Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Nervous System Diseases

Substance Related Disorders

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Neurotoxicity Syndromes

Neoplasms by Histologic Type

Hematologic Diseases

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Antineoplastic Agents

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Vitamins

Methotrexate

Folic Acid

Vitamin B Complex

Folinic Acid

Folate

Vitamin B9

Leukemia survivors with neuro-cognitive deficit phenotype. Based on DIVERGET and other phenotyping tools, we will identify those with the deficit phenotype. This will be treated as "case".

Leukemia survivors who did not show impaired neurocognitive function, compared to the Control group defined above.

Dr. Shinya Ito, MD

Dr. Sharon Guger

Dr. Johann Hitzler

Dr. Deborah L O'Connor

Dr. Russell Schachar

Dr. Brenda Spiegler

Dr. Rosanna Weksberg

To find possible therapeutic targets to help prevent long-term brain and behavioural side effects in survivors of childhood leukemia that may have been caused by chemotherapy (Treatment-Related late Adverse Neuro-Cognitive Effects: TRANCE). The study hypothesis is that genetic variations of the elements in the folate-related cycles and methotrexate disposition networks are associated with the deficit phenotype (TRANCE) of childhood leukemia survivors.

Hypothesis Genetic variants of the elements in the folate-related cycles and methotrexate disposition networks are associated with the TRANCE phenotype of childhood leukemia survivors.

Objectives

1. To identify TRANCE phenotypes of the childhood leukemia survivors.
2. To characterize the folate and vitamin B12 levels of these children
3. To identify DNA methylation patterns associated with TRANCE trait in the leukemia survivors
4. To identify SNPs associated with the TRANCE trait in the leukemia survivors.
5. To identify the "deficit genotype" associated only with the TRANCE leukemia survivors, but not with general population children who show developmental phenotypes similar to TRANCE: TRANCE-unique deficit variant
6. To replicate the association between the TRANCE-unique deficit variants and the TRANCE trait in a population of childhood leukemia survivors.
7. To evaluate the importance of rare genetic variants in the TRANCE trait in the leukemia survivors.

Study design: A case-control study of leukemia survivors

Analyses

1. Leukemia survivors will be characterized by their status of neurocognitive function, and categorized into the Deficit case and the non-deficit Control case.
2. They will be also characterized by the following attributes

   1. Pathway-based genetic variant status (folate and PK-related genes)
   2. Folate and vitamin B12 status
   3. Epigenetic markers
3. Comparative analyses between neuro-cognitiive deficit phenotype (TRANCE) and Control on those parameters

DNA samples obtained via blood, saliva and buccal sample collection.

N-PhenoGENICS: Neurocognitive-Phenome, Genome, Epigenome and Nutriome In Childhood Leukemia Survivors

DNA methylation signals represent one of the most stable epigenetic markers, which are known to be affected by environmental factors including drugs and nutrients such as folate. Environmental information conveyed through these factors is translated into gene expression changes mediated by DNA methylation. Although this may contribute to neuro-cognitive deficits of the leukemia survivors, there is no prior data in this regard. Therefore, the aim of this exploratory analysis is to determine if there is any indication that DNA methylation patterns are altered in the participants. DNA will be isolated from each of the blood, buccal swab, and saliva samples and modified using sodium bisulfite, which will then be used to determine DNA methylation patterns.

This is a short battery of tests that has been shown to be predictive of both global and academic impairment in survivors of childhood cancer. All neuro-cognitive tests are done on a same day.

Response inhibition, disturbed by behavioral inattention, will be characterized using our task-based computer program, the Stop Signal Task (SST). All neuro-cognitive tests are done on a same day.

To characterize behavioural aspects, we will administer the standard measure based on parent report. All neuro-cognitive tests are done on a same day.

In the hypothesis-driven genome-wide approach, we will focus on the candidate pathways/regions including (but not limited to): a) Folate/methionine cycle genes and transporters; b) drug metabolizing enzymes and transporters (including families of CYP, SLC and ABC transporters); c) epigenetic modifying factors; and d) neuro-regeneration and tissue repair.

In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will include tests of general cognitive function (WISC-IV). All neuro-cognitive tests are done on a same day.

In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will include tests of general cognitive function: WIAT-III numerical operations and math fluency composite score. All neuro-cognitive tests are done on a same day.

In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will administer Brief Rating Inventory of Executive Function (BRIEF), which is designed to assess executive functioning in the home environment. All neuro-cognitive tests are done on a same day.

In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will administer N-Back Task, which is a continuous performance computerized task used to measure aspects of working memory. All neuro-cognitive tests are done on a same day.

Folate and other vitamin intakes vary among individuals. Folic acid fortification in Canadian food product has changed the Canadian population norm of folate status, virtually eliminating folate deficiency status. However, a large inter-individual variation still remains. We will use a Supplement Questionnaire to capture information on all and any supplements that participants may be currently taking.

In order to complement the Supplement Questionnaire (above), we will measure the folate concentration in plasma and red blood cells.

Vitamin B12 and folate pathways interact to maintain biochemical homeostasis. To complement the intake assessment (above), we will measure serum vitamin B12.

Iron status affects cognitive function of children. In addition to the intake assessment (above), we will estimate iron status by measuring hemoglobin and soluble transferrin receptor.

Canadian Institutes of Health Research (CIHR)

Canadian Cancer Society (CCS)

C17 Council

Garron Family Cancer Centre

Pediatric Oncology Group of Ontario

The Hospital for Sick Children

Division Head, Clinical Pharmacology and Toxicology

Musculoskeletal Diseases

Glioma

Brain Neoplasms

Ependymoma

Craniopharyngioma

Adamantinoma

Neoplasms, Germ Cell and Embryonal

Ameloblastoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Bone Neoplasms

Bone Diseases

Germ Cells Tumors

Neuroepithelioma

Anti-Dyskinesia Agents

Cardiotonic Agents

Memantine

Antiparkinson Agents

Dopamine

Dopamine Agents

Neurotransmitter Agents

Excitatory Amino Acid Antagonists

Beginning at least two weeks prior to radiation therapy, participants receive memantine. Treatment continues for 12 weeks with periodic cognitive assessments and lab work.

Beginning at least two weeks prior to radiation therapy, participants receive a placebo. Treatment and assessment are identical to the memantine group.

Medication dosing will be overseen by one of the study neurologists, with step-wise dose reductions (5 mg intervals) allowable in the case of side effects.

A placebo that appears exactly like the study drug, memantine, will be given in a manner identical to the study drug.

Placebo

Cognitive and neurologic examinations will be conducted to assess cognitive, social, quality of life, and neurological outcomes associated with memantine will be completed at baseline prior to medication start, and at 6 weeks (end of radiation therapy), 12 weeks (discontinuation of study medication or placebo), and one year post radiation therapy.

Cognitive Assessment

Heather M. Conklin, PhD

Children with brain tumors who have had radiation therapy are at risk for problems with attention, memory, and problem solving. Such problems may cause difficulty in school and daily life. Memantine, the drug being used for this study, is not yet approved for use in children by the U.S. Food and Drug Administration. However, studies have shown some improvements in memory for patients with dementia, Attention Deficit Hyperactivity Disorder, and autism. Scientists have also used this medication for adult cancer patients receiving radiation therapy with results showing less cognitive declines over time compared to patients taking a placebo (inactive pill). These studies have also shown few side effects.

This is a pilot/feasibility study and the first known study involving children with a cancer diagnosis or brain tumor.

PRIMARY OBJECTIVES:

* To estimate the participation rate in a study of memantine used as a neuro-protective agent in children undergoing radiotherapy for localized brain tumors (low grade glioma, craniopharyngioma, ependymoma, or germ cell tumor)
* To estimate the rate of memantine medication adherence
* To estimate the rate of completion of cognitive assessments

SECONDARY OBJECTIVES:

* To estimate the effect size of change in neurobehavioral outcomes (cognitive, social, quality of life, neurologic) associated with memantine
* To evaluate the frequency and nature of memantine side effects as measured by the Systematic Assessment for Treatment Emergent Events (SAFTEE)

Participants will be randomized to take part in one of two groups:

* The Memantine Group will be prescribed memantine at a dosage following FDA-approved adult labeling. A low dose will initially be given beginning at least two weeks (± 7 days) prior to beginning radiation therapy. The dose will increase until participants reach the target dose of 20 mg/day. Memantine will be given for a total of 12 weeks.
* The Placebo Group will be prescribed identical capsules with no active drug. The placebo drug will be given in the same dose and frequency as described for the Memantine group.

Participants will undergo the same evaluations and monitoring throughout the medication phase. Assessments will be done at baseline prior to study start, with follow-up assessments at 6 weeks (end of radiation therapy), and 12 weeks (end of study medication). Psychological testing to measure attention, working memory, problem solving, intelligence and academics will be done for each participant. Caregivers will also complete questionnaires about attention, problem solving, mood and interpersonal interactions. Caregivers will also be asked to complete a questionnaire about the family's general characteristics and medical history.

At the time points noted above, blood work, vital signs and echocardiograms will be obtained, and the study neurologist will examine the participant to monitor side effects and neurological functioning. A study nurse will contact the participant once per week during the 12 weeks of medication administration to identify possible medication-related side effects and to check on rate of compliance with taking the medication. A remote app will be installed on the participant's home computer or cell phone to help remind them to take the medication and track success. At one year post medication, psychological and neurological examinations will be repeated.

Randomized, double-blind, placebo-controlled trial design.

Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors

Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors: A Pilot Study

The rates of study participation and related 90% Blyth-Still-Casella intervals, as well as their regular 90% confidence interval, will be estimated. Test of one proportion will be performed against an estimated rate of 60%. The rate will be evaluated for the group as a whole as well as separately for the memantine intervention and placebo-control groups.

The rates of medication adherence and related 90% Blyth-Still-Casella intervals, as well as their regular 90% confidence interval, will be estimated. Test of one proportion will be performed against an estimated rate of 80%. The rate will be evaluated for the group as a whole as well as separately for the memantine intervention and placebo-control groups.

The rates of completion of cognitive assessments and related 90% Blyth-Still-Casella intervals, as well as their regular 90% confidence interval, will be estimated. Test of one proportion will be performed against an estimated rate of 75%. The rate will be evaluated for the group as a whole as well as separately for the memantine intervention and placebo-control groups.

The effect size (Cohen's d- the standardized difference between two means) of memantine on neurobehavioral outcomes (cognitive, social, quality of life, neurologic) will be estimated by comparing performance at baseline to performance at 6 weeks (end of radiation therapy) using paired difference divided by its estimated standard deviation. In addition, due to the missing data, mixed-effects models will be fitted to investigate the change of outcome from baseline to 6 weeks.

The effect size (Cohen's d- the standardized difference between two means) of memantine on neurobehavioral outcomes (cognitive, social, quality of life, neurologic) will be estimated by comparing performance at baseline to performance at 12 weeks (end of medication trial) using paired difference divided by its estimated standard deviation. In addition, due to the missing data, mixed-effects models will be fitted to investigate the change of outcome from baseline to 12 weeks.

The effect size (Cohen's d- the standardized difference between two means) of memantine on neurobehavioral outcomes (cognitive, social, quality of life, neurologic) will be estimated by comparing performance at baseline to performance at follow-up (up to 1 year) using paired difference divided by its estimated standard deviation. In addition, due to the missing data, mixed-effects models will be fitted to investigate the change of outcome from baseline to 1 year.

The frequency and nature of memantine side effects as measured by the SAFTEE will be evaluated qualitatively by calculating the frequency of side effect reporting by severity rating at different time points in the medication trial and comparing these frequencies across the memantine intervention and placebo-control groups. The frequency of side effects will be compared between the intervention and placebo-control groups using at t-test or other appropriate test, depending on the data distribution features of the compared outcome.

National Cancer Institute (NCI)

St. Jude Children's Research Hospital

Symptoms and General Pathology

Fatigue

Brain Tumor, Childhood

Participants are exposed to bright light (1,000 lux at eye level) using light glasses (Luminette Version 3) for a maximum duration of 30 minutes upon awakening each day from Monday to Friday for 6 weeks while wearing an actigraph and periodic completion of questionnaires, cognitive assessments, and lab work.

Participants are exposed to exposed to dim light (equivalent intensity of \<25 lux) using light glasses (Luminette) for a maximum duration of 30 minutes upon awakening each day from Monday to Friday for 6 weeks while wearing an actigraph and periodic completion of questionnaires, cognitive assessments, and lab work.

Research coordinator will follow-up with participant on Days 2 \& 5, and weekly thereafter to assess for the presence of potential side effects. If side effects are present with bright light initiation and they do not resolve by Day 5, the intervention will be discontinued.

Bright Light Exposure

A placebo pair of glasses that is identical in form to the bright light glasses with the exception of light intensity will be used in a manner identical to the bright light glasses.

Dim Light Exposure

Cognitive examinations will be completed in-person and remotely via an online platform; caregivers and participants will also be asked to complete questionnaires assessing fatigue, sleep, and mood. These outcomes will be completed at baseline (prior to intervention/placebo), Week 4, Week 6 (end of intervention/placebo), and Week 8 (2-weeks post intervention/placebo).

Kimberly P Raghubar, PhD

Heather M Conklin, PhD

Children and adolescents treated for a brain tumor often experience fatigue and cognitive symptoms, such as slowed information processing and inattention. These symptoms may cause difficulty carrying out daily activities at home and at school. There are few well-researched, non-pharmacological interventions aimed at improving symptoms of fatigue and by extension cognitive symptoms. Systematic bright light exposure has been shown to improve symptoms of fatigue in adult survivors of cancer and children treated for some forms of cancer. This is a pilot/feasibility study and the first known study in children treated for a brain tumor. Findings from this study will be used to help plan a larger study to examine the effectiveness of this intervention and mechanisms of action.

PRIMARY OBJECTIVE:

1. To evaluate feasibility and adherence in a study of systematic bright light exposure used to improve fatigue and cognitive efficiency in survivors of pediatric brain tumor, including rates of enrollment, adherence, and acceptability.

   SECONDARY OBJECTIVES:
2. To estimate the effect size of change in fatigue associated with bright light exposure.
3. To estimate the effect size of change in cognitive efficiency associated with bright light exposure.

Participants will be randomized to take part in one of two groups:

1. The Bright Light Group will be exposed to bright light (1,000 lux at eye level) using light glasses (Luminette Version 3) for a maximum duration of 30 minutes each day from Monday to Friday for a total of 6 weeks. Duration of light exposure will be gradually increased over the first few days until the target of 30 minutes is reached on Day 5. Light duration is for 10 mins on Days 1 \& 2, 20 mins on Days 3 \& 4, and finally, 30 mins on Day 5.
2. The Dim Light Group will be exposed to dim light (equivalent intensity of \<25 lux) for a maximum duration of 30 minutes. Dim light will be given in the same manner and frequency as described for the Bright Light group.

Participants will undergo the same evaluations and monitoring throughout the intervention and post-intervention follow-up. All participants will receive a pair of light glasses, with a phone app to track usage, and be fitted with an actigraph following consent to participate. Assessments will be completed at baseline (prior to intervention), with additional assessments at Week 4 (of intervention), Week 6 (end of intervention), and 2-weeks post-intervention (Week 8). Participants and their caregivers will complete questionnaires assessing fatigue, sleep, and mood. Psychological testing to measure attention, working memory, executive control, and processing speed will be completed using a computerized, online battery at each time point and in person at baseline and end of intervention. Caregivers will also be asked to complete a questionnaire about the family's general characteristics and medical history.

At baseline and end of intervention (Week 6), saliva will be collected. For each day of the intervention, participants will share their usage data and complete a daily sleep diary that includes time spent in bed, sleep/wake times, estimated amount of natural sunlight exposure, and medication use. A research coordinator will contact families on Days 2 and 5 and weekly thereafter for the duration of the intervention to identify possible light-related side effects and to check on compliance with light exposure (both frequency and duration). A remote app will be installed on the participant's or caregiver's cell phone to share light usage, which is tracked automatically once the device is turned on. At end of intervention (Week 6), participants and their caregivers will be asked to complete a short acceptability questionnaire.

Randomized, double-blind, placebo-controlled trial design

Systematic Light Exposure in Pediatric Brain Tumor Survivors

Systematic Light Exposure Intervention for Fatigue and Cognitive Efficiency in Pediatric Brain Tumor Survivors

The investigators will share de-identified data for all IPD that underlie results in a publication upon reasonable request.

The rates of study participation and related 90% Blyth-Still-Casella intervals, as well as their regular 90% confidence interval, will be estimated. Test of one proportion will be performed against an estimated rate of 70%. The rate will be evaluated for the group as a whole as well as separately for the bright light intervention and placebo-control groups.

The rates of light intervention adherence and related 90% Blyth-Still-Casella intervals, as well as their regular 90% confidence interval, will be estimated. Test of one proportion will be performed against an estimated rate of 77% of sessions completed on average. The rate will be evaluated for the group as a whole as well as separately for the bright light intervention and placebo-control groups.

The rates of completion of cognitive assessments and related 90% Blyth-Still-Casella intervals, as well as their regular 90% confidence interval, will be estimated. Test of one proportion will be performed against an estimated rate of 75%. The rate will be evaluated for the group as a whole as well as separately for the bright light intervention and placebo-control groups.

For the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, the raw score is converted to a standardized T-score (range 34-85) with a mean of 50 and standard deviation of 10, where a higher score represents greater severity of symptoms. The effect size (Cohen's d- the standardized difference between two means) of bright light exposure on fatigue will be estimated by comparing performance at baseline to that at Week 4 (comparison point in adult literature), using the paired difference divided by its estimated standard deviation. In addition, given potential for missing data, a mixed-effect model will be fit to investigate change in outcome from baseline to Week 4.

For the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, the raw score is converted to a standardized T-score (range 34-85) with a mean of 50 and standard deviation of 10, where a higher score represents greater severity of symptoms. The effect size (Cohen's d- the standardized difference between two means) of bright light exposure on fatigue will be estimated by comparing performance at baseline to that at Week 6 (end of systematic light exposure), using the paired difference divided by its estimated standard deviation. In addition, given potential for missing data, a mixed-effect model will be fit to investigate change in outcome from baseline to Week 6.

Attention serves as the primary neurobehavioral endpoint, and it is measured by Omissions T-score (M = 50, SD = 10) from the Conners Continuous Performance Test, Third Edition (CPT-3), where higher scores indicate worse performance (\<45 is low and 70+ is very elevated). The effect size (Cohen's d- the standardized difference between two means) of bright light exposure on attention will be estimated by comparing performance at baseline to that at Week 4 (comparison point in adult literature), using the paired difference divided by its estimated standard deviation. In addition, given potential for missing data, a mixed-effect model will be fit to investigate change in outcome from baseline to Week 4.

Attention serves as the primary neurobehavioral endpoint, and it is measured by Omissions T-score (M = 50, SD = 10) from the Conners Continuous Performance Test, Third Edition (CPT-3), where higher scores indicate worse performance (\<45 is low and 70+ is very elevated). The effect size (Cohen's d- the standardized difference between two means) of bright light exposure on attention will be estimated by comparing performance at baseline to that at Week 6 (comparison point in adult literature), using the paired difference divided by its estimated standard deviation. In addition, given potential for missing data, a mixed-effect model will be fit to investigate change in outcome from baseline to Week 6.

National Institute of Nursing Research (NINR)

Baylor College of Medicine

Assistant Professor

Central Nervous System Stimulants

Atomoxetine Hydrochloride

Adrenergic Agents

Atomoxetine

Ronald T Brown, Ph.D.

The purpose of the study is to evaluate the effectiveness and safety of atomoxetine in enhancing attention and concentration among childhood survivors of cancer.

In previous years, it had often been assumed that cognitive and behavioral declines in children who survived cancer therapy were largely a function of the prophylactic therapies (e.g., radiation, chemotherapy) that these children had received. Regardless of the etiologies of these specific late effects, the data regarding the long-term outcome of these children are strikingly consistent. Generally, the studies to date suggest significant impairments in attention and concentration that result in marked declines in academic performance and social and behavior difficulties.

Despite the clear evidence of problems with attention and concentration, as well as associated fucntional impairments (e.g., poor academic achievement and poor peer relationships), there have been few clinical trials designed to manage the cogntive late effects and neurological toxicities associated with radiation therapy and chemotherapy for children and adolescents who have survived cancer.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
N-PhenoGENICS: Neurocognitive-Phenome, Genome, Epigenome and Nutriome In Childhood Leukemia Survivors	NCT01913093	Childhood Leuke...		8 Years - 20 Years	The Hospital for Sick Children
Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors	NCT03194906	Glioma of Brain Craniopharyngio... Ependymoma Germ Cell Tumor	Memantine Placebo Cognitive Asses...	6 Years - 21 Years	St. Jude Children's Research Hospital
Systematic Light Exposure in Pediatric Brain Tumor Survivors	NCT05340881	Brain Tumor	Bright Light Ex... Dim Light Expos... Cognitive Asses...	10 Years - 18 Years	Baylor College of Medicine
Systematic Light Exposure in Pediatric Brain Tumor Survivors	NCT05340881	Brain Tumor	Bright Light Ex... Dim Light Expos... Cognitive Asses...	10 Years - 18 Years	Baylor College of Medicine
Efficacy of Atomoxetine Therapy Versus Placebo for Cognitive Late Effects	NCT00255138	Cancer Cognitive Late ...	Atomoxetine	6 Years - 18 Years	Temple University
Systematic Light Exposure in Pediatric Brain Tumor Survivors	NCT05340881	Brain Tumor	Bright Light Ex... Dim Light Expos... Cognitive Asses...	10 Years - 18 Years	Baylor College of Medicine
Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors	NCT03194906	Glioma of Brain Craniopharyngio... Ependymoma Germ Cell Tumor	Memantine Placebo Cognitive Asses...	6 Years - 21 Years	St. Jude Children's Research Hospital
Efficacy of Atomoxetine Therapy Versus Placebo for Cognitive Late Effects	NCT00255138	Cancer Cognitive Late ...	Atomoxetine	6 Years - 18 Years	Temple University

Spots Global Cancer Trial Database for cognitive late effects