Clinical trial NCT05535166: Molecular and Clinical Risk-Directed Therapy for Infants and Young Children With Newly Diagnosed Medulloblastoma
Official title: SJiMB21: Phase 2 Study of Molecular and Clinical Risk-Directed Therapy for Infants and Young Children With Newly Diagnosed Medulloblastoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Medulloblastoma
Keywords: SJiMB21
Brain Cancer
Brain Tumors in Children
Medulloblastoma Sonic Hedgehog subgroup 1
Medulloblastoma Sonic Hedgehog subgroup 2
Medulloblastoma Sonic Hedgehog subgroup 3
Medulloblastoma Sonic Hedgehog subgroup 4
Medulloblastoma Sonic Hedgehog-not otherwise specified
Medulloblastoma G3
Medulloblastoma G4
Medulloblastoma indeterminate
MLPNet
Neural Net Classification Pipeline
Non-WNT non-SHH medulloblastoma
Posterior fossa syndrome
St. Jude Brain Tumor Studies
Treatment for Brain Tumors in Infants and Young Children
Untreated Childhood Medulloblastoma
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2022-09-10
Enrollment: 120
Sex: ALL
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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 repeats 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 repeats 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 (A1A2A3A4B1B2)
* Age: ≥28 to \<30-months-old: 8 cycles (A1A2A3A4B1B2C1C2)
* Age: \< 28 months-old: 8 cycles + multiple cycles of Course D until 36 months old (A1A2A3A4 B1B2 C1C2D1D2D3D4...)

Courses A, B, C and E repeats 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. The patients receiving 4 or more courses of chemotherapy prior to radiation will not receive additional adjuvant chemotherapy after completing CSI.

Patients will be followed for 84 months following enrollment.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: Up to 7 years after enrollment with PFS estimation occurring 2 years after treatment initiation of last patient
measure: Progression free survival of SHH-1 infant (0-2.99 years) medulloblastoma patients treated with systemic HD-MTX-based chemotherapy augmented with IVT-MTX.
timeFrame: Up to 7 years after enrollment with PFS estimation occurring 2 years after treatment initiation of last patient
measure: 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.
timeFrame: Up to 7 years after enrollment with PFS estimation occurring 2 years after treatment initiation of last patient
measure: IQ among infants and young children treated with systemic chemotherapy only compared to patients treated with systemic chemotherapy and intra-ventricular chemotherapy or delayed risk-adapted craniospinal irradiation
timeFrame: Baseline through 5 years after enrollment
measure: Executive function among infants and young children treated with systemic chemotherapy only compared to patients treated with systemic chemotherapy and intra-ventricular chemotherapy or delayed risk-adapted craniospinal irradiation
timeFrame: Baseline through 5 years after enrollment
measure: Health-related quality of life among infants and young children treated with systemic chemotherapy only compared to patients treated with systemic chemotherapy and intra-ventricular chemotherapy or delayed risk-adapted craniospinal irradiation
timeFrame: Baseline through 5 years after enrollment
Secondary outcomes:
measure: Change in IQ among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma
timeFrame: Baseline through 5 years after enrollment
measure: Change in executive function among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma
timeFrame: Baseline through 5 years after enrollment
measure: Change in health-related quality of life among infants (0-2.99 years) and young children (3-4.99 years) treated for medulloblastoma
timeFrame: Baseline through 5 years after enrollment
measure: Association of familial factors and environmental factors with socioeconomic status
timeFrame: Baseline through 5 years after enrollment
measure: Association of familial factors and environmental factors with cognitive late effects.
timeFrame: Baseline through 5 years after enrollment
measure: Evaluate family interest in caregiver education combined with interactive neurodevelopmental games.
timeFrame: Baseline through 6 months after enrollment
measure: Evaluate intervention feasibility by measuring the rate of participants completing a caregiver education combined with interactive. neurodevelopmental games.
timeFrame: Baseline through 6 months after enrollment
measure: Evaluate the acceptability of a caregiver education combined with interactive neurodevelopmental games.
timeFrame: Baseline through 6 months after enrollment
measure: Magnitude of change in cognition and social-emotional development associated with a caregiver education program combined with interactive neurodevelopmental games.
timeFrame: Baseline and 6 months after enrollment
measure: To characterize the plasma systemic clearance (CL) of cyclophosphamide (CTX) in infants and young children with medulloblastoma.
timeFrame: Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E.
measure: To characterize the area under the concentration-time curve (AUC0-24h) of carboxyethylphosphoramide (CEPM) in infants and young children with medulloblastoma receiving cyclophosphamide.
timeFrame: Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E.
measure: To characterize the area under the concentration-time curve (AUC0-24h) of 4-hydroxy-cyclophosphamide (4OHCTX) in infants and young children with medulloblastoma receiving cyclophosphamide.
timeFrame: Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E.
measure: To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in in the plasma systemic clearance (CL) of CTX in infants and young children with medulloblastoma receiving CTX.
timeFrame: Data for CTX from Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E.
measure: To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in CEPM AUC0-24h in infants and young children with medulloblastoma receiving CTX.
timeFrame: Data for CEPM from Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E.
measure: To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in 4OHCTX AUC0-24h in infants and young children with medulloblastoma receiving CTX.
timeFrame: Data for 4OHCTX from Day 9 of the first course of A, AIVT, B or BIVT therapy and Days 4 and 5 of course C or Days 2 and 3 of E.
measure: To characterize the plasma systemic clearance (CL) of vincristine (VCR) in infants and young children with medulloblastoma.
timeFrame: Beginning on Day 8 of the first course of A or AIVT and B or BIVT (or E).
measure: To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in VCR PK parameter (CL) in infants and young children with medulloblastoma receiving VCR.
timeFrame: Beginning on Day 8 of the first course of A or AIVT and B or BIVT (or E).
measure: To characterize the plasma systemic clearance (CL) of topotecan (TPT) in infants and young children with medulloblastoma.
timeFrame: All samples acquired during each course C for domestic patients and patients at St. Jude only.
measure: To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in TPT PK parameter (CL) in infants and young children with medulloblastoma receiving TPT.
timeFrame: All samples acquired during each course C for domestic patients and patients at St. Jude, only.
measure: To characterize the plasma systemic methotrexate (MTX) clearance (CL) in infants and young children with medulloblastoma.
timeFrame: Day 1 of each course A, AIVT, B, and BIVT.
measure: To characterize the area under the concentration-time curve (AUC0-24h) of 7-hydroxymethotrexate (7OHMTX) in infants and young children with medulloblastoma receiving methotrexate.
timeFrame: Day 1 of each course A, AIVT, B, and BIVT.
measure: To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in MTX PK parameter CL in infants and young children with medulloblastoma receiving MTX.
timeFrame: Day 1 of each course A, AIVT, B, and BIVT.
measure: To assess potential covariates (e.g., demographics, clinical chemistry) explaining inter- and intra-patient variability in 7OHMTX PK parameter AUC0-24h in infants and young children with medulloblastoma receiving MTX.
timeFrame: Day 1 of each course A, AIVT, B, and BIVT.
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Lucille Packard Children's Hospital at Stanford University
state: California
city: Orlando
country: United States
facility: Orlando Health Arnold Palmer Hospital for Children
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Children's Hospital
state: Florida
city: Ann Arbor
country: United States
facility: C.S. MOTT Children's Hospital, University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospital and Clinics of Minnesota
state: Minnesota
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Giles W. Robinson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Jude Children's Research Hospital
name: Aditi Bagchi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: