Nutritional and Metabolic Diseases

All Conditions

Neoplasms

Nervous System Diseases

Dyslipidemias

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

All Drugs and Chemicals

Hormones

Hormone Antagonists

childhood cancer survivals after complex management of cranial and craniospinal tumors formed the main group

Echocardiography - standart protocol. Pulse wave characteristics were obtained using finger photopletysmography (PPG) (Angioscan-01, AngioScan-Electronics) from an infrared light sensor. Endothelial function was also evaluated using occlusion index and shear rate during post-occlusive reactive hyperemia (PORH). CPET was conducted on a treadmill (Intertrack 8100, Schiller, Switzerland) with a breath-by-breath algorithm of gas exchange analysis (Cardiovit CS-200 Ergo-Spiro, Schiller, Switzerland), using Bruce, modified Bruce or Naughton protocols depending on the level of physical tolerance.

12-lead ECG, hormone and lipid blood tests, echocardiography (Echo-CG), cardiopulmonary exercise testing (CPET) and pulse wave analysis

The purpose of research is to study to adverse cardiovascular disorder and risks factors in childhood cranial and craniospinal tumors survivors. In this research the investigators investigate cardiological instrumental diagnostic, such as electrocardiography, echocardiography with the determination of global longitudinal strain, cardiopulmonary exercise test, and diagnostic of endothelial function by Angioscan for the prediction of cardiovascular complications after cranial and craniospinal radiotherapy and chemotherapy.

Cardiovascular disease, after recurrence of the original cancer and development of second primary cancers, has been reported to be the leading cause of premature mortality among long-term childhood cancer survivors. Childhood cancer survivors after chemotherapy and radiotherapy for cranial and craniospinal tumors are at increased risk of transient ischemic attack, ischemic stroke. The mechanisms of vascular damage are not well understood. Preventive measures are not developed.

The purpose of my research is to study to adverse cardiovascular disorder and risks factors in childhood cranial and craniospinal tumors survivors.

Cardiovascular risk factors monitoring and modification, development of nursing and follow-up guides of adult patients may improve outcomes in these patients after treatment for cranial and craniospinal tumors in childhood. Attempts to develop more individualized risk prediction for cardiovascular disease may help refine surveillance and counseling in the future.

This was an open prospective observational study. 68 people were enrolled in the study: 48 childhood cancer survivals after complex management of cranial and craniospinal tumors formed the main group, and 20 healthy people formed the control group.

Criteria of inclusion to the main group were: age 16-40 years, radiation and chemotherapy for cranial and craniospinal tumors in childhood or adolescence, completion of the therapy at least one year before enrollment, signed informed consent. There were three separate types of informed consent - for adults, for minors and for their parents. Minors were signing informed consent in the presence of their parents.

Criteria of inclusion to the control group for healthy volunteers were demographics comparable to the main group.

Criteria of exclusion were: standard contraindications to exercise testing, anemia, pregnancy, psychiatric disease, alcohol or drug abuse, active malignancy, acute infection.

The study has been approved by the local ethics committee. At baseline, all patients underwent comprehensive evaluation including collection of medical history, complete physical exam, 12-lead ECG, hormone and lipid blood tests, echocardiography (Echo-CG), cardiopulmonary exercise testing (CPET) and pulse wave analysis. Additional carotid duplex scanning was performed in patients after craniospinal radiation therapy.

Echocardiography Left ventricular (LV) systolic and diastolic function, cardiac chamber volumes, valve function and systolic pulmonary artery pressure were evaluated using conventional transthoracic 2D-echocardiography (Dimension/Vivid 7 PRO, General Electric Medical System, Norway) according to current guidelines. Left ventricle (LV) end diastolic volume (LVEDV), end systolic volume (LVESV) and ejection fraction (LVEF) were measured with the modified Simpson method.

Cardiopulmonary exercise testing CPET was conducted on a treadmill (Intertrack 8100, Schiller, Switzerland) with a breath-by-breath algorithm of gas exchange analysis (Cardiovit CS-200 Ergo-Spiro, Schiller, Switzerland), using Bruce, modified Bruce or Naughton protocols depending on the level of physical tolerance. The researchers evaluated VO2 peak (highest oxygen uptake attained during exercise) and METs as its derivative, percentage from predicted VO2 peak (based on age, sex, height, and weight), anaerobic threshold (AT, defined by the V-slope method as the level of oxygen uptake at the moment of dislinear rise in minute ventilation and CO2 output relative to VO2, reflecting the shift to anaerobic metabolism and bicarbonate buffering of increased lactic acid), O2 pulse (VO2 peak/peak heart rate), ventilatory equivalent for carbon dioxide (VE/VCO2 slope), end-tidal CO2 pressure at rest and at peak exercise (PetCO2 rest and PetCO2 peak). Patient's effort was considered substantial if the self-reported number using a 1-10 modified Borg scale was ≥ 7 points and respiratory exchange ratio (RER, defined as VCO2/VO2 ratio) was ≥1.0.

Endothelial function assessment Pulse wave characteristics were obtained using finger photopletysmography (PPG) (Angioscan-01, AngioScan-Electronics) from an infrared light sensor. The amount of light transmitted to the finger directly depends on the alterations in its blood flow. The signal obtained during PPG is displayed as a digital volume pulse (DVP) waveform. This wave usually demonstrates two deflections: an early systolic peak (a), reflecting a direct pressure wave propagation from the left ventricle to the finger, and the diastolic peak (b), that reflects backward pressure wave propagation to the aorta. The time between these two peaks (peak-to-peak time, PPT) is proportional to the subject's height. We measured large artery stiffness index (SI, a ratio between the length of aorta calculated automatically based on height to PPT), reflection index of small resistive arteries (RI, calculated as b/a x 100%), augmentation index (AI, defined as the ratio between late and early systolic pulse wave peaks, expressed as percent from the pulse pressure) and augmentation index normalized for pulse rate of 75 beats per minute (AIp75%) with regard to the fact that the heart rate has a major impact on the augmentation of pulse pressure. Endothelial function was also evaluated using occlusion index and shear rate during post-occlusive reactive hyperemia (PORH) representing the magnitude of limb reperfusion after a brief period of brachial artery occlusion. The probe was performed in the morning hours in supine position after 15 minutes of rest in a comfortable quiet warm environment according to a standardized protocol on subject preparation (fasting state, restriction of moderate-to-high physical activity, nicotine, alcohol, caffeine or other vasoactive drugs 24 hours before the probe).

Statistical analysis Microsoft Excel spreadsheet application was used for data storage and preparation for future analysis. Statistical analysis was performed using Prism 9.2.0 software. Python software was applied for multiple logistic regression models. The continuous data were expressed as a mean value (M) ± standard deviation (SD) with a 95% confidence interval (CI). Categorical variables were presented in absolute numbers and percentage and computed by using two-tailed Fischer's exact test. Normality of distribution for quantitative variables was tested using Anderson-Darling test as the first step and using Student t-test or Mann-Whitney U-test as the second step. Normality of distribution was initially evaluated as well before correlation analysis with a Pearson coefficient for normal data and with a Spearmen coefficient for non-normal data. Multiple regression models were performed considering multiple testing of hypotheses. The results of the study were presented as histograms with pairwise comparison of correlation matrices. P-value \<0.05 was considered significant.

Cardiovascular Disorders and Risk Factors in Childhood Cranial and Craniospinal Tumors Survivors

change сoncentration of total cholesterol \>5 mmol/l, change сoncentration of LDL \> 3 mmol/l, сoncentration of HDL \<1,2 mmol/l, change сoncentration of TG \>1,7 mmol/

change in endothelial function by Angioscan

change anaerobic threshold\<14,0 ml/kg/min

I.M. Sechenov First Moscow State Medical University

Symptoms and General Pathology

Rare Diseases

Recurrence

Glioma

Astrocytoma

Ganglioneuroma

Oligodendroglioma

Neoplasms, Neuroepithelial

Ganglioglioma

Neurocytoma

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Gangliocytoma

Diffuse Astrocytoma

Pilocytic Astrocytoma

Oligoastrocytoma

Desmoplastic Infantile Astrocytoma

Papillary Glioneuronal Tumors

Central Neurocytoma

Dysembryoplastic Neuroepithelial Tumor

Neuroepithelioma

Participants will receive mirdametinib at one of the dose levels twice daily days 1-28. For the first cycle of treatment, participants will take mirdametinib tablets dissolved in water. After the first cycle of treatment, participants may receive the medicine the same way (dissolved in water) or may receive capsules. Treatment repeats every 28 days for up to 26 cycles of treatment (24 months) in the absence of disease progression or unacceptable toxicity.

Participants will receive the RP2D of mirdametinib. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.

Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.

Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants with previous exposure to mirdametinib may receive a starting dose lower than the RP2D, depending on the dose they tolerated during their previous exposure. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.

Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.

By mouth, nasogastric (NG) tube or gastrostomy tube (G-tube) BID, days 1-28

Mirdametinib

Tabatha E. Doyle, RN

Giles W. Robinson, MD

Anna Vinitsky, MD, MS

This is an open-label, multi-center, Phase 1/2 study of the brain-penetrant MEK inhibitor, mirdametinib (PD-0325901), in patients with pediatric low-grade glioma (pLGG).

The objectives of this study are:

Phase 1

Primary Objectives:

* To determine the safety and tolerability and estimate the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of mirdametinib dosed twice daily on a continuous schedule in pediatric patients with progressive or recurrent low-grade glioma.
* To characterize the plasma pharmacokinetics (PK) of mirdametinib.

Phase 2

Cohort 1: Newly diagnosed and/or previously untreated (except surgery)

Primary Objectives:

* To assess the efficacy, defined as the sustained objective response rate \[a Partial Response (PR), Major Response, and/or Complete Response (CR) sustained over 8 weeks\] observed over any time on active treatment with mirdametinib in previously untreated patients (except surgery) with WHO grade I or grade II glioma.
* To characterize the plasma pharmacokinetics of mirdametinib in children, adolescents, and young adults with low-grade gliomas.
* To describe the toxicity profile of mirdametinib in pediatric patients.

Secondary Objectives:

* Estimate the efficacy of mirdametinib as measured by progressive free survival (PFS) and overall survival (OS) in patients with previously untreated WHO grade I or grade II glioma.
* To describe treatment responses (Progressive Disease, Stable Disease, Minor Response, Partial Response, Major Response, and Complete Response) observed in previously untreated patients (except surgery) with WHO grade I or grade II glioma over any time on active treatment with mirdametinib.
* To characterize and monitor patient neurocognitive function and quality of life in patients while on study.

Cohort 2: Recurrent and/or Progressive without prior exposure to MEK inhibitors

Primary Objectives:

* To assess the efficacy, defined as the sustained objective response rate (a PR, Major Response, and/or CR sustained over 8 weeks) observed anytime on active treatment with mirdametinib in patients with recurrent and/or progressive WHO grade I or grade II glioma not previously treated with MEK inhibitors.
* To characterize the plasma pharmacokinetics of mirdametinib in children, adolescents, and young adults with low-grade gliomas.
* To describe the toxicity profile of mirdametinib in pediatric patients with recurrent or progressive disease, not previously treated with MEK inhibitors.

Secondary Objectives:

* Estimate the efficacy of mirdametinib as measured by PFS and OS in patients with recurrent and/or progressive WHO grade I or grade II glioma not previously treated with MEKi
* To describe treatment responses (Progressive Disease, Stable Disease, Minor Response, Partial Response, Major Response, and Complete Response) observed in patients with recurrent and/or progressive WHO grade I or grade II glioma without prior exposure to MEK inhibitors.
* To characterize and monitor patient neurocognitive function and quality of life in patients while on study.

Cohort 3: Re-treatment (recurrent and/or progressive disease previously treated with a MEK inhibitor)

Primary Objectives:

* To estimate the 1-year disease stabilization rate (defined as lack of disease progression for ≥ 12 courses of mirdametinib) in patients with recurrent and/or progressive WHO grade I or grade II glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy (cohort 3A).
* To estimate the 6-month disease stabilization rate (defined as lack of disease progression for ≥ 6 courses of mirdametinib) in patients with recurrent and/or progressive WHO grade I or grade II glioma who previously received a MEK inhibitor, other than mirdametinib, and progressed while on active MEKi therapy (cohort 3B).
* To characterize the plasma pharmacokinetics of mirdametinib in children, adolescents, and young adults with low-grade gliomas.
* To describe the toxicity profile of mirdametinib in pediatric patients with recurrent or progressive disease, previously treated with MEK inhibitors.

Secondary Objectives:

* Estimate the efficacy of mirdametinib as measured by PFS and OS in patients with recurrent and/or progressive WHO grade I or grade II glioma previously treated with MEK inhibitors
* To describe treatment responses (Progressive Disease, Stable Disease, Minor Response, Partial Response, Major Response, and Complete Response) observed in patients with recurrent and/or progressive WHO grade I or grade II glioma previously treated with a MEK inhibitor.
* To characterize and monitor patient neurocognitive function and quality of life in patients while on study.

SJ901 will proceed in two phases. Phase 1 will evaluate the safety, tolerability and pharmacokinetics of mirdametinib when dosed continuously up to 3 mg/m\^2/dose twice daily (BID) in patients with progressive or recurrent pLGG without prior MEK inhibitor (MEKi) exposure. This phase will identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) and will contain a small expansion cohort before launching phase 2. Phase 2 will utilize the MTD/RP2D to evaluate mirdametinib efficacy, pharmacokinetics, safety and tolerability in broader cohorts of patients with newly diagnosed or progressive/recurrent pLGG (+/- prior MEK inhibitor exposure).

In Phase 1 of the study, participants with progressive or recurrent pLGG without prior MEKi exposure are eligible and will be enrolled onto a single dose level. The Rolling 6 design will be used to estimate the MTD/RP2D and to determine the dose limiting toxicities (DLTs) of the escalating doses. Once a candidate MTD or RP2D based on 6 subjects has been determined additional evaluable subjects will be enrolled as part of a Phase 1 expansion cohort in order to better describe the safety and tolerability of the MTD/RP2D. The data from all subjects treated at the MTD/RP2D (patients from the dose-finding/dose-escalation study plus expansion cohort) will also be used to assess the stage I efficacy criteria for cohort 2 as part of the Phase 2 design. If these criteria are met, cohort 2 sample size will be expanded beyond the interim analysis and the Phase 2 study will be initiated in cohort 1.

Mirdametinib will be administered twice daily in cycles of 28 days and may be continued for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity. Doses will be based on the BSA calculated before each cycle of therapy. During the DLT period (i.e., cycle 1), all phase 1 participants (including those in the phase 1 expansion cohort) will receive mirdametinib in dispersible tablets only. Thereafter, patients who can swallow capsules may transition to capsules if permitted by their specific dose level.

Once the phase 2 is open to enrollment, participants from the phase 1 on a dose level that differs from the RP2D, may choose to change to the RP2D as long as they have not undergone a dose-reduction for toxicity, and if the treating physician and the patient/family agree it is in the best interest of the patient.

In Phase 2 of the study, participants will be stratified into 3 disease cohorts:

* Cohort 1: Patients with Newly Diagnosed Low-Grade Glioma
* Cohort 2: Patients with Progressive or Recurrent Low-Grade Glioma without Previous MEKi Exposure
* Cohort 3: Patients with Progressive or Recurrent Low-Grade Glioma with Previous MEKi Exposure and:

  * Cohort 3A: Previously received 6 or more cycles of MEKi therapy and did not progress on MEKi therapy
  * Cohort 3B: Previously treated with MEKi, other than mirdametinib, and progressed while on MEKi therapy

Therapy will be administered at RP2D in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity. Patients in Cohort 3 with previous exposure to mirdametinib may receive a starting dose lower than the RP2D, depending on the dose they tolerated during their previous exposure. Phase 2 will utilize both the dispersible tablet and capsule formulations.

SJ901: Evaluation of Mirdametinib in Children, Adolescents, and Young Adults With Low-Grade Glioma

SJ901: Phase 1/2 Evaluation of Single Agent Mirdametinib (PD-0325901), a Brain-Penetrant MEK1/2 Inhibitor, for the Treatment of Children, Adolescents, and Young Adults With Low-Grade Glioma

Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request

The maximum tolerated dose (MTD) is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level determined to be too toxic. The MTD estimate will not be available if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose may be considered as the recommended phase 2 dose (RP2D). The MTD estimation will be limited to evaluable patients and toxicity assessments from course 1 (28 days). We will require that at least 12 DLT evaluable subjects are assessed before the MTD/RP2D is declared.

Incidence of adverse event data at least possibly related to treatment will be summarized in cohort specific tables by grade and attribution throughout treatment.

Mirdametinib plasma concentration will be provided and area under the curve (AUC0-8h) estimated based on course 1, days 1 and 15 PK samples

The response rate, defined as the rate of minor response, partial response (PR), major response, or complete response (CR) will be calculated as the percentage of confirmed responders among all response assessable patients. These rates as well as their exact confidence intervals will be provided and will be summarized by each response category (i.e., PR, major response, and CR). Subjects without an assessment will be considered non-responders.

Rate of stable disease from start of treatment until the time of progression or time of last follow-up.

PFS will be measured using Kaplan Meier approaches from the date of initial treatment to the earliest date of progressive disease, death due to any cause, or date last follow-up.

Minor Response is defined as a 25-49% reduction in target lesion area relative to baseline measurements. Overall, the patient should be clinically stable or have improved on physical examination and functional or neurological assessment. Responses and duration will be measured for each cohort from the date of initial treatment to the earliest date of progressive disease, or data of last follow-up.

Partial Response (PR) is defined as a 50-75% reduction in the target lesion area relative to baseline measurements. Overall, the patient should be clinically stable or have improved on physical examination and functional or neurological assessment. Responses and duration will be measured for each cohort from the date of initial treatment to the earliest date of progressive disease, or data of last follow-up.

Major Response is defined as more than 75% reduction in target lesion area relative to baseline measurements. Overall, the patient should be clinically stable or have improved on physical examination and functional or neurological assessment. Responses and duration will be measured for each cohort from the date of initial treatment to the earliest date of progressive disease, or data of last follow-up.

Complete Response is defined as disappearance of the target lesion and, if applicable, all areas of metastatic disease as compared to reference scan (baseline or best recorded MRI). Overall, the patient should be clinically stable or have improved on physical examination and functional or neurological assessment. Responses and duration will be measured for each cohort from the date of initial treatment to the earliest date of progressive disease, or data of last follow-up.

Stable disease is defined as an increase or decrease in target lesion area that is not sufficient to qualify as progressive or responsive disease (i.e. minor, partial, major, or complete). Overall, the patient should be clinically stable or have improved on physical examination and functional or neurological assessment. Responses and duration will be measured for each cohort from the date of initial treatment to the earliest date of progressive disease, or data of last follow-up.

Progressive Disease is defined as any of the following: A greater than 25% increase in target lesion area relative to reference scan, the development of a new tumor lesion, substantial growth (\>25%) of a measurable metastatic lesion, or worsening of clinical and/or functional assessment directly related to tumor progression. Responses will be measured for each cohort from the date of initial treatment to the earliest date of progressive disease, or data of last follow-up.

To evaluate the effects of mirdametinib treatment on intellectual function among children treated for low-grade glioma. This will be assessed in children 2.6-5.11 years of age using Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV), in children 6-16.11 years of age using the Wechsler Intelligence Scale for Children (WISC-V), and for children 17 years and older using Wechsler Adult Intelligence Scale (WAIS-IV). Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

To evaluate the effects of mirdametinib treatment on attention and executive function in children treated for low-grade glioma. This will be assessed using different instruments as age appropriate: Cogstate will be used to measure attention, working memory and processing speed in children 4 years and older; WPPSI-IV (4-5.11 years of age), WISC-V (6-16.11 years of age) and WAIS-IV (17 years of age and older) will assess brief attention and working memory; Kaufman Test of Educational Achievement, Third Edition (KTEA-3) will assess verbal fluency in children 4-25 years of age; and Behavior Rating Inventory of Executive Function (BRIEF; BRIEF-2) will assess behavioral manifestations of executive function. Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

To evaluate the effects of mirdametinib treatment on memory in children treated for low-grade glioma. This will be assessed using different instruments as age appropriate: California Verbal Learning Test, Children's Version (CVLT-C) will be used to measure verbal list learning in children 6-16.11 years of age; the NEPSY-II Memory for Designs subtest (ages 6-16.11) and Wechsler Memory Scale (WMS-IV, ages 17 and older ) will assess nonverbal memory; the Children's Memory Scale (CMS, ages 5-16.11) and WMS-IV (ages 17 and older) Story Memory subtests will assess immediate recall, delayed recall, and recognition of details. Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

To evaluate the effects of mirdametinib treatment on processing speed in children treated for low-grade glioma. This will be assessed using the age appropriate Wechsler Processing Speed Index \[WPPSI-IV (ages 4-5.11), WISC-V (ages 6-16), and WAIS-IV (ages 17 and older)\]. Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

To evaluate the effects of mirdametinib treatment on academic achievement in children treated for low-grade glioma. Reading and math abilities will be assessed using age-appropriate KTEA-3 subtests: Letter \& Word Recognition (ages 4 and older), Word Recognition Fluency (ages 6 and older), Math Computation (ages 5 and older), and Math Fluency (ages 6 and older). Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

To evaluate the effects of mirdametinib treatment on psychosocial function in children treated for low-grade glioma. Social-emotional measures will include the Behavior Assessment System for Children, Third Edition (BASC-3, ages 2-20.11) to assess behavioral, emotional, and adaptive functioning, as well as the PedsQL (ages 2 and older) to assess health-related quality of life. Scores for each measure will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

To evaluate the effects of mirdametinib treatment on adaptive behavior in children treated for low-grade glioma. This will be assessed using the Adaptive Behavior Assessment System, Third Edition (ABAS-3, ages 2-21.11), which rates the child's ability to independently perform age-appropriate daily living skills. Scores will be summarized by timepoint and cohort using descriptive statistics and appropriate plots.

SpringWorks Therapeutics, Inc.

St. Jude Children's Research Hospital

Medulloblastoma

Infratentorial Neoplasms

Brain Tumor, Childhood

Medulloblastoma, Childhood

Antineoplastic Agents

Antirheumatic Agents

Vasoconstrictor Agents

Respiratory System Agents

Micronutrients

Hematinics

Vitamins

Gemcitabine

Cyclophosphamide

Pemetrexed

Epinephrine

Vincristine

Cisplatin

Racepinephrine

Epinephryl borate

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antimetabolites

Tubulin Modulators

Antimitotic Agents

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Folinic Acid

Folate

Vitamin B9

Participants in stratum W1 will undergo reduced dose Craniospinal Irradiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

Participants in stratum W2 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

Participants in stratum W3 will undergo high dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

Participants in stratum S1 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. After completion of 4 cycles of chemotherapy, participants who are skeletally mature will receive maintenance chemotherapy with vismodegib. Some participants will complete aerobic training and/or neurocognitive remediation.

Participants in stratum S2 will undergo high dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. After completion of 4 cycles of chemotherapy, participants who are skeletally mature will receive maintenance chemotherapy with vismodegib. Some participants will complete aerobic training and/or neurocognitive remediation.

Participants in stratum N1 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive one cycle of chemotherapy (cisplatin, vincristine, cyclophosphamide) once every 4 weeks for 4 cycles in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

Participants in stratum N2 will undergo standard dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive standard chemotherapy (cisplatin, vincristine, cyclophosphamide) for 4 cycles intermixed with an additional 3 cycles of chemotherapy with pemetrexed and gemcitabine in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

Participants in stratum N3 will undergo high dose craniospinal radiation with boost to the primary tumor site once daily 5 days a week for 6 weeks. Six weeks after completion of radiotherapy, patients receive standard chemotherapy (cisplatin, vincristine, cyclophosphamide) for 4 cycles intermixed with an additional 3 cycles of chemotherapy with pemetrexed and gemcitabine in absence of unacceptable toxicity. Some participants will complete aerobic training and/or neurocognitive remediation.

All participants will undergo craniospinal irradiation (CSI) with boost to the primary tumor site. The dose given is based on the molecular and risk group as noted in the arm descriptions. The type of radiation used includes conformal radiation therapy (photons) or intensity modulated radiation therapy (IMRT) or proton beam therapy.

Craniospinal Irradiation with boost to the primary tumor site

Route of Administration (ROA): Intravenously (IV)

Vismodegib

Aerobic Training

Neurocognitive Remediation

Amar Gajjar, MD

Giles Robinson, MD

Historically, medulloblastoma treatment has been determined by the amount of leftover disease present after surgery, also known as clinical risk (standard vs. high risk). Recent studies have shown that medulloblastoma is made up of distinct molecular subgroups which respond differently to treatment. This suggests that clinical risk alone is not adequate to identify actual risk of recurrence. In order to address this, we will stratify medulloblastoma treatment in this phase II clinical trial based on both clinical risk (low, standard, intermediate, or high risk) and molecular subtype (WNT, SHH, or Non-WNT Non-SHH). This stratified clinical and molecular treatment approach will be used to evaluate the following:

* To find out if participants with low-risk WNT tumors can be treated with a lower dose of radiation to the brain and spine, and a lower dose of the chemotherapy drug cyclophosphamide while still achieving the same survival rate as past St. Jude studies with fewer side effects.
* To find out if adding targeted chemotherapy after standard chemotherapy will benefit participants with SHH positive tumors.
* To find out if adding new chemotherapy agents to the standard chemotherapy will improve the outcome for intermediate and high risk Non-WNT Non-SHH tumors.
* To define the cure rate for standard risk Non-WNT Non-SHH tumors treated with reduced dose cyclophosphamide and compare this to participants from the past St. Jude study.

All participants on this study will have surgery to remove as much of the primary tumor as safely possible, radiation therapy, and chemotherapy. The amount of radiation therapy and type of chemotherapy received will be determined by the participant's treatment stratum. Treatment stratum assignment will be based on the tumor's molecular subgroup assignment and clinical risk.

The participant will be assigned to one of three medulloblastoma subgroups determined by analysis of the tumor tissue for tumor biomarkers:

* WNT (Strata W): positive for WNT biomarkers
* SHH (Strata S): positive for SHH biomarkers
* Non-WNT Non-SHH, Failed, or Indeterminate (Strata N): negative for WNT and SHH biomarkers or results are indeterminable

Participants will then be assigned to a clinical risk group (low, standard, intermediate, or high) based on assessment of:

* How much tumor is left after surgery
* If the cancer has spread to other sites outside the brain \[i.e., to the spinal cord or within the fluid surrounding the spinal cord, called cerebrospinal fluid (CSF)\]
* The appearance of the tumor cells under the microscope
* Whether or not there are chromosomal abnormalities in the tumor, and if present, what type (also called cytogenetics analysis)

Primary Objectives:

* To estimate the progression free survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide.
* To estimate progression-free survival distribution of Non-WNT Non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide.
* To estimate the progression free survival distribution of skeletally mature SHH medulloblastoma patients assigned to Stratum S1 and treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after the adjuvant chemotherapy regimen is complete and to compare the outcome to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts.
* To evaluate the effect of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on cardiopulmonary fitness.
* To assess the impact of a computer-based working memory intervention (administered prophylactically at the end of chemotherapy), relative to standard of care, on a performance-based measure of working memory.

Secondary Objectives:

* To estimate overall survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
* To estimate the progression free (in S1 skeletally immature and S2 both sub-strata) and overall survival distributions of SHH medulloblastoma patients enrolled on Strata S1 and S2 some of whom will be treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after adjuvant chemotherapy regimen is complete and compare these outcomes to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts.
* To estimate the progression free and overall survival distributions of Non-WNT Non-SHH medulloblastoma patients treated on Strata N2 and N3 with 3 cycles of pemetrexed and gemcitabine in addition to 4 cycles of conventional adjuvant chemotherapy and compare the progression-free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study separately for each stratum.
* To estimate the overall survival distribution of Non-WNT Non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from St. Jude SJMB03 study.
* To evaluate the feasibility and toxicity of adding pemetrexed and gemcitabine to adjuvant chemotherapy regimen of intermediate and high risk Non-WNT Non-SHH medulloblastoma patients (Strata N2 and N3).
* To evaluate the feasibility and toxicity of oral maintenance therapy with the targeted SHH inhibitor (vismodegib) after conventional adjuvant chemotherapy regimen is complete.
* To estimate the cumulative incidence of local disease failure at 2 and 5 years based on treatment regimen, strata, and clinical and treatment factors.
* To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on physical performance, fatigue, health related quality of life, memory, attention and executive function at the end of the intervention, at the end of adjuvant chemotherapy, and one, two and five years off adjuvant chemotherapy, among children treated for medulloblastoma.
* To evaluate the impact of an aerobic training intervention on sleep quality and quantity in children with medulloblastoma.
* To evaluate the relation between baseline cognitive performance and the variables of sleep quality and quantity, and fatigue in children with medulloblastoma.
* To estimate change in neurocognitive performance using a comprehensive assessment battery (e.g., measures of intellectual function, academic abilities, attention, memory, processing speed and executive functions) and investigate the relationship of change to relevant demographic factors (e.g., gender, age at treatment, time since treatment and socioeconomic status) and clinical factors (e.g., treatment intensity/risk group, posterior fossa syndrome).
* To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measures of attention, processing speed and executive functions.
* To compare the impact of a computer-based working memory intervention in conjunction with an aerobic training intervention, relative to either intervention in isolation, on measures of attention, processing speed and executive functions.
* To evaluate the maintenance of improvements on measures of attention, working memory, processing speed and executive functions six months following participation in the computer-based working memory intervention program.

Outline: This is a multicenter study. Patients are stratified according to molecular subgroup assignment (WNT, SHH, or Non-WNT Non- SHH) and then by clinical risk stratification (extent of resection, M stage, histologic subtype, and cytogenetic features). All patients will be treated with risk-adapted radiation therapy and adjuvant chemotherapy. Patients assigned to Stratum W1 will receive reduced dose radiation therapy. Patients assigned to Stratum W2, S1, N1, or N2 will receive standard dose radiation therapy. Patients assigned to Stratum W3, S2, or N3 will receive high dose radiation therapy. Radiation therapy will be followed by 4 cycles of adjuvant conventional chemotherapy with cyclophosphamide, cisplatin and vincristine for all patients. Patients assigned to Stratum N2 or N3 (Non-WNT Non-SHH with high risk factors) will receive 3 additional cycles of pemetrexed and gemcitabine chemotherapy intermixed into the conventional adjuvant chemotherapy cycles. Patients with SHH subtype (Stratum S1 or S2) who are skeletally mature will receive 12 months additional maintenance therapy with vismodegib.

Patients may consent to provide tumor tissue, blood, and CSF samples for biological studies. Tumor tissues are analyzed for the activation of the WNT signaling pathway, activation of the SHH signaling pathway, validation of novel patterns of gene expression via immunohistochemical (IHC) analysis; validation of genetic abnormalities via interphase fluorescence in situ hybridization (iFISH); construction of gene expression profiles via microarray analysis; construction of DNA methylation profiling via microarrays; single nucleotide polymorphism (SNP) analysis for DNA copy number aberrations; potential oncogenes and tumor suppressor genes via DNA sequence analysis; expression of a number of cell signal proteins implicated in the biology of medulloblastoma via western blot; expression of additional proteins encoded by genes associated through SNP and gene expression array analysis with clinical disease behavior. Blood samples are analyzed from patients whose tumors contain gene mutations via sequence analysis of constitutional DNA. CSF and blood samples are analyzed for identification of potential tumor markers. Parents may consent to have blood samples analyzed for inheritable gene mutations associated with medulloblastoma.

Patients may also consent to exploratory research that include additional functional MRI imaging to investigate damage to neural connections from therapy; additional psychological testing to identify neurocognitive effects of therapy; additional heart and lung testing to identify treatment effects; additional endocrine studies to identify treatment effect on growth and development.

After completion of study treatment, patients are followed every 6 months for 5 years.

A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma

Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact.

Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum S1 skeletally mature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.

To evaluate the effect of an aerobic training intervention on cardiopulmonary fitness.

To assess the impact of a computer-based working memory intervention, relative to standard of care, on a performance-based measure of working memory.

Progression-free survival (PFS) in stratum W1 will be compared to historical controls from SJMB03 using log-rank test.

Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum W1 will be compared to historical controls from SJMB03 using log-rank test.

Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum S1 skeletally immature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.

Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum S2 skeletally mature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.

Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum S2 skeletally immature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.

Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum S1 skeletally mature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.

Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum S1 skeletally immature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.

Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum S2 skeletally mature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.

Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum S2 skeletally immature cohort will be compared to historical controls from SJMB03 as well as from another published cohort (Thompson et al., 2016) using log-rank test.

Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum N2 will be compared to historical controls from SJMB03 using log-rank test.

Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum N2 will be compared to historical controls from SJMB03 using log-rank test.

Progression-free survival (PFS) will be measured from diagnosis to the earliest of disease progression or death from any cause. Patients who have not experienced one of these events will be censored at their last date of contact. PFS in SJMB12 stratum N3 will be compared to historical controls from SJMB03 using log-rank test.

Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum N3 will be compared to historical controls from SJMB03 using log-rank test.

Progression-free survival (PFS) in stratum N1 will be compared to historical controls from SJMB03 using log-rank test.

Overall survival (OS) will be measured from diagnosis to death from any cause. Patients who survive will be censored at their last date of contact. OS in SJMB12 stratum N1 will be compared to historical controls from SJMB03 using log-rank test.

Intermediate and high risk Non-WNT Non-SHH medulloblastoma patients treated on strata N2 and N3 will receive pemetrexed and gemcitabine during adjuvant chemotherapy. Percentage of participants who complete treatment will be estimated and reported with an exact 2-sided 95% confidence interval.

Patients with SHH tumor treated on strata S1 and S2 will receive 12 courses of vismodegib during maintenance therapy. For each risk-based stratum separately, percentage of participants who complete treatment will be estimated and reported with an exact 2-sided 95% confidence interval.

To estimate stratum specific cumulative incidence of local disease failure at 2 and 5 years.

To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on hand grip strength as measured using a hand-held dynamometer among children treated for medulloblastoma. Participants will be seated with the shoulder at 0-10 degrees and the elbow in 90 degrees of flexion. The forearm will be positioned in neutral. Each participant will complete three trials, the average used for analysis.

To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on range of motion as measured with a goniometer among children treated for medulloblastoma. The goniometer is a reliable and valid measure of active and passive range of motion with standard procedures.

To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on overall flexibility among children treated for medulloblastoma. Flexibility will be measured by having participants perform a "sit and reach test." A yardstick is placed on a firm flat surface and tape is placed across it at a right angle to the 15 inch mark. The participant sits with the yardstick between the legs, with legs extended at right angles to the taped line on the floor. The heels of the feet touch the edge of the taped line and are 10-12 inches apart. The participant reaches forward with both hands as far as possible, and the best value for three trials, in centimeters, at the fingertips is recorded.

Measured by the Bruininks-Oseretsky Test of Motor Proficiency, Version 2 (BOT-2). To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on motor proficiency among children treated for medulloblastoma.

To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy on health related quality of life (QoL) among children treated for medulloblastoma. QoL will be assessed using the 23-item PedsQL(TM) 4.0 Generic Core Scales which encompasses four subscales (1) physical functioning (eight items), (2) emotional functioning (five items), (3) social functioning (five items), and (4) school functioning (five items) and the 24-item PedsQL(TM) Brain Tumor Module which encompasses six scales: (1) cognitive problems (seven items), (2) pain and hurt (three items), (3) movement and balance (three items), (4) procedural anxiety (three items), (5) nausea (five items), and (6) worry (three items).

To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on fatigue among children treated for medulloblastoma. Fatigue will be assessed using the 18-item PedsQL(TM) Multidimensional Fatigue Scale which encompasses three subscales: (1) general fatigue (six items), (2) sleep/rest fatigue (six items), and (3) cognitive fatigue (six items).

To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on memory function at the end of the intervention and at the end of adjuvant chemotherapy, among children treated for medulloblastoma. Memory will be measured using different instruments as age appropriate: CogStage for age 5 and older (Continuous Paired Associate Learning task), California Verbal Learning Test, Children's Version (CVLT-C) for age 6 to \< 17 years or California Verbal Learning Test, Second Edition (CVLT-II) for age ≥17 years.

To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on attention at the end of the intervention and at the end of adjuvant chemotherapy, among children treated for medulloblastoma. Attention will be measured using different instruments as age appropriate: Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for ages 3 to \< 6 years (Digit Span Forward subtest), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for ages 6 to \< 17 years (Digit Span Forward subtest) or Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for ages ≥17 years (Digit Span Forward subtest). We will also use Conners' Continuous Performance Test, Kiddie Version V.5 for ages 4 to \< 6 years and Conner's Continuous Performance Test, Second Edition (CPT-II) for ages ≥6 years, in addition to Cog Stage for children ≥5 years (Detection and Identification tasks).

To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on executive function at the end of the intervention and at the end of adjuvant chemotherapy, among children treated for medulloblastoma. Executive function is measured as age-appropriate by the following: BRIEF-P (age 3 to \<6 years), BRIEF (age 6 to \<19 years) and BREIF-A (age ≥19 years). Connor's Parent Rating Scale, Third Edition (CPRS-III) will also be used for age 6 to \<19 years, as well as CogState One-Back and Groton Maze tasks for age ≥5 years.

To evaluate the impact of an aerobic training intervention on sleep quality and quantity in children with medulloblastoma. Sleep quality and quantity will be measured by Actigraph accelerometer as well as a sleep diary.

To evaluate the relation between baseline cognitive performance and sleep quality in children with medulloblastoma. Multivariable general linear mixed models will be used to look for associations between sleep quality as measured by Actigraph accelerometer and a sleep diary with measures of cognitive performance (memory, attention and executive function (detailed above) and internalizing and externalizing behavior. Internalizing and externalizing behaviors will be measured using the Behavior Assessment System for Children, 2nd Edition (BASC-2). There are Preschool, Child and Adolescent versions.

To evaluate the relation between baseline cognitive performance and sleep quantity in children with medulloblastoma. Multivariable general linear mixed models will be used to look for associations between sleep quantity as measured by a sleep diary with measures of cognitive performance (memory, attention and executive function and internalizing and externalizing behavior (detailed above).

To evaluate the relation between baseline cognitive performance and fatigue in children with medulloblastoma. Multivariable general linear mixed models will be used to look for associations between fatigue score as measured by the Multidimensional Fatigue Scale with measures of cognitive performance (memory, attention and executive function and internalizing and externalizing behavior (detailed above).

Intellectual function will be measured as age-appropriate using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for age 3 to \< 6 years, Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for age 6 to \< 17 years, and Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for age ≥17 years. Linear mixed-effects models will be used to model change in intellectual function over time.

Intellectual function will be measured as age-appropriate using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for age 3 to \< 6 years, Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for age 6 to \< 17 years, and Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for age ≥17 years. Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in intellectual function with demographic and clinical factors.

Academic ability will be measured using the Woodcock Johnson Tests of Academic Achievement-Third Edition (WJ-III-ACH) which has six subsets: Letter-Word Identification, Passage Comprehension, Reading Fluency, Calculation, Applied Problems, and Math Fluency. Academic ability will also be measured using the Comprehensive Test of Phonological Processing (CTOPP) which has three subsets: Elision, Blending Words, and Rapid Naming. Linear mixed-effects models will be used to model change in academic ability over time.

Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in academic ability (measured as described above) with demographic and clinical factors.

Attention will be measured using different instruments as age appropriate: Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for ages 3 to \< 6 years old (Digit Span Forward subtest), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for ages 6 to \< 17 years (Digit Span Forward subtest) or Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for ages ≥17 years (Digit Span Forward subtest). We will also use Conners' Continuous Performance Test, Kiddie Version V.5 for ages 4 to \< 6 years and Conner's Continuous Performance Test, Second Edition (CPT-II) for ages ≥6 years, in addition to Cog Stage for children ≥5 years (Detection and Identification tasks). Linear mixed-effects models will be used to model change in the measure of attention over time.

Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in attention (measured as described above) with demographic and clinical factors.

Memory will be measured using different instruments as age appropriate: CogStage for age 5 and older (Continuous Paired Associate Learning task), California Verbal Learning Test, Children's Version (CVLT-C) for age 6 to \< 17 years or California Verbal Learning Test, Second Edition (CVLT-II) for age ≥17 years. Linear mixed-effects models will be used to model change in memory over time.

Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in memory (measured as described above) with demographic and clinical factors.

Cognitive processing speed function will be measured using the age-appropriate processing speed indices: WPPSI-IV which has two subsets: Bug Search and Cancellation, for age 3 to \< 6 years old; WISC-IV which has two subsets: Coding and Symbol Search subtests, for 6 to \< 17 years, and WAIS-IV which has two subsets: Coding and Symbol Search subtests, for age ≥17 years. Linear mixed-effects models will be used to model change in cognitive processing speed over time.

Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in cognitive processing speed (measured as described above) with demographic and clinical factors.

Neurocognitive executive function will be measured using the Behavioral rating inventory of executive function (BRIEF). There are age-appropriate versions: BRIEF-P for age 3 to \< 6 years, BRIEF for age 6 to \<19 years, and BRIEF-A for age ≥19 years. Executive function will also be measured using Conner's Parent Rating Scale, Third Edition (CPRS-III), for age 6 to \< 19 years and also CogState, for age ≥5 years, One-Back and Groton Maze tasks. Linear mixed-effects models will be used to model change in executive function over time.

Linear mixed-effects models and multivariate linear mixed-effects models will be used to examine change in executive function (measured as described above) with demographic and clinical factors.

To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measure of attention. Attention will be measured using different instruments as age appropriate: Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for ages 3 to \< 6 years (Digit Span Forward subtest), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for ages 6 to \< 17 years (Digit Span Forward subtest) or Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for ages ≥17 years (Digit Span Forward subtest). We will also use Conners' Continuous Performance Test, Kiddie Version V.5 for ages 4 to \< 6 years and Conner's Continuous Performance Test, Second Edition (CPT-II) for ages ≥6 years, in addition to Cog Stage for children ≥5 years (Detection and Identification tasks). T tests will be used to compare changes in attention between the intervention and standard of care groups.

To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measure of processing speed. Cognitive processing speed function will be measured using the age-appropriate processing speed indices: WPPSI-IV which has two subsets: Bug Search and Cancellation, for age 3 to \< 6 years; WISC-IV which has two subsets: Coding and Symbol Search subtests, for 6 to \< 17 years, and WAIS-IV which has two subsets: Coding and Symbol Search subtests, for age ≥17 years. T tests will be used to compare changes in processing speed between the intervention and standard of care groups.

To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measure of executive function. Executive function is measured as age-appropriate by the following: BRIEF-P (age 3 to \<6 years), BRIEF (age 6 to \<19 years) and BREIF-A (age ≥19 years). Connor's Parent Rating Scale, Third Edition (CPRS-III) will also be used for age 6 to \<19 years, as well as CogState One-Back and Groton Maze tasks for age ≥5 years. T tests will be used to compare changes in executive function between the intervention and standard of care groups.

Working memory intervention baseline=7-10 months after on treatment. Physical exercise intervention baseline=at patient enrollment. Attention will be measured using different instruments as age appropriate: Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for 3 to \< 6 years (Digit Span Forward subtest), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for 6 to \< 17 years (Digit Span Forward subtest) or Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for ≥17 years (Digit Span Forward subtest). We will also use Conners' Continuous Performance Test, Kiddie Version V.5 for 4 to \< 6 years and Conner's Continuous Performance Test, Second Edition (CPT-II) for ≥6 years, in addition to Cog Stage for children ≥5 years (Detection and Identification tasks). ANOVA will be used to compare changes in memory among the groups. In addition, T-tests will be used to compare the combined intervention group to each of the other two groups.

Working memory intervention baseline=7-10 months after on treatment. Physical exercise intervention baseline=at patient enrollment. Cognitive processing speed function will be measured using the age-appropriate processing speed indices: WPPSI-IV which has two subsets: Bug Search and Cancellation, for 3 to \< 6 years; WISC-IV which has two subsets: Coding and Symbol Search subtests, for 6 to \< 17 years, and WAIS-IV which has two subsets: Coding and Symbol Search subtests, for ≥17 years. ANOVA will be used to compare changes in processing speed among the groups. In addition, T-tests will be used to compare the combined intervention group to each of the other two groups.

Working memory intervention baseline=7-10 months after on treatment. Physical exercise intervention baseline=at patient enrollment. Executive function is measured as age-appropriate by the following: BRIEF-P (3 to \<6 years), BRIEF (6 to \<19 years) and BREIF-A (≥19 years). Connor's Parent Rating Scale, Third Edition (CPRS-III) will also be used for 6 to \<19 years, as well as CogState One-Back and Groton Maze tasks for ≥5 years. ANOVA will be used to compare changes in executive function among the groups. In addition, T-tests will be used to compare the combined intervention group to each of the other two groups.

Attention will be measured using different instruments as age appropriate: Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) for 3 to \< 6 years (Digit Span Forward subtest), Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for 6 to \< 17 years (Digit Span Forward subtest) or Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for ≥17 years (Digit Span Forward subtest). We will also use Conners' Continuous Performance Test, Kiddie Version V.5 for 4 to \< 6 years and Conner's Continuous Performance Test, Second Edition (CPT-II) for ≥6 years, in addition to Cog Stage for ≥5 years (Detection and Identification tasks). Differences between 6 months following assessment and immediate post-intervention testing, and difference between 6 months following assessment and pre-intervention testing, will be calculated for each subject and then group difference (intervention group vs. control group) will be examined using t-tests.

To evaluate the maintenance of improvements in working memory three months following participation in the computer-based working memory intervention program. Memory will be measured using different instruments as age appropriate: CogStage for ≥5 years (Continuous Paired Associate Learning task), California Verbal Learning Test, Children's Version (CVLT-C) for 6 to \< 17 years or California Verbal Learning Test, Second Edition (CVLT-II) for ≥17 years. The differences between six months following assessment and immediate post-intervention testing, as well as the difference between six months following assessment and pre-intervention testing, will be calculated for each subject and then the group difference (intervention group vs. control group) will be examined using t-tests.

To evaluate the maintenance of improvements on processing speed three months following participation in the computer-based working memory intervention program. Cognitive processing speed function will be measured using the age-appropriate processing speed indices: WPPSI-IV which has two subsets: Bug Search and Cancellation, for 3 to \< 6 years; WISC-IV which has two subsets: Coding and Symbol Search subtests, for 6 to \< 17 years, and WAIS-IV which has two subsets: Coding and Symbol Search subtests, for ≥17 years. The differences between six months following assessment and immediate post-intervention testing, as well as the difference between six months following assessment and pre-intervention testing, will be calculated for each subject and then the group difference (intervention group vs. control group) will be examined using t-tests.

To evaluate the maintenance of improvements in executive function three months following participation in the computer-based working memory intervention program. Executive function is measured as age-appropriate by the following: BRIEF-P (3 to \<6 years), BRIEF (6 to \<19 years) and BREIF-A (≥19 years). Connor's Parent Rating Scale, Third Edition (CPRS-III) will also be used for 6 to \<19 years, as well as CogState One-Back and Groton Maze tasks for ≥5 years. The differences between six months following assessment and immediate post-intervention testing, as well as the difference between six months following assessment and pre-intervention testing, will be calculated for each subject and then the group difference (intervention group vs. control group) will be examined using t-tests.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cardiovascular Disorders and Risk Factors in Childhood Cranial and Craniospinal Tumors Survivors	NCT05641636	Tumors of the C... Childhood Cance...	12-lead ECG, ho...	16 Years - 40 Years	I.M. Sechenov First Moscow State Medical University
SJ901: Evaluation of Mirdametinib in Children, Adolescents, and Young Adults With Low-Grade Glioma	NCT04923126	Low-Grade Gliom... Recurrent Low-G... Progressive Low...	Mirdametinib	2 Years - 24 Years	St. Jude Children's Research Hospital
A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma	NCT01878617	Medulloblastoma	Craniospinal Ir... Cyclophosphamid... Cisplatin Vincristine Vismodegib Pemetrexed Gemcitabine Aerobic Trainin... Neurocognitive ...	3 Years - 39 Years	St. Jude Children's Research Hospital
A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma	NCT01878617	Medulloblastoma	Craniospinal Ir... Cyclophosphamid... Cisplatin Vincristine Vismodegib Pemetrexed Gemcitabine Aerobic Trainin... Neurocognitive ...	3 Years - 39 Years	St. Jude Children's Research Hospital
Cardiovascular Disorders and Risk Factors in Childhood Cranial and Craniospinal Tumors Survivors	NCT05641636	Tumors of the C... Childhood Cance...	12-lead ECG, ho...	16 Years - 40 Years	I.M. Sechenov First Moscow State Medical University

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