of the blood brain barrier.
- 3-month Progression Free Survival (PFS3) [ Time Frame: Up to 3 months after last focused ultrasound treatment ]Progression Free Survival is defined as the duration of the time from the start of focused ultrasound treatment to time of progression or death from any cause, whichever occurs first. Patient's vitality status will be monitored with a monthly follow-up phone call for 3 months post-treatment.
- 3-month Overall Survival (OS3) [ Time Frame: Up to 3 months after last focused ultrasound treatment ]Overall survival is defined as the duration of time from the start of focused ultrasound treatment to death from any cause. Overall survival will be measured by follow-up with a study participant every 3-6 months until death for any reason. Patient's vitality status will be monitored with a monthly follow-up phone call for 3 months post-treatment.
- Blood brain barrier/Tumor imaging changes [ Time Frame: Up to 90 days after the end of the last focused ultrasound treatment ]MRI and other radiological evidence to show successful BBB opening and closing
- Number of severe or serious adverse events [ Time Frame: Up to 90 days after the last focused ultrasound treatment ]All severe adverse events (SAEs), and adverse events (AEs), grade 3 and higher (except for thrombocytopenia which will include grade 2) will be collected and reported on each patient over the course of their treatment, according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All SAEs and any AEs grade 3 and higher (except for thrombocytopenia which will include grade 2) will be tallied.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05762419
|Contact: Cheng-Chia Wu, MD, PhDfirstname.lastname@example.org|
|Contact: Luca Szalontay, MDemail@example.com|
|United States, New York|
|Columbia University Irving Medical Center||Recruiting|
|New York, New York, United States, 10032|
|Contact: Cheng-Chia Wu, MD, PhD firstname.lastname@example.org|
|Principal Investigator: Cheng-Chia Wu, MD, PhD|
|Principal Investigator:||Cheng-Chia Wu, MD, PhD||Columbia University|