| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Newly Diagnosed Medulloblastoma | |
| E.1.1.1 | Medical condition in easily understood language | | A malignant tumor originating from brain cells during embryo phase of life and grows in the area of brain stem. | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10027107 | | E.1.2 | Term | Medulloblastoma | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | 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. | |
| E.2.2 | Secondary objectives of the trial | In experimental versus standard arm and in the 3 molecular subgroups separately (except otherwise stated):
• To compare PFS by central reviewer in WNT & Group 4 subgroups
• To compare PFS by local investigator in 3 molecular subgroups
• To compare overall survival (OS) in 3 molecular subgroups
• 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 | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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
Step 2: Enrollment/randomization
• Newly diagnosed, histologically proven, genetically classified, centrally confirmed medulloblastoma (WNT M0-1, SHH (p53wt) M0-1, Group 4 M0-1)
• Molecular subtype: medulloblastoma, SHH-activated and TP53-wildtype, M0-1; medulloblastoma, WNT-activated, M0-1; medulloblastoma, Group 4, M0-1
• Histologic subtype: medulloblastoma, classic (CMB); medulloblastoma, desmoplastic/nodular (DNMB); medulloblastoma, with extensive nodularity (MBEN); medulloblastoma, large cell/anaplastic (LCA)
• Adults (≥ 18 years) in WNT-activated and Group 4 medulloblastoma
• Post-pubertal patients (<18y of age), or adults (18 y of age and above) in SHH-activated and TP53-wildtype medulloblastoma
• Patients (<18 years) must have completed puberty
• Patients (<18 years) must have a radiologically confirmed bone age of minimum 15 years for females and 17 years for males
Non-SHH dependent patients under age 18 should be transferred to a paediatric site for inclusion in the PNET5 trial in countries where PNET5 is open. SHH-activated patients under age 18 with M1 disease or above should be transferred to a paediatric site for inclusion in the HRMB trial in countries where HRMB is open.
• Clinical status within 2 weeks of randomization/enrollment: Karnofsky 50-100. NANO-score 0 to 9 (allowing full-blown cerebellar symptoms)
• Clinically standard-risk (centrally assessed MRI review) defined as: total or near total surgical resection with less than or equal to 1.5 cm2 (measured in axial plane) of residual tumour on early post-operative MRI, without and with contrast; no CNS metastasis on MRI (cranial and spinal); Chang stage M0-1 with no clinical evidence of extra-CNS metastasis
• Full recovery from surgery or any post-surgical complication (e.g. bleeding, infections etc.)
• Post-surgery (within 72h) MRI available (pre-surgery MRI upload is encouraged if available)
• Baseline brain MRI and spinal MRI for uploading available within 2 weeks of randomization/enrollment
• Normal liver, renal and haematological function within 2 weeks of randomization/enrollment.
• WBC ≥ 3×10^9/L
• ANC ≥ 1.5×10^9/L
• Platelet count of ≥ 100×10^9/L independent of transfusion
• Hemoglobin ≥ 10 g/dl
• Total Bilirubin ≤ 1.5 × ULN
• ALT (SGPT), AST (SGOT), alkaline phosphatase (ALP) ≤ 2.5 × ULN
• Serum creatinine < 1.5 × ULN or creatinine clearance (CrCl) >60 ml/min (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 WOCBP
• Patients of childbearing / reproductive potential (WOCBP) must use two methods of adequate birth control, including a highly effective method and a barrier method during the study treatment period and for at least 20 months after the last study treatment is mandatory for the patients that received sonidegib, for all other patients this period is at least 12 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Male patients even those who have had a vasectomy must always use a condom during treatment and for 12 months after last treatment. Men should not donate semen during treatment and for at least 12 months after ending treatment (donation of semen for the semen analyses in the 1 b fertility project is allowed.
• Female subjects who are breast feeding must discontinue nursing prior to the first dose of study treatment and until 20 months after the last study treatment | |
| E.4 | Principal exclusion criteria | Exclusion criteria
Step 2: Enrollment/randomization
• Prior treatment for medulloblastoma
• Unavailability of central review pathology results
• Known prognostic markers (MYC/MYCN amplification, MYC/MYCN mutation)
•Exclusion of germline alterations prognostically linked to medulloblastoma (e.g., TP53, PTCH, SUFU, BRCA2, PALB2), if known before randomization
• Inability to start radiotherapy within 43 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
• Prior or current use of mitoxantrone, methotrexate, topotecan, imatinib, irinotecan or statins
• 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.
All eligibility criteria must be adhered to. A deviation of 5% for hematological and 10% for biochemistry values will be acceptable.
The randomization/enrollment process can start after central pathology results are available.
Treatment must start within 14 days of randomization/enrollment BUT the latest on day 43 after surgery. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Progression-Free Survival (PFS) according to RAPNO assessed by central reviewer of a personalized intensity-modulated therapy (experimental arm; sonidegib) in SHH-activated patients. | |
| E.5.1.1 | 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
| |
| E.5.2 | Secondary end point(s) | • PFS by central reviewer in WNT and Group 4 patients.
• PFS by local investigator in the 3 molecular subgroups
• 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 + 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
• Clinical endocrine function parameters: adynamia, tiredness, reduced concentration, depression, intolerance against cold, muscle weakness, obesity, oligomenorrhea, intermenstrual bleeding, sexual dysfunction, decline in libido, pain during intercourse, infertility, constipation, polydipsia, polyuria, hair loss, dry skin, osteoporosis, skin edema, decreased weight, and thyroid function parameters: TSH, if abnormal FT3 and FT4
• Frequencies and percentages of second malignancies
| |
| E.5.2.1 | 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
| |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description | | Radiotherapy, QOL, radiogenomics, neurocognitive function, long term effects, impact on fertility, biobanking | |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Australia | | Austria | | France | | Netherlands | | Spain | | Switzerland | | Germany | | Italy | | Denmark | | United Kingdom | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | End of study occurs when all of the following criteria have been satisfied:
• 5 months after all patients have stopped protocol treatment.
• The trial is mature for the analysis of the primary endpoint as defined in the protocol.
• The database has been fully cleaned and frozen for this analysis. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 83 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 83 |
