GliomaNCT04065776
Evaluation of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma
A study testing Hippocampal-avoidance proton therapy in people with Glioma and Pilocytic Astrocytoma, run by St. Jude Children's Research Hospital at 2 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 6 to 21 years
- Conditions the study is for
- Glioma, Pilocytic Astrocytoma, Pilomyxoid Astrocytoma
- What is being tested?
- Hippocampal-avoidance proton therapy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 48 participants
- Where
- 2 sitesUnited States
- Study dates
- 28 Aug 2019to Jul 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
Show all 13Show fewer
- 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
Who cannot join
- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
St. Jude Children's Research Hospital
Memphis, Tennessee, 38105
Mayo Clinic
Rochester, Minnesota, 55905
About this study
Official title: 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:
Read more
- 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.
- First priority RT dose constraints for bilateral hippocampi: volume receiving 40 CGE (V40CGE) ≤ 25%, dose to 100% of Hippocampus (D100%) ≤ 5CGE.
- 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.
Read the 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.
- Conditions
- Glioma, Pilocytic Astrocytoma, Pilomyxoid Astrocytoma, Pleomorphic Xanthoastrocytoma, Ganglioglioma, Optic Pathway Glioma
- Being tested
- Hippocampal-avoidance proton therapy
- Medical subject headings
- Glioma, Astrocytoma, Ganglioglioma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Hippocampal-avoidance proton therapyRadiation
Hippocampal-avoidance proton therapy
| Study group | Role | What they receive |
|---|---|---|
| Hippocampal-avoidance proton therapy | Experimental | Hippocampal-avoidance proton therapy Receives: Radiation: Hippocampal-avoidance proton therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of plans meet the first or second dose constraints.
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.
Measured: 4 years after activation
Secondary outcomes (9)
EFS of LGGs treated with HA
EFS will be calculated from the date of RT starts until disease progression, second malignancy, death of any cause or last follow up date.
Measured: 3 years
The change in CVLT-SD scores from baseline to 3 years
CVLT-SD scores change of patients with HA feasible from baseline evaluation date to 3 years after treatment
Measured: Baseline evaluation date, 3 years after treatment
The change in CVLT-SD scores from baseline to 5 years
CVLT-SD scores change from baseline evaluation date to 5 years after treatment
Measured: Baseline evaluation date, 5 years after treatment
Cogstate neurocognitive scores
Cogstate neurocognitive scores in patients with proton therapy plans
Measured: Baseline evaluation date
Cogstate neurocognitive scores
Cogstate neurocognitive scores in patients with proton therapy plans
Measured: 3 years after treatment
Cogstate neurocognitive scores
Cogstate neurocognitive scores in patients with proton therapy plans
Measured: 5 years after treatment
CVLT-SD neurocognitive scores
CVLT-SD neurocognitive scores in patients with proton therapy plans
Measured: Baseline evaluation date
CVLT-SD neurocognitive scores
CVLT-SD neurocognitive scores in patients with proton therapy plans
Measured: 3 years after treatment
CVLT-SD neurocognitive scores
CVLT-SD neurocognitive scores in patients with proton therapy plans
Measured: 5 years after treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Aug 2019
- Study start28 Aug 2019
- Primary completionJul 2027 (estimated)
- Study completionJul 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for GliomaStudies of the same condition, open and under way.
- More trials run by St. Jude Children's Research HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 48 participants (actual)
Sponsor and investigators
- Lead sponsor
- St. Jude Children's Research Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Thomas Merchant, MD, Principal investigator, St. Jude Children's Research Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04065776
- Sponsor's protocol ID
- HALGG
- Status last verified
- Sep 2026
- First submitted
- 20 Aug 2019
- Last updated
- 15 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 15 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma
- ClinicalTrials.gov ID
- NCT04065776
- Acronym / sponsor ID
- HALGG
- Conditions
- Glioma, Pilocytic Astrocytoma, Pilomyxoid Astrocytoma, Pleomorphic Xanthoastrocytoma, Ganglioglioma, Optic Pathway Glioma
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 48 participants (actual)
- Lead sponsor
- St. Jude Children's Research HospitalUniversity, hospital or other
- Study start
- 28 Aug 2019 (actual)
- Primary completion
- Jul 2027 (estimated)
- Study completion
- Jul 2028 (estimated)
- First posted
- 22 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
- First priority RT dose constraints for bilateral hippocampi: volume receiving 40 CGE (V40CGE) ≤ 25%, dose to 100% of Hippocampus (D100%) ≤ 5CGE.
- 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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Hippocampal-avoidance proton therapy | Experimental | Radiation: Hippocampal-avoidance proton therapyHippocampal-avoidance proton therapy |
Who may qualify
- Ages
- 6 to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (13 listed)
- 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.
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Hippocampal-avoidance proton therapyHippocampal-avoidance proton therapy | Radiation | Hippocampal-avoidance proton therapy |
Primary outcome
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.
9 secondary outcomes
EFS of LGGs treated with HA
Time frame: 3 years
The change in CVLT-SD scores from baseline to 3 years
Time frame: 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
Cogstate neurocognitive scores
Time frame: Baseline evaluation date
Cogstate neurocognitive scores
Time frame: 3 years after treatment
Cogstate neurocognitive scores
Time frame: 5 years after treatment
CVLT-SD neurocognitive scores
Time frame: Baseline evaluation date
CVLT-SD neurocognitive scores
Time frame: 3 years after treatment
CVLT-SD neurocognitive scores
Time frame: 5 years after treatment
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Sep 2026.
- St. Jude Children's Research HospitalLink provided by the sponsor.
- Clinical Trials Open at St. JudeLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Merchant, MD principal investigator
St. Jude Children's Research Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Hippocampal-avoidance proton therapy in people with Glioma and Pilocytic Astrocytoma, run by St. Jude Children's Research Hospital at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 15 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of plans meet the first or second dose constraints. (time frame: 4 years after activation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Sep 2026.