Molecular and Clinical Risk-Directed Therapy for Infants and Young Children With Newly Diagnosed Medulloblastoma

SJiMB21: Phase 2 Study of Molecular and Clinical Risk-Directed Therapy for Infants and Young Children With Newly Diagnosed Medulloblastoma

This is a multi-center, multinational phase 2 trial that aims to explore the use of molecular and clinical risk-directed therapy in treatment of children 0-4.99 years of age with newly diagnosed medulloblastoma.

The objectives of this study are:

Primary Objectives

• 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 HD-MTX- based chemotherapy only.
• 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 IVT-MTX.
• To estimate the progression free survival of G3/G4 infant (0-2.99 years) medulloblastoma patients treated with systemic chemotherapy and delayed risk- adapted CSI augmented with carboplatin.
• 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

• 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.
• 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.
• 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. (funded by NCI via the R21CA280187)
• To estimate the magnitude of change in parent-child interactions following participation in a caregiver education paired with interactive neurodevelopmental games. (funded by NCI via the R21CA280187)
• To estimate the magnitude of change in cognition and social-emotional development associated with a caregiver education program combined with interactive neurodevelopmental games. (funded by NCI via the R21CA280187)
• 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.
• To determine the extent of inter- and intra-patient pharmacokinetic variability of methotrexate in ventricular CSF after intraventricular methotrexate dose administration in infants with medulloblastoma, and to explore associations between methotrexate CSF pharmacokinetics and clinical effects.

All participants enrolled will be treated with systemic chemotherapy post-surgical resection of the tumor. Participants will be assigned to treatment strata based first on tumor molecular group and subgroup assignment [SHH (including SHH-1, SHH-2, SHH-3, SHH-4 and SHH-NOS), G3, G4, (including NWNS NOS, or indeterminate cases] and then by clinical risk stratification (age and metastatic state).

Infants and young children on Stratum S-2 and infants on Stratum S-1 will be treated with chemotherapy-only strategies.

• Stratum S-2:

Patients on S-2 will receive 8 courses of chemotherapy consisting of:

• 4 Course A (A1A2A3A4)
• 2 Course B (B1B2)
• 2 Course C (C1C2) Courses repeat every 28 days/4 weeks.
• Stratum S-1:

Patients on S-1 will receive the same systemic chemotherapy regimen as S-2, with the addition of intraventricular (IVT)- MTX, administered via Ommaya reservoir, with each systemic MTX infusion. Each S-1 patient is scheduled to receive 12 doses of IVT-MTX. Each patient on S-1 will also receive 8 courses of combination chemotherapy. (4 Course A with IVT, 2 Course B with IVT and 2 Course C). Courses repeat every 28 days/4 weeks.

• Stratum N:

Stratum N participants will be treated with post-surgery chemotherapy until 36-months-of age followed by radiation CSI with Boost. There is no defined maximum number of systemic chemotherapy courses in stratum N. The length of chemotherapy (number of courses) will depend on the patient's age at enrollment. The chemotherapy plan for stratum N is divided into 5 sub-cohorts:

• Age ≥34 months and < 36 months: 4 cycles - 2 cycles (A1A2) prior to radiation and 2 cycles (E1, E2) post-radiation
• Age: ≥32 to <34 months-old: 4 cycles (A1A2A3A4)
• Age: ≥30 to <32 months-old: 6 cycles (A1A2A3A4 B1B2)
• Age: ≥28 to <30-months-old: 8 cycles (A1A2A3A4 B1B2 C1C2)
• Age: < 28 months-old: 8 cycles + multiple cycles of Course D until 36 months old (A1A2A3A4 B1B2 C1C2 D1D2D3D4…)

Courses A, B, C and E repeat every 28 days/4 weeks and Course D repeats every 42 days.

Prior to radiation therapy, around when stratum N patients achieve 36 months of age, they will be re-stratified onto substratum N-1, N-2 or N-3 based on their response to chemotherapy.

Patients who receive less than or equal to 4 cycles of systemic chemotherapy prior to CSI regardless of their substratum assignment (N-1, N-2 or N-3) will have their radiation therapy augmented by IV carboplatin. Carboplatin will be given to each of these patients 1-4 hours before each radiation fraction is delivered.

Patients enrolled in stratum N who have received only 2 courses of pre-radiation chemotherapy will receive 2 additional courses of adjuvant chemotherapy after completing CSI . The adjuvant chemotherapy consists of Cisplatin, Cyclophosphamide, and Vincristine. Patients who receive equal to 4 courses of systemic chemotherapy prior to CSI will have their radiation therapy augmented by IV carboplatin. The patients receiving more than 4 courses of chemotherapy prior to radiation will not receive additional adjuvant chemotherapy after completing CSI.

Patients will be followed for 84 months following enrollment.

Inclusion Criteria - Screening Phase (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 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.

Exclusion Criteria - Screening Phase

• 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.

Inclusion Criteria - 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 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 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.

• Participant must have adequate organ function prior to study entry, as defined by:

  • 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.

• Adequate renal function as defined by a serum creatinine concentration:

  • Age - 0 to <1year; Maximum Serum Creatinine (mg/dl) - Male 0.5; Female 0.5
  • Age - 1 to < 2years; Maximum Serum Creatinine (mg/dl) - Male 0.6; Female 0.6
  • Age - 1 to < 2yearsr; Maximum Serum Creatinine (mg/dl) - Male 0.8; Female 0.8

• 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.

Inclusion Criteria - 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) Inclusion Criteria - 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.

Inclusion Criteria - 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

Exclusion Criteria - All Patients

• CNS embryonal tumor other than medulloblastoma, for example, patients with diagnosis of Atypical Teratoid/Rhabdoid Tumor (ATRT), PNET, Pineoblastoma, Ependymoma, and 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 juvenile rheumatoid arthritis, JAK inhibitor therapy for eczema, etc.)

• Participant who is actively receiving any other investigational agents.

• Participant 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 procedures or results.