Newly Diagnosed Medulloblastoma MedDRA version: 20.0 Level: PT Classification code 10027107 Term: Medulloblastoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
European Organisation for Research and Treatment of
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Step 1: Registration • Before patient registration/randomization/enrollment, written informed consent must be given according to ICH/GCP, and national/local regulations. For patients under the age of legal consent, consent has to be obtained from the parent(s) or legal representative according to ICH/GCP, and national/local regulations. • FFPE tumor tissue from surgical resection and whole blood for central pathology review must be available. Step 2: Enrollment/randomization • Newly diagnosed, histologically proven, genetically classified, centrally confirmed medulloblastoma • Molecular subtype: medulloblastoma, SHH-activated and TP53- wildtype, M0-1; medulloblastoma, WNT-activated, M0-1; medulloblastoma, Group 3 & Group 4, M0-1 • Histologic subtype: medulloblastoma, classic (CMB); medulloblastoma, desmoplastic/nodular (DNMB); medulloblastoma, with extensive nodularity (MBEN); medulloblastoma, large cell/anaplastic (LCA) • Post-pubertal patients (60 mL/min (the estimated GFR should be in mL/min/1.73m² unit, using the MDRD formula) • According to CTFG recommendations related to contraception and pregnancy testing during clinical trials, a negative serum or urine pregnancy test within 7 days before randomization/enrollment for women of childbearing / reproductive potential (WOCBP). • WOCBP must use two methods of adequate birth control, including a highly effective method and a barrier method. Birth control during the stu
Exclusion criteria
Exclusion criteria: Step 2: Enrollment/randomization • Prior treatment for medulloblastoma • Unavailability of central review pathology results • Post-pubertal patients with known negative prognostic markers (MYC/MYCN amplification and/or TP53 germline alteration in the SHH subgroup) • Inability to start radiotherapy within 56 days after surgery. • Significant sensorineural hearing deficit as defined by pure tone audiometry with bone conduction or air conduction and normal tympanogram showing impairment = 20 dB at 1-3 kHz • Any medical contraindication to radiotherapy or chemotherapy • Hypersensitivity to contrast medium for MRI. • Hypersensitivity towards the active substance of any of study drugs or their excipients • Current use of BCRP substrates such as mitoxantrone, methotrexate, topotecan, imatinib or irinotecan or if patient is within 5 times the halflife of these medications • Concurrent severe or uncontrolled medical disease (e.g., active systemic infection, diabetes, psychiatric disorder) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study. • Prior or second invasive malignancy, except non-melanoma skin cancer, completely resected cervical carcinoma in situ, low risk prostate cancer (cT1-2a N0 and Gleason score = 6 and PSA < 10 ng/mL), either totally resected or irradiated with curative intent (with PSA of less than or equal to 0.1 ng/mL) or under active surveillance as per ESMO guidelines. Other cancers for which the subject has completed potentially curative treatment more than 5 years prior to diagnosis of medulloblastoma study entry are allowed. • Known history or current evidence of active Hepatitis B (e.g., positive HBV surface antigen) or C (e.g., HCV RNA [qualitative] is detected) • Known or current evidence of Human Immunodeficiency Virus (HIV) infection (positive HIV-1/2 antibodies) • Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare progression-free survival (PFS) by central review of a personalized intensity-modulated therapy (experimental arm; sonidegib) vs. standard therapy in the SHH-activated subgroup in post-pubertal patients with newly diagnosed standard risk medulloblastoma.;Secondary Objective: In experimental versus standard arm and in the 3 clinical subgroups separately (SHH, WNT and pooled Group 3 & Group 4) except if otherwise stated: • To compare PFS by central reviewer in WNT and Group 3 & 4 subgroups • To compare PFS by local investigator • To compare overall survival (OS) • To evaluate safety and tolerability profile • To evaluate short- and long-term health-related quality of life (HRQoL) with a particular emphasis on the social functioning scale • To evaluate issues linked to survivorship (fear of recurrence, having problems with insurance/mortgage, work opportunities, life plans/goals and relationships with family or friends) • To evaluate short- and long-term neurocognitive function (NCF) • To evaluate short- and long-term endocrine function • To assess the incidence of second malignancies See protocol for the following: Exploratory objectives Fertility sub-study objectives (in selected centres) Translational research objectives;Primary end point(s): Progression-Free Survival (PFS) according to RAPNO assessed by central reviewer of a personalized intensity-modulated therapy (experimental arm; sonidegib) compared to standard therapy in SHH-activated patients in post-pubertal patients with newly diagnosed standard risk medulloblastoma.;Timepoint(s) of evaluation of this end point: [ Time Frame: 91 months after the date of recruitment of the first patient ] Compare progression-free survival (PFS) by central review of a personalized intensity-modulated therapy (experimental arm; sonidegib) vs. standard therapy in the SHH-activated subgroup in post-pubertal patients with newly diagnosed standard risk medulloblastoma | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): In experimental versus standard arm in 3 subgroups separately (SHH, WNT and pooled Group 3 & Group 4) except if otherwise stated: • PFS by central reviewer in WNT and Group 3 & Group 4 subgroups • PFS by local investigator • OS • Frequencies and percentages of worst adverse events (AEs) or laboratory event; grades according to CTCAE v.5 (with neurological, kidney, auditory, endocrine and radiotherapy associated as AE of special interest) • Patient reported outcomes: - Health-related Quality of life (HRQol): EORTC QLQ-C30 and BN20, social functioning as scale of special interest - Survivorship outcomes (five items from EORTC QLQ-SURV111) • Neurocognitive function (NCF): Hopkins Verbal Learning Test, Controlled Oral Word Association Trail Making Test Part A, Trail Making Test Part B, cerebellar cognitive affective/Schmahmann syndrome scale.;Timepoint(s) of evaluation of this end point: 1. (PFS) [ when 43 PFS events are observed estimated to occur 91 months after the date of recruitment of 1st patient] 2. (OS) [ when 43 PFS events are observed estimated to occur 91 m after the date of recruitment of 1st patient] 3.safety and tolerability profile: CTCAE v5 [ when 43 PFS events are observed estimated to occur 91 months after the date of recruitment of 1st patient] 4. (HRQoL) [ when 43 PFS events are observed estimated to occur 91 m after the date of recruitment of 1st patient] The primary HRQoL endpoint that is considered relevant for this study is social functioning. The other scales from the QLQ-C30 and BN20 considered as exploratory in nature. 5.OS[when 43 PFS events are observed estimated to occur 91 M after the date of recruitment of 1st patient | — |
Countries
Australia, Austria, Denmark, France, Germany, Italy, Netherlands, Spain, Switzerland, United Kingdom
Contacts
Public ContactRegulatory Affairs Department
Organisation for Research and Treatment of
Outcome results
None listed