Clinical trial NCT04402073: Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma
Official title: Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma (PersoMed-I)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Medulloblastoma
Keywords: brain
medullobalstoma
MRI
radiotherapy
biomarkers
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2020-05-26
Enrollment: 20
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase II, comparative, randomized (experimental : standard arm 1:1, no blinding, no active or placebo control, parallel group, therapeutic
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: Medulloblastoma is a rare brain malignancy, mainly affecting children. Treatment of this rapidly growing tumor begins with maximal surgical removal plus radiation and chemotherapy. Treatment toxicity is high. Post-pubertal and pediatric medulloblastomas are biologically and prognostically different, which mandates age-adapted treatment strategies. Patients after puberty bear an intermediate to high prognostic risk. This means that a large number of these patients, are faced with death and/or disability (mainly neurocognitive). Therefore, the scientific and medical need is high. One of the genetic subgroups of medulloblastoma, the SHH-subgroup (Sonic HedgeHog- subgroup), is highly overrepresented in medulloblastoma patients after puberty. This subgroup can be treated with a targeted therapy. The investigators will therefore randomize patients and treat SHH-subgroup patients with sonidegib and a reduction of radiotherapy dose in the experimental arm of the trial. The hypothesis that this personalized risk-adapted therapy will improve outcomes in view of increased efficacy and decreased toxicity.


Eligibility criteria: Inclusion Criteria:

* Newly diagnosed, histologically proven, genetically classified, centrally confirmed medulloblastoma (WNT M0-1, SHH M0-1 (p53wt), 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)
* Adult (18 years and above): in WNT-activated and Group 4 medulloblastoma
* Post-pubertal, defined as females with a bone age of at least 15 years and males with a bone age of at least 17 years, or adult (greater than 18 y of age) (see appendix N) in SHH-activated and TP53-wildtype medulloblastoma
* Availability of prognostic markers (MYC/MYCN amplification, MYC/MYCN mutation)
* Availability of paraffin embedded tumour tissue (FFPE) (1 block or 30 unstained slides) and whole blood sample (10 ml) for central review
* For patients with SHH activated tumours: exclusion of germline alteration of TP53, PTCH, SUFU, BRCA2 and PALB2 if known before randomization
* Clinical status within 2 weeks of randomization: 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)
* Pre-surgery and/or post-surgery MRI available.
* Baseline brain MRI and spinal MRI available within 2 weeks of randomization.
* Normal liver, renal and haematological function within 2 weeks of randomization.
* WBC greater than or equal to 3×10\^9/L
* ANC greater than or equal to 1.5×10\^9/L
* Platelet count of greater than or equal to 100×10\^9/L independent of transfusion
* Hemoglobin greater than or equal to 10 g/dl
* Total Bilirubin less than or equal to 1.5 ULN
* ALT (SGPT), AST (SGOT), alkaline phosphatase (ALP) less than or equal to 2.5 × ULN
* Serum creatinine less than 1.5 x ULN or creatinine clearance (CrCl) greater than 30 mL/min (using the Cockcroft-Gault formula)
* Negative serum or urine pregnancy test within 7 days of randomization 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 6 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 6 months after last treatment. Men should not donate semen during treatment and for at least 6 months after ending treatment (donation of semen for the semen analyses of the fertility project 1 b is allowed). Appendix H.
* 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.
* Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. For patients less than 18 years of age, consent has to be obtained from the parent(s) or legal representative.

Exclusion Criteria:

* Prior treatment for medulloblastoma
* Unavailability of central review pathology results.
* Inability to start radiotherapy within 43 days of surgery
* Significant sensorineural hearing deficit as defined by pure tone audiometry with bone conduction or air conduction and normal tympanogram showing impairment greater than or equal to 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 less than or equal to 6 and PSA less than 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.

Primary outcomes:
measure: Progression Free Survival
timeFrame: 91 months after the date of recruitment of the first patient
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.
measure: overall survival (OV)
timeFrame: when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.
measure: safety and tolerability profile: CTCAE
timeFrame: when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.
measure: health-related quality of life (HRQoL)
timeFrame: when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.
measure: overall survival
timeFrame: when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital - University Of Queensland
city: Melbourne
country: Australia
facility: Austin Health - Austin hospital
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Institute
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
city: New Lambton Heights
country: Australia
facility: John Hunter Children's Hospital
city: Sydney
country: Australia
facility: Prince Of Wales Hospital
city: Sydney
country: Australia
facility: Royal North Shore Hospital
city: Sydney
country: Australia
facility: Sydney Children's Hospital
city: Westmead
country: Australia
facility: Westmead Hospital - Crown Princess Mary Cancer Center
city: Innsbruck
country: Austria
facility: A.O Landeskrankenhaus - Innsbruck Universitaetsklinik
city: Wien
country: Austria
facility: AKH unikliniken
city: Lille
country: France
facility: CHRU de Lille
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Hopital de La Timone (APHM)
city: Nice
country: France
facility: CHU de Nice - Hopital Pasteur
city: Paris
country: France
facility: Hopital la Pitie-Salpetriere
city: Saint-Herblain
country: France
facility: Institut de Cancerologie de l'Ouest (ICO) - Saint Herblain
city: Toulouse
country: France
facility: CHU de Toulouse - Institut Claudius Regaud - IUCT oncopole
city: Bochum
country: Germany
facility: Knappschaft Krankenhaus Langendreer
city: Bonn
country: Germany
facility: Universitaetsklinikum Bonn
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus
city: Erfurt
country: Germany
facility: HELIOS Kliniken - HELIOS Klinikum Erfurt GmbH
city: Essen
country: Germany
facility: Universitaetsklinikum - Essen
city: Frankfurt
country: Germany
facility: University Frankfurt - Goethe Univ. - University Hospital Frankfurt -Senckenberg Institute of Neurooncology
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg - Klinik fuer Neurochirurgie
city: Goettigen
country: Germany
facility: Universitaetsmedizin Goettingen - Georg-August Universitaet
city: Hamburg
country: Germany
facility: Universitaets Krankenhaus Eppendorf - Universitaetsklinikum Hamburg-Eppendorf KE - University Cancer Center
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig-Klinik fuer Strahlentherapie und Radioonkologie
city: Mainz
country: Germany
facility: Univ. Mainz - Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz-University Medical Center
city: Mannheim
country: Germany
facility: UniversitaetsMedizin Mannheim
city: Munich
country: Germany
facility: Klinikum Rechts der isar Der Technische Universitaet Muenchen
city: Munich
country: Germany
facility: Ludwig-Maximilians-Universitaet Muenchen - Campus Grosshadern
city: Regensburg
country: Germany
facility: Universitaetskliniken Regensburg - Universitaetsklinikum Regensburg
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen- Crona Kliniken
city: Bologna
country: Italy
facility: AUSL Bologna - Ospedale Bellaria
city: Florence
country: Italy
facility: Univ. of Florence -Azienda Ospedaliero-Universitaria Careggi
city: Milano
country: Italy
facility: IRCCS - Istituto Neurologico Carlo Besta
city: Torino
country: Italy
facility: Azienda Ospedaliera Citta della Salute e della Scienza di Torino
city: Treviso
country: Italy
facility: ULSS2 - Marca Trevigniana
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Badalona
country: Spain
facility: Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario 12 De Octubre
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois - Lausanne
city: Zürich
country: Switzerland
facility: University Hospital zurich
Study officials:
affiliation: EORTC study coordinator
name: Peter Hau
role: PRINCIPAL_INVESTIGATOR
References: