Molecular and Clinical Risk Directed Therapy for Infants and Young Children with Newly Diagnosed Medulloblastoma
This phase II trial tests the effect of using tumor molecular groups and subgroups to guide treatment in infants and young children with newly diagnosed medulloblastoma. Medulloblastoma in children is a fast-growing tumor. This tumor can spread into the fluid that surrounds the brain and spinal cord (cerebrospinal fluid or CSF). In older children, surgery followed by high doses of radiation therapy and chemotherapy are usually given to the brain and spine to prevent the tumor from spreading. However, radiation therapy to the developing brain and spine of infants and young children may cause permanent problems with thinking, learning, and growing. In these infants and young children, researchers would like to postpone or avoid using radiation therapy if possible. Anti-cancer drugs (chemotherapy) have been used to kill brain tumor cells in patients. Chemotherapy allows the brain more time to develop before the radiation is given, or, in some cases, it may prevent radiation from being needed at all for treatment. Research studies from the last twenty years have shown that a fraction of medulloblastoma cases may be cured by just chemotherapy, allowing avoidance of radiation, and thus protecting developing brains from problems with thinking and learning. In this study researchers will use molecular groups and subgroups of medulloblastoma to differentiate between medulloblastoma patients who are more likely to respond to just chemotherapy from those who need radiation. In this study, a new method for diagnosing specific molecular groups and subgroups of medulloblastoma based on biological features of the tumor will be used. The method is called “methylation”, which detects molecular patterns (marks) on deoxyribonucleic acid (DNA) of the cells from the tumor. Different groups and subgroups of medulloblastoma will be identified based on their unique molecular patterns. Treatment will then be guided based on the tumor group and subgroup. The main goal of this study is to determine whether using tumor molecular group and subgroup to guide treatment intensity results in improved treatment efficacy while limiting long-term treatment-related problems in infants and young children.
Inclusion Criteria
- SCREENING PHASE INCLUSION CRITERIA (ALL PATIENTS)
- Participants with presumptive/suspected newly diagnosed medulloblastoma
- Participant meets one of the following criteria at the time of screening: * Age < 36 months or * Age >= 36 months and < 60 months with presumptive/suspected non-metastatic disease
- Participant must have adequate tumor tissue from primary tumor for central review of pathology and molecular classification by methylation and immunohistochemistry (IHC)
- Participant must be able to begin treatment as outlined in the protocol within 36 days of definitive surgery (day of surgery is Day 0). In case a second surgery is clinically indicated to remove the residual tumor prior to starting treatment, the second surgery will be considered as the definitive surgery (Day 0)
- Parent or legal guardian can understand and is willing to sign a written informed consent document according to institutional guidelines
- STUDY ENROLLMENT (ALL PATIENTS)
- Participant must be < 60 months of age at time of enrollment * Note: Each treatment stratum has additional specific age requirements
- Participant must have confirmation of newly diagnosed medulloblastoma per central review * Central review includes histopathology, IHC and St. Jude Clinical Genomic Methylation Profiling conducted on MLPNet. If tissue or the extracted DNA does not meet quality control criteria for methylation analysis or if methylation classifier is unable assign molecular group/subgroup within the assigned classifier (MLPNet) parameters, then IHC will be used to define molecular group of these cases. IHC cannot be used to determine molecular subgroup. Therefore, IHC defined SHH patients will be enrolled on Stratum S-1 under "SHH-NOS", and all Non-WNT non-SHH medulloblastoma (NWNS) and indeterminate molecular group will be enrolled on stratum N * Note: Diagnosis of medulloblastoma, as well as group and subgroup assignment, will be done by central pathology review at St. Jude only. No outside testing is allowed for trial enrollment
- Participant must have disease staged by MRI of the brain and spine and by cytologic examination of CSF and be placed into the following categories: * M0: no evidence of metastatic disease. ** Must include a negative CSF cytology result * M1: Tumor cells found in the CSF but no other evidence of metastasis * M2: Intracranial tumor beyond the primary tumor site * M3: Metastatic disease in the spine * M4: Extraneural metastatic disease * All participants are to undergo CSF cytologic examination regardless of presence or absence of gross metastatic disease unless procedure is medically contraindicated. CSF is to be obtained by lumbar puncture (LP) performed at least 10 days after surgery. If LP is medically contraindicated, ventricular CSF from a shunt or Ommaya reservoir may be used for staging but this is not the preferred option due to lower sensitivity. If LP is medically contraindicated and the patient doesn’t have a shunt or reservoir for CSF sampling, the treating physician should reach out to principal investigator (PI) or Co-PI regarding decision on enrollment to SJiMB21. The decision to enroll without CSF cytology will be made on case-by-case basis ** Note: Participants who have M2 disease and positive CSF will be assigned to M3 ** Note: Participants will be assigned to the highest stage number for which they meet eligibility ** Note: Treatment stratums may have additional stage requirements
- Patient must have received no previous radiotherapy, chemotherapy, or other brain tumor-directed therapy other than corticosteroid therapy and surgery
- Participant must have a Lansky performance score of >= 30 (except for patients with posterior fossa syndrome
- Absolute neutrophil counts (ANC) > 750/mm^3
- Platelet count >= 50,000/mm^3 without support of a platelet transfusion within 7 days
- Hemoglobin >= 8.0 g/dL (with or without support of a blood transfusion)
- Normal liver function as defined by alanine aminotransferase (ALT) concentration <= 3 x 45 U/L and total bilirubin =< 3 x 1.0
- Maximum Serum Creatinine Based on patient age * Age 0 to < 1 year: maximum serum creatinine 0.5 mg/dl; (male); 0.5 mg/dl (female) * Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dl; (male); 0.6 mg/dl (female) * Age 2 to 5 years: maximum serum creatinine 0.8 mg/dl; (male); 0.8 mg/dl (female)
- Participant’s parent or legal guardian has the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines
- STRATUM S-2
- Participant must have confirmed diagnosis of the following medulloblastoma molecular group and subgroup per central review * Medulloblastoma SHH-2
- Participant must meet one of the following criteria at time of enrollment: * Age < 36 months or * Age >= 36 months and < 60 months with non-metastatic disease (M0)
- STRATUM S-1
- Participant must have confirmed diagnosis of one of the following medulloblastoma molecular subgroups per central review * Medulloblastoma SHH-1 * Medulloblastoma SHH-3 * Medulloblastoma SHH-4 * Medulloblastoma SHH-NOS ** Includes medulloblastoma cases that could not be assigned to a molecular subgroup using the DNA methylation classifier, but which are in the SHH group and/or cases defined as SHH by IHC
- Participant must be < 36 months of age at time of enrollment * Note: Patients who are < 36 months of age, regardless of metastatic status (M0/M+), are eligible for enrollment on stratum S-1
- STRATUM N
- Participant must have confirmed diagnosis of one of the following medulloblastoma molecular subgroups per central review * Medulloblastoma G3 * Medulloblastoma G4 * Medulloblastoma – Not classified into SHH (i.e., NWNS or indeterminate) ** Includes medulloblastoma cases that could not be assigned to a molecular group using the DNA methylation classifier but which are in the NWNS class and/or defined as NWNS by IHC
- Participant must be < 36 months of age at time of enrollment
- All NWNS patients (M+ and M0) are eligible for enrollment in stratum N
- STRATUM P
- Biological parent(s) of participant (child) enrolling on SJiMB21. These parents will be assigned to Stratum P. The exclusion criteria below do not apply to this stratum
Exclusion Criteria
- SCREENING PHASE EXCLUSION CRITERIA (ALL PATIENTS)
- Participants with other clinically significant medical disorders (i.e., serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with the study procedure
- EXCLUSION (ALL PATIENTS)
- CNS embryonal tumor other than medulloblastoma, for example, patients with diagnosis of atypical teratoid/rhabdoid tumor (ATRT), primitive neuroectodermal tumor (PNET), pineoblastoma, ependymoma, and embryonal tumor with multilayered rosettes (ETMR) are excluded
- Participant with prior treatment for medulloblastoma, including: * Radiotherapy * Chemotherapy * Cancer directed immunotherapy * Targeted agents NOTE: Corticosteroid therapy is acceptable; prior treatment with chemotherapy, immunotherapy or targeted agents for non-cancer directed indications are acceptable as long as these have been stopped at least 14 days prior to start of therapy or 2 half-lives from last dose. (i .e., methotrexate for JAK inhibitor therapy for eczema, etc.)
- Participant who is actively receiving any other investigational agents
- Participant with other clinically significant medical disorder s (i.e., serious infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ dysfunction) that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results
Additional locations may be listed on ClinicalTrials.gov for NCT05535166.
Locations matching your search criteria
United States
California
Palo Alto
Florida
Orlando
Tampa
Michigan
Ann Arbor
Minnesota
Minneapolis
Tennessee
Memphis
Texas
Dallas
Fort Worth
Houston
Utah
Salt Lake City
PRIMARY OBJECTIVES:
I. To estimate the progression free survival of SHH-2 infant (0-2.99 years) and young child (3-4.99 years) medulloblastoma patients treated with systemic high dose methotrexate (HD-MTX) based chemotherapy only.
II. To estimate the progression free survival of SHH-1 infant (0-2.99 years) medulloblastoma patients treated with systemic HD-MTX based chemotherapy augmented with intraventricular (IVT)-MTX.
III. To estimate the progression free survival of medulloblastoma, group 3 (G3)/ group 4 (G4) infant (0-2.99 years) medulloblastoma patients treated with systemic chemotherapy and delayed risk-adapted craniospinal irradiation (CSI) augmented with carboplatin.
IV. To compare cognitive outcomes among infants (0-2.99 years) and young children (3-4.99 years) treated with systemic chemotherapy only to patients treated with systemic chemotherapy and intra-ventricular chemotherapy or delayed risk-adapted craniospinal irradiation.
SECONDARY OBJECTIVES:
I. To investigate change in neurocognitive performance among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma, and examine the impact of demographic factors (e.g., age at treatment, gender, and socioeconomic status), disease-related factors (e.g., presence of hydrocephalus, posterior fossa syndrome) and variants of proposed treatment regimen (e.g., systemic chemotherapy with or without IVT-MTX, radiation dosimetry to key brain structures, treatment-related ototoxicity) on cognitive late effects.
II. To investigate which familial factors (e.g., family cohesion, family coping with medical management, parent-child interaction style) and environmental factors (e.g., parental verbal abilities, home literacy, adherence with rehabilitative therapies, participation in early intervention, school advocacy) associate with socioeconomic status and examine the impact of these factors on cognitive late effects.
III. To evaluate the feasibility and acceptability of a caregiver education program paired with interactive neurodevelopmental games used to improve parent-child interactions, cognitive and social-emotional functioning in infants undergoing treatment for medulloblastoma.
IV. To estimate the magnitude of change in parent-child interactions following participation in a caregiver education paired with interactive neurodevelopmental games.
V. To estimate the magnitude of change in cognition and social-emotional development associated with a caregiver education program combined with interactive neurodevelopmental games.
VI. To determine the extent of inter-and intra-patient variability in the plasma pharmacokinetics of high-dose systemic methotrexate, cyclophosphamide, vincristine, and topotecan in infants and young children with medulloblastoma, to assess potential covariates to explain this variability, and to explore associations between clinical effects and methotrexate, cyclophosphamide, vincristine, and topotecan pharmacokinetics.
VII. To determine the extent of inter- and intra-patient pharmacokinetic variability of methotrexate in ventricular cerebrospinal fluid (CSF) after intraventricular methotrexate dose administration in infants with medulloblastoma, and to explore associations between methotrexate CSF pharmacokinetics and clinical effects.
EXPLORATORY OBJECTIVES:
I. To estimate the relationship of specific tumor molecular abnormalities (mutation, amplification, deletion, mutation burden, mutation signatures, methylation, expression, transcription) acquired from genome wide analysis (exome/genome/methylome /transcriptome /proteome) on fresh frozen or formalin fixed paraffin embedded (FFPE) tissue on outcome and therapeutic response.
II. To identify and define genes and germ line DNA methylation patterns associated with hereditary cancer predisposition in patients and their parents to provide evidence for future germline screening guidelines.
III. To explore the clinical utility of serial CSF and plasma-derived circulating cell free DNA (cfDNA) profiling for detection of minimal residual disease in a prospective cohort of infant and young child medulloblastoma (MB).
IV. To assess the relationship between the pharmacogenetic variation in drug-metabolizing enzymes or drug transporters and the pharmacokinetics of methotrexate, cyclophosphamide, vincristine, and topotecan in infants and young children with medulloblastoma.
V. To explore the associations between pharmacogenetic variation in gene for CEP72 genotypes and neurotoxicity in infants and young children with medulloblastoma.
VI. To explore the clinical impact of increased frequency of audiology evaluations in infants and young children with medulloblastoma carrying ACYP2 single nucleotide polymorphism (SNP) rs1872328, including those that are either homozygous or heterozygous for this SNP.
VII. To investigate hearing aid use and barriers to hearing aid uptake among infants and young children treated for medulloblastoma diagnosed with significant unilateral or bilateral hearing loss warranting the recommendation of a hearing aid(s), and examine the impact of demographic factors (e.g., age at hearing loss diagnosis, socioeconomic status, sex) and severity of hearing loss (i.e., International Society of Paediatric Oncology (SIOP) ototoxicity grade 2, 3, or 4) on hearing aid use.
VIII. To compare auditory development and functional performance by parent-report questionnaires in children with consistent hearing aid use versus children with reduced hearing aid use.
IX. To compare speech and language development in children with consistent hearing aid use versus children with reduced hearing aid use.
X. To examine the association of hearing aid use with long-term neurocognitive performance.
XI. To explore the feasibility of using machine learning to quantify metastatic disease burden in the brain and spine, monitor and quantify longitudinal changes and evaluate the relationship to clinical outcomes.
XII. To use artificial intelligence/machine learning techniques to differentiate active versus (vs). “treated tumor” (in a way that is translatable to the reading room).
XIII. To study incidence, symptoms, and risk factors for postoperative posterior fossa syndrome and its recovery in infants and young children with medulloblastoma.
XIV. To study long-term neurologic and development outcome of children with posterior fossa syndrome.
XV. To explore neurologic symptoms before diagnosis to identify factors that contribute to delayed diagnosis.
XVI. To study long-term neuroendocrine and growth-related outcomes, including longitudinal changes in growth hormone secretion, in infants and young children with medulloblastoma treated with clinical risk-directed therapy.
XVII. To correlate radiation dosimetry of tumor and normal tissues with disease control (local and/or distant tumor progression; survival outcomes) and longitudinal measures (audiologic, endocrine and cognitive outcomes) and explore the association of radiation technique (i.e ., three-dimensional conformal radiation therapy [3DCRT], volumetric modulated arc therapy [VMAT]), radiation quality (i.e., photon, proton), and receipt of carboplatin with these outcomes.
XVIII. To estimate the cumulative incidence of radiation necrosis and explore the association of radiation dosimetry, radiation technique (i.e., 3DCRT, VMAT), radiation quality (i.e., photon, proton), and receipt of carboplatin with this outcome.
XIX. To explore the relationship of specific tumor molecular abnormalities (mutation, amplification, deletion, methylation, expression, transcription) acquired from genome wide analysis (exome/genome/methylome /transcriptome/proteome) on patterns of disease progression in the context of composite radiation dosimetry.
OUTLINE: Patients are assigned to 1 of 3 strata.
STRATUM S-1: This stratum enrolls patients with SHH-1, SHH-3, SHH-4, or SHH-NOS medulloblastoma (0 to < 3 years of age).
* COURSE A: Patients receive methotrexate intravenously (IV), methotrexate intraventricularly (IVT), cisplatin IV, vincristine IV, and cyclophosphamide IV throughout A courses.
* COURSE B: Patients receive methotrexate IV, methotrexate IVT, carboplatin IV, vincristine IV, and cyclophosphamide IV throughout B courses.
* COURSE C: Patients receive topotecan IV and cyclophosphamide IV throughout C courses.
* Patients also undergo magnetic resonance imaging (MRI) and echocardiography (ECHO) scans throughout the trial.
STRATUM S-2: This stratum enrolls patients with SHH-2 medulloblastoma (0 to < 3 years of age, or without evidence of metastatic disease and 3 to < 5 years of age)
* COURSE A: Patients receive methotrexate IV, cisplatin IV, vincristine IV, and cyclophosphamide IV throughout A courses.
* COURSE B: Patients receive methotrexate IV, carboplatin IV, vincristine IV, and cyclophosphamide IV throughout B courses.
* COURSE C: Patients receive topotecan IV and cyclophosphamide IV throughout C courses.
* Patients also undergo MRI and ECHO scans throughout the trial.
STRATUM N: This stratum enrolls patients with medulloblastoma, G3, G4, or NWNS (0 to < 3 years of age).
* CHEMOTHERAPY PHASE:
** COURSE A: Patients receive methotrexate IV, cisplatin IV, vincristine IV, and cyclophosphamide IV throughout A courses.
** COURSE B: Patients receive methotrexate, carboplatin IV, vincristine IV, and cyclophosphamide IV throughout B courses.
** COURSE C: Patients receive topotecan IV and cyclophosphamide IV throughout C courses.
** COURSE D: Patients receive carboplatin IV, etoposide IV, and cyclophosphamide IV throughout D courses.
** COURSE E (NOTE: Begins AFTER completion of Radiation Phase): Patients who are 34-36 months of age at baseline/study enrollment receive cisplatin IV, vincristine IV, and cyclophosphamide IV throughout E courses.
* RADIATION PHASE: Patients are assigned to 1 of 3 sub-strata.
** STRATUM N-1: Patients without evidence of metastatic disease at baseline/study enrollment and with an adequate response after Chemotherapy Phase receive low-dose CSI throughout the Radiation Phase. Patients who completed fewer than 4 courses of treatment during the Chemotherapy Phase also receive carboplatin IV throughout the Radiation Phase.
** STRATUM N-2: Patients with evidence of metastatic disease at baseline/study enrollment, but, in the opinion of the study doctor, have shown an adequate response after Chemotherapy Phase receive intermediate-dose CSI throughout the Radiation Phase. Patients who completed fewer than 4 courses of treatment during the Chemotherapy Phase also receive carboplatin IV throughout the Radiation Phase.
** STRATUM N-3: Patients with evidence of metastatic disease and have not shown adequate response after Chemotherapy Phase receive standard-dose CSI throughout the Radiation Phase. All patients with MYC-amplification regardless of metastatic status at baseline/study enrollment also receive standard-dose CSI throughout the Radiation Phase. Patients who completed fewer than 4 courses of treatment during the Chemotherapy Phase also receive carboplatin IV throughout the Radiation Phase.
* Patients also undergo MRI and ECHO scans throughout the trial.
OPTIONAL COGNITIVE STUDY: Patients and their caregivers are randomized to 1 of 2 groups.
GROUP I: Participants watch a 75-minute caregiver education video program and receive access to interactive games on a smartphone or tablet throughout the optional cognitive study.
GROUP II: Standard-of-care treatment during main cognitive study. After the one-year serial cognitive evaluation, participants will be offered participation in the cognitive study group I intervention.
After completion of study treatment, patients are followed periodically for 7 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSaint Jude Children's Research Hospital
Principal InvestigatorGiles W. Robinson
- Primary IDSJiMB21
- Secondary IDsNCI-2022-07099
- ClinicalTrials.gov IDNCT05535166