Evaluation of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma

April 23, 2026 updated by: St. Jude Children's Research Hospital

A Phase II Study of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma

Low-grade gliomas (LGGs) are the most common brain tumors in children, and a subset of these tumors are treated definitively with focal radiation therapy (RT). These patients often survive for many years after receiving RT and experience late deficits in memory. Verbal recall is an important measure of memory and is associated with other important functional outcomes, such as problem-solving, independence of every-day functioning, and quality of life. Decline in memory, as measured by verbal recall, is associated with RT dose to the hippocampi. Therefore, this phase II study investigates the feasibility of reducing RT doses to the hippocampi (i.e., hippocampal avoidance [HA]) by using proton therapy for midline or suprasellar LGGs.

Primary Objective:

  • To determine the feasibility of HA with proton therapy in suprasellar or midline LGGs. Feasibility will be established if 70% of plans meet the first or second dose constraints shown below.

    1. First priority RT dose constraints for bilateral hippocampi: volume receiving 40 CGE (V40CGE) ≤ 25%, dose to 100% of Hippocampus (D100%) ≤ 5CGE.

    2. Second priority RT dose constraints for bilateral hippocampi: V40CGE ≤ 35%, D100% ≤ 10 CGE.

      Secondary Objectives:

  • To estimate the 3-year event-free-survival (EFS) for LGGs treated with HA.
  • To estimate the change in California Verbal Learning Test short-term delay (CVLT-SD) from baseline to 3 years and from baseline to 5 years
  • To compare CVLT-SD and Cogstate neurocognitive scores in patients with proton therapy plans that: (1) meet first priority RT dose constraints, (2) meet second priority RT dose constraints but not first priority RT dose constraints, and (3) that did not meet either first or second RT priority dose constraints

Exploratory Objectives:

  • To describe the change in overall cognitive performance from baseline to 3 years and from baseline to 5 years with an age appropriate battery, including gold standard measures shown in the published studies to be sensitive to attention, memory processing speed and executive function that will afford comparison to historical controls.
  • To characterize longitudinal changes in connection strength within brain networks in the first 3 years after proton therapy and to investigate associations between these changes and neurocognitive performance with focus on the hippocampi.
  • To correlate the distribution and change in L-methyl-11C-methionine positron emission tomography (MET-PET) uptake to tumor progression and from baseline to 3 years and to investigate whether cases of pseudoprogression exhibit a differential pattern of uptake and distribution compared to cases of true progression after controlling for histology.
  • To investigate the effect of BRAF alteration, tumor histology and tumor location on PFS and OS in a prospective cohort of patients treated in a homogenous manner.
  • To investigate whether the methylation profiles of LGGs differ by tumor location (thalamic/midbrain vs. hypothalamic/optic pathway vs. others) and histologies (pilocytic astrocytoma vs. diffuse astrocytoma vs. others), which, in conjunction with specific genetic alterations, may stratify patients into different subgroups and highlight different therapeutic targets.
  • To record longitudinal measures of circulating tumor DNA (ctDNA) in plasma and correlate these measures with radiographic evidence of disease progression.
  • To bank formalin-fixed, paraffin-embedded (FFPE)/frozen tumors and whole blood from subjects for subsequent biology studies not currently defined in this protocol.
  • To quantify and characterize tumor infiltrating lymphocytes (TILs) and to characterize the epigenetics of T cells and the T cell receptor repertoire within the tumor microenvironment.
  • To estimate the cumulative incidence of endocrine deficiencies, vision loss, hearing loss and vasculopathy after proton therapy and compare these data to those after photon therapy.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

All patients will receive HA proton therapy to 52.2 CGE or 54 CGE in 29 or 30 fractions, depending on tumor location. Patients will receive weekly magnetic resonance imaging (MRI) scans during the course of proton therapy to monitor changes in solid tumor or cystic volume. Such changes may prompt adaptive therapy to improve coverage or minimize the RT dose to healthy structures. Neurocognitive outcomes, sensitive to measures of memory and learning, will be collected at baseline and continue to 5 years post therapy. Disease evaluation will be monitored with brain MRI.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
74

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • United States
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Completed
        • Mayo Clinic
    • Tennessee
      • Memphis, Tennessee, United States, 38105
        • Recruiting
        • St. Jude Children's Research Hospital
        • Principal Investigator:
          • Thomas Merchant
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

6 years to 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients must have a diagnosis of pilocytic astrocytoma, pilomyxoid astrocytoma, pleomorphic xanthoastrocytoma, ganglioglioma, optic pathway glioma, diffuse astrocytoma, low-grade neuroepithelial tumor, low-grade glioneuronal tumor or LGG, or not otherwise specified (NOS).
  • Patient with eligible diagnosis other than optic pathway glioma or tumors of the brainstem/midbrain/tectum has histologic verification of disease at diagnosis or recurrence OR
  • Patient with optic pathway glioma or tumors of the brainstem/midbrain/tectum has radiologic verification of disease at diagnosis or recurrence
  • A repeat biopsy was done because the recurrent tumor was enhancing but did not originally enhance because there was a high index of suspicion regarding high-grade transformation
  • Tumor must be located in the suprasellar region or midline structures. Midline structures include, but are not limited to, the thalamus, basal ganglia, internal capsule, midbrain, tectum, third ventricle, fourth ventricle, cerebellum, pons, and medulla. Tumors may involve the optic pathway. For questions about tumor locations that are not specified on this list, please contact the Study PI.
  • Patients must be at least 6 years but less than 22 years of age at the time of enrollment.
  • Patients must have a performance status greater or equal to 70 (use Karnofsky scale for patients aged 16 years and older and Lansky scale for patients aged less than 16 years).
  • Patients may not receive concurrent chemotherapy or targeted therapy, including but not limited to BRAF-inhibitors and MEK-inhibitors.
  • All patients must be able to undergo contrast-enhanced brain MRI.

  • All patients must have adequate organ function as described below.

    • Peripheral absolute neutrophil count (ANC) ≥ 1000/µL
    • Platelet count ≥ 10,000/µL (transfusion independent)
    • Patients with seizures may be enrolled if well controlled on anticonvulsants

Exclusion Criteria:

  • Patients may not have received prior CNS radiation.
  • Patients with gross total resection and no measurable disease via MRI are not eligible. Patients must have measurable disease of at least 1 cm via MRI.
  • Patients with evidence of metastatic disease are not eligible.
  • Patients with WHO grade II midline tumors that harbor the H3K27M mutation, IDH-mutant gliomas, grade II ependymomas and subependymomas, pituicytomas, spindle cell oncocytomas, or granular cell tumors of the sellar region are not eligible.
  • Patients with tumors that directly invade the hippocampus or with gross tumor volumes that extend into the hippocampus are not eligible.
  • Patients with tumors in the spine or cervicomedullary junction.
  • Females of child-bearing potential cannot be pregnant or breast feeding. Female participants > 10 years of age or post menarche must have a negative serum or urine pregnancy test before enrollment. Males and females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
  • Patients who are status post resection of bilateral hippocampi. Patients who are status post resection of one hippocampus will be eligible for the study and the hippocampal dose constraints will be applied to the intact hippocampus.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Hippocampal-avoidance proton therapy
Radiation: Hippocampal-avoidance proton therapy
Hippocampal-avoidance proton therapy

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Percentage of plans meet the first or second dose constraints.
Time Frame: 4 years after activation
To determine the feasibility of HA with proton therapy in suprasellar or midline LGGs. Feasibility will be established if 70% of plans meet the first or second dose constraints. First RT dose constraints for bilateral hippocampi: volume receiving 40 CGE (V40CGE) ≤ 25%, dose to 100% of hippocampus (D100%) ≤ 5CGE. Second RT dose constraints for bilateral hippocampi: V40CGE ≤ 35%, D100% ≤ 10 CGE.
4 years after activation

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
EFS of LGGs treated with HA
Time Frame: 3 years
EFS will be calculated from the date of RT starts until disease progression, second malignancy, death of any cause or last follow up date.
3 years
The change in CVLT-SD scores from baseline to 3 years
Time Frame: Baseline evaluation date, 3 years after treatment
CVLT-SD scores change of patients with HA feasible from baseline evaluation date to 3 years after treatment
Baseline evaluation date, 3 years after treatment
The change in CVLT-SD scores from baseline to 5 years
Time Frame: Baseline evaluation date, 5 years after treatment
CVLT-SD scores change from baseline evaluation date to 5 years after treatment
Baseline evaluation date, 5 years after treatment
Cogstate neurocognitive scores
Time Frame: Baseline evaluation date
Cogstate neurocognitive scores in patients with proton therapy plans
Baseline evaluation date
Cogstate neurocognitive scores
Time Frame: 3 years after treatment
Cogstate neurocognitive scores in patients with proton therapy plans
3 years after treatment
Cogstate neurocognitive scores
Time Frame: 5 years after treatment
Cogstate neurocognitive scores in patients with proton therapy plans
5 years after treatment
CVLT-SD neurocognitive scores
Time Frame: Baseline evaluation date
CVLT-SD neurocognitive scores in patients with proton therapy plans
Baseline evaluation date
CVLT-SD neurocognitive scores
Time Frame: 3 years after treatment
CVLT-SD neurocognitive scores in patients with proton therapy plans
3 years after treatment
CVLT-SD neurocognitive scores
Time Frame: 5 years after treatment
CVLT-SD neurocognitive scores in patients with proton therapy plans
5 years after treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
St. Jude Children's Research Hospital

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Thomas Merchant, MD, St. Jude Children's Research Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 28, 2019

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2027

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 1, 2028

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 20, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 20, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 22, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 24, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 23, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • HALGG

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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