<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04402073</url>
  </required_header>
  <id_info>
    <org_study_id>1634</org_study_id>
    <nct_id>NCT04402073</nct_id>
  </id_info>
  <brief_title>Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma</brief_title>
  <acronym>PersoMed-I</acronym>
  <official_title>Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma (PersoMed-I)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>European Organisation for Research and Treatment of Cancer - EORTC</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>European Organisation for Research and Treatment of Cancer - EORTC</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Medulloblastoma is a rare brain malignancy, mainly affecting children. Treatment of this&#xD;
      rapidly growing tumor begins with maximal surgical removal plus radiation and chemotherapy.&#xD;
      Treatment toxicity is high. Post-pubertal and pediatric medulloblastomas are biologically and&#xD;
      prognostically different, which mandates age-adapted treatment strategies. Patients after&#xD;
      puberty bear an intermediate to high prognostic risk. This means that a large number of these&#xD;
      patients, are faced with death and/or disability (mainly neurocognitive). Therefore, the&#xD;
      scientific and medical need is high. One of the genetic subgroups of medulloblastoma, the&#xD;
      SHH-subgroup (Sonic HedgeHog- subgroup), is highly overrepresented in medulloblastoma&#xD;
      patients after puberty. This subgroup can be treated with a targeted therapy. The&#xD;
      investigators will therefore randomize patients and treat SHH-subgroup patients with&#xD;
      sonidegib and a reduction of radiotherapy dose in the experimental arm of the trial. The&#xD;
      hypothesis that this personalized risk-adapted therapy will improve outcomes in view of&#xD;
      increased efficacy and decreased toxicity.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 11, 2022</start_date>
  <completion_date type="Anticipated">March 1, 2030</completion_date>
  <primary_completion_date type="Anticipated">March 1, 2030</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Phase II, comparative, randomized (experimental : standard arm 1:1, no blinding, no active or placebo control, parallel group, therapeutic</intervention_model_description>
    <primary_purpose>Health Services Research</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>91 months after the date of recruitment of the first patient</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall survival (OV)</measure>
    <time_frame>when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>safety and tolerability profile: CTCAE</measure>
    <time_frame>when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.</time_frame>
    <description>This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, for adverse event reporting (with neurological, kidney, auditory, endocrine and radiotherapy associated as AE of special interest). The highest CTCAE v. 5 grading per cycle and per patient will be computed at the EORTC HQ for analysis . Safety and tolerability analyses will be performed in the safety population. Severe grades (3/4) which did not resolve after treatment discontinuation or emerged during follow-up will be identified and listed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>health-related quality of life (HRQoL)</measure>
    <time_frame>when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.</time_frame>
    <description>The primary HRQoL endpoint that is considered relevant for this study is social functioning. The other scales from the QLQ-C30 and BN20 will be considered as exploratory in nature.&#xD;
A difference of 10 points on the 100-point QLQ-C30 social functioning scale between the two arms will be considered as clinically relevant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall survival</measure>
    <time_frame>when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">205</enrollment>
  <condition>Medulloblastoma</condition>
  <arm_group>
    <arm_group_label>standard arms</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Criteria: Adult SHH (p53wt) M0-1, adult WNT M0-1, adult Group 4 M0-1.&#xD;
Radiotherapy to the cranio-spinal axis of 35.2 Gy in 22 daily fractions of 1.6 Gy, followed by an additional boost to the tumour site of 19.8 Gy in 11 daily fractions of 1.8 Gy, summing up to a total dose of 55.0 Gy in 33 daily fractions of 1.6/1.8 Gy.&#xD;
Criteria: Post pubertal &lt; 18 y SHH (p53wt) M0.&#xD;
Radiotherapy to the cranio-spinal axis of 23.4 Gy in 13 daily fractions of 1.8 Gy, followed by an additional boost to the tumour site of 30.6 Gy in 17 daily fractions of 1.8 Gy, summing up to a total dose of 54.0 Gy in 30 daily fractions of 1.8 Gy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>experimental arms</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Radiotherapy Criteria: Adult and post-pubertal SHH (p53wt) M0; adult WNT M0, adult Group 4 M0.&#xD;
Radiotherapy to the cranio-spinal axis of 23.4 Gy in 13 daily fractions of 1.8 Gy, followed by an additional boost to the tumour site of 30.6 Gy in 17 daily fractions of 1.8 Gy, summing up to a total dose of 54.0 Gy in 30 daily fractions of 1.8 Gy.&#xD;
SMO-inhibitor Criteria: Adult and post-pubertal SHH (p53wt) M0.&#xD;
Sonidegib 200 mg/day (daily) from first day of radio-chemotherapy until end of maintenance chemotherapy, including 6w chemotherapy break.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sonidegib</intervention_name>
    <description>Sonidegib is a selective smoothened inhibitor that inhibits the sonic hedgehog-signaling pathway. It is used in patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.</description>
    <arm_group_label>experimental arms</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>Cisplatin (CIS) is a platinum derivate used in the treatment in several epithelial tumours. The application route is through the veins.</description>
    <arm_group_label>experimental arms</arm_group_label>
    <arm_group_label>standard arms</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lomustine</intervention_name>
    <description>Lomustine is a nitrosourea used in the treatment of brain tumours and Hodgkin's disease. The application route is oral.</description>
    <arm_group_label>experimental arms</arm_group_label>
    <arm_group_label>standard arms</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vincristine</intervention_name>
    <description>Vincristine sulfate (VCR) is an inhibitor of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage. Vincristine sulfate is indicated in acute leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor. The application route is through the vein.</description>
    <arm_group_label>experimental arms</arm_group_label>
    <arm_group_label>standard arms</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>radiotherapy</intervention_name>
    <description>Radiotherapy to the cranio-spinal axis of 35.2 Gy in 22 daily fractions of 1.6 Gy, followed by an additional boost to the tumour site of 19.8 Gy in 11 daily fractions of 1.8 Gy, summing up to a total dose of 55.0 Gy in 33 daily fractions of 1.6/1.8 Gy.</description>
    <arm_group_label>experimental arms</arm_group_label>
    <arm_group_label>standard arms</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Newly diagnosed, histologically proven, genetically classified, centrally confirmed&#xD;
             medulloblastoma (WNT M0-1, SHH M0-1 (p53wt), Group 4 M0-1)&#xD;
&#xD;
          -  Molecular subtype: medulloblastoma, SHH-activated and TP53-wildtype, M0-1;&#xD;
             medulloblastoma, WNT-activated, M0-1; medulloblastoma, Group 4, M0-1&#xD;
&#xD;
          -  Histologic subtype: medulloblastoma, classic (CMB); medulloblastoma,&#xD;
             desmoplastic/nodular (DNMB); medulloblastoma, with extensive nodularity (MBEN);&#xD;
             medulloblastoma, large cell/anaplastic (LCA)&#xD;
&#xD;
          -  Adult (18 years and above): in WNT-activated and Group 4 medulloblastoma&#xD;
&#xD;
          -  Post-pubertal, defined as females with a bone age of at least 15 years and males with&#xD;
             a bone age of at least 17 years, or adult (greater than 18 y of age) (see appendix N)&#xD;
             in SHH-activated and TP53-wildtype medulloblastoma&#xD;
&#xD;
          -  Availability of prognostic markers (MYC/MYCN amplification, MYC/MYCN mutation)&#xD;
&#xD;
          -  Availability of paraffin embedded tumour tissue (FFPE) (1 block or 30 unstained&#xD;
             slides) and whole blood sample (10 ml) for central review&#xD;
&#xD;
          -  For patients with SHH activated tumours: exclusion of germline alteration of TP53,&#xD;
             PTCH, SUFU, BRCA2 and PALB2 if known before randomization&#xD;
&#xD;
          -  Clinical status within 2 weeks of randomization: Karnofsky 50-100. NANO-score 0 to 9&#xD;
             (allowing full-blown cerebellar symptoms)&#xD;
&#xD;
          -  Clinically standard-risk (centrally assessed MRI review) defined as: total or near&#xD;
             total surgical resection with less than or equal to 1.5 cm2 (measured in axial plane)&#xD;
             of residual tumour on early post-operative MRI, without and with contrast; no CNS&#xD;
             metastasis on MRI (cranial and spinal); Chang stage M0-1 with no clinical evidence of&#xD;
             extra-CNS metastasis&#xD;
&#xD;
          -  Full recovery from surgery or any post-surgical complication (e.g. Bleeding,&#xD;
             infections etc)&#xD;
&#xD;
          -  Pre-surgery and/or post-surgery MRI available.&#xD;
&#xD;
          -  Baseline brain MRI and spinal MRI available within 2 weeks of randomization.&#xD;
&#xD;
          -  Normal liver, renal and haematological function within 2 weeks of randomization.&#xD;
&#xD;
          -  WBC greater than or equal to 3×10^9/L&#xD;
&#xD;
          -  ANC greater than or equal to 1.5×10^9/L&#xD;
&#xD;
          -  Platelet count of greater than or equal to 100×10^9/L independent of transfusion&#xD;
&#xD;
          -  Hemoglobin greater than or equal to 10 g/dl&#xD;
&#xD;
          -  Total Bilirubin less than or equal to 1.5 ULN&#xD;
&#xD;
          -  ALT (SGPT), AST (SGOT), alkaline phosphatase (ALP) less than or equal to 2.5 × ULN&#xD;
&#xD;
          -  Serum creatinine less than 1.5 x ULN or creatinine clearance (CrCl) greater than 30&#xD;
             mL/min (using the Cockcroft-Gault formula)&#xD;
&#xD;
          -  Negative serum or urine pregnancy test within 7 days of randomization for WOCBP.&#xD;
&#xD;
          -  Patients of childbearing / reproductive potential (WOCBP) must use two methods of&#xD;
             adequate birth control, including a highly effective method and a barrier method&#xD;
             during the study treatment period and for at least 20 months after the last study&#xD;
             treatment is mandatory for the patients that received sonidegib, for all other&#xD;
             patients this period is at least 6 months after the last study treatment. A highly&#xD;
             effective method of birth control is defined as those which result in low failure rate&#xD;
             (i.e. less than 1% per year) when used consistently and correctly. Male patients even&#xD;
             those who have had a vasectomy must always use a condom during treatment and for 6&#xD;
             months after last treatment. Men should not donate semen during treatment and for at&#xD;
             least 6 months after ending treatment (donation of semen for the semen analyses of the&#xD;
             fertility project 1 b is allowed). Appendix H.&#xD;
&#xD;
          -  Female subjects who are breast feeding must discontinue nursing prior to the first&#xD;
             dose of study treatment and until 20 months after the last study treatment.&#xD;
&#xD;
          -  Before patient registration/randomization, written informed consent must be given&#xD;
             according to ICH/GCP, and national/local regulations. For patients less than 18 years&#xD;
             of age, consent has to be obtained from the parent(s) or legal representative.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior treatment for medulloblastoma&#xD;
&#xD;
          -  Unavailability of central review pathology results.&#xD;
&#xD;
          -  Inability to start radiotherapy within 43 days of surgery&#xD;
&#xD;
          -  Significant sensorineural hearing deficit as defined by pure tone audiometry with bone&#xD;
             conduction or air conduction and normal tympanogram showing impairment greater than or&#xD;
             equal to 20 dB at 1-3 kHz&#xD;
&#xD;
          -  Any medical contraindication to radiotherapy or chemotherapy.&#xD;
&#xD;
          -  Hypersensitivity to contrast medium for MRI.&#xD;
&#xD;
          -  Hypersensitivity towards the active substance of any of study drugs or their&#xD;
             excipients&#xD;
&#xD;
          -  Prior or current use of mitoxantrone, methotrexate, topotecan, imatinib, irinotecan or&#xD;
             statins&#xD;
&#xD;
          -  Concurrent severe or uncontrolled medical disease (e.g., active systemic infection,&#xD;
             diabetes, psychiatric disorder) that, in the opinion of the investigator, would&#xD;
             compromise the safety of the patient or compromise the ability of the patient to&#xD;
             complete the study&#xD;
&#xD;
          -  Prior or second invasive malignancy, except non-melanoma skin cancer, completely&#xD;
             resected cervical carcinoma in situ, low risk prostate cancer (cT1-2a N0 and Gleason&#xD;
             score less than or equal to 6 and PSA less than 10 ng/mL), either totally resected or&#xD;
             irradiated with curative intent (with PSA of less than or equal to 0.1 ng/mL) or under&#xD;
             active surveillance as per ESMO guidelines. Other cancers for which the subject has&#xD;
             completed potentially curative treatment more than 5 years prior to diagnosis of&#xD;
             medulloblastoma study entry are allowed&#xD;
&#xD;
          -  Known history or current evidence of active Hepatitis B (e.g., positive HBV surface&#xD;
             antigen) or C (e.g., HCV RNA [qualitative] is detected)&#xD;
&#xD;
          -  Known or current evidence of Human Immunodeficiency Virus (HIV) infection (positive&#xD;
             HIV-1/2 antibodies)&#xD;
&#xD;
          -  Presence of any psychological, familial, sociological or geographical condition&#xD;
             potentially hampering compliance with the study protocol and follow-up schedule; those&#xD;
             conditions should be discussed with the patient before registration in the trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Peter Hau</last_name>
    <role>Principal Investigator</role>
    <affiliation>EORTC study coordinator</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>EORTC HQ</last_name>
    <phone>003227741611</phone>
    <email>eortc@eortc.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Royal Adelaide Hospital</name>
      <address>
        <city>Adelaide</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Eryn Dow</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Princess Alexandra Hospital - University Of Queensland</name>
      <address>
        <city>Brisbane</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rick Walker</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Peter Maccallum Cancer Institute</name>
      <address>
        <city>Melbourne</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>James Whittle</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Royal North Shore Hospital</name>
      <address>
        <city>Sydney</city>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Helen Wheeler</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Knappschaft Krankenhaus Langendreer</name>
      <address>
        <city>Bochum</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sabine Seidel</last_name>
    </contact>
    <investigator>
      <last_name>Sabine Seidel, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Bonn</name>
      <address>
        <city>Bonn</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Ulrich Herrlinger, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Carl Gustav Carus</name>
      <address>
        <city>Dresden</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dietmar Krex</last_name>
    </contact>
    <investigator>
      <last_name>Dietmar Krex, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>HELIOS Kliniken - HELIOS Klinikum Erfurt GmbH</name>
      <address>
        <city>Erfurt</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ruediger Gerlach</last_name>
    </contact>
    <investigator>
      <last_name>Ruediger Gerlach, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum - Essen</name>
      <address>
        <city>Essen</city>
        <zip>45147</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Martin Glas, MD</last_name>
    </contact>
    <investigator>
      <last_name>Martin Glas, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Gudrun Fleischhack, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Frankfurt - Goethe Univ. - University Hospital Frankfurt -Senckenberg Institute of Neurooncology</name>
      <address>
        <city>Frankfurt</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Martina Becker</last_name>
    </contact>
    <investigator>
      <last_name>Martina Becker, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Michael Burger, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Freiburg - Klinik fuer Neurochirurgie</name>
      <address>
        <city>Freiburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Oliver Schnell</last_name>
    </contact>
    <investigator>
      <last_name>Oliver Schnell, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Miriam van Buiren, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitaetsmedizin Goettingen - Georg-August Universitaet</name>
      <address>
        <city>Goettigen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Christof Kramm, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitaets Krankenhaus Eppendorf - Universitaetsklinikum Hamburg-Eppendorf KE - University Cancer Center</name>
      <address>
        <city>Hamburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Malte Mohme, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Martin Mynarek, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital</name>
      <address>
        <city>Heidelberg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Antje Wick, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Leipzig-Klinik fuer Strahlentherapie und Radioonkologie</name>
      <address>
        <city>Leipzig</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Clemens Seidel, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Univ. Mainz - Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz-University Medical Center</name>
      <address>
        <city>Mainz</city>
        <zip>55131</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Florian Ringel</last_name>
    </contact>
    <investigator>
      <last_name>Jörg Faber, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Florian Ringel, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UniversitaetsMedizin Mannheim</name>
      <address>
        <city>Mannheim</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Karremann</last_name>
    </contact>
    <investigator>
      <last_name>Michael Karremann, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Iris Mildenberger, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Klinikum Rechts der isar Der Technische Universitaet Muenchen</name>
      <address>
        <city>Munich</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stephanie Combs</last_name>
    </contact>
    <investigator>
      <last_name>Stephanie Combs, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ludwig-Maximilians-Universitaet Muenchen - Campus Grosshadern</name>
      <address>
        <city>Munich</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Louisa von Baumgarten</last_name>
    </contact>
    <investigator>
      <last_name>Louisa von Baumgarten, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitaetskliniken Regensburg - Universitaetsklinikum Regensburg</name>
      <address>
        <city>Regensburg</city>
        <zip>93053</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Peter Hau, MD</last_name>
    </contact>
    <contact_backup>
      <last_name>Marcus Jakob, MD</last_name>
    </contact_backup>
    <investigator>
      <last_name>Peter Hau, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Marcus Jakob, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Tuebingen- Crona Kliniken</name>
      <address>
        <city>Tuebingen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ghazaleh Tabatabai</last_name>
    </contact>
    <investigator>
      <last_name>Ghazaleh Tabatabai, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Thomas Eichholz, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospital zurich</name>
      <address>
        <city>Zürich</city>
        <zip>8091</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Michael Weller, PI</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Germany</country>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>April 1, 2020</study_first_submitted>
  <study_first_submitted_qc>May 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 26, 2020</study_first_posted>
  <last_update_submitted>August 11, 2023</last_update_submitted>
  <last_update_submitted_qc>August 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>brain</keyword>
  <keyword>medullobalstoma</keyword>
  <keyword>MRI</keyword>
  <keyword>radiotherapy</keyword>
  <keyword>biomarkers</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Medulloblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vincristine</mesh_term>
    <mesh_term>Lomustine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04402073
org study id: 1634
nct id: NCT04402073
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
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.
allocation: Randomized
intervention model: Parallel Assignment
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
masking: None (Open Label)
measure: Progression Free Survival
time frame: 91 months after the date of recruitment of the first patient
description: 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.
measure: Progression Free Survival (PFS)
time frame: 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)
time frame: 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
time frame: when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.
description: This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, for adverse event reporting (with neurological, kidney, auditory, endocrine and radiotherapy associated as AE of special interest). The highest CTCAE v. 5 grading per cycle and per patient will be computed at the EORTC HQ for analysis . Safety and tolerability analyses will be performed in the safety population. Severe grades (3/4) which did not resolve after treatment discontinuation or emerged during follow-up will be identified and listed.
measure: health-related quality of life (HRQoL)
time frame: when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.
description: The primary HRQoL endpoint that is considered relevant for this study is social functioning. The other scales from the QLQ-C30 and BN20 will be considered as exploratory in nature.
A difference of 10 points on the 100-point QLQ-C30 social functioning scale between the two arms will be considered as clinically relevant.
measure: overall survival
time frame: when 43 PFS events are observed which is estimated to occur 91 months after the date of recruitment of the first patient.
arm group label: standard arms
arm group type: Other
description: Criteria: Adult SHH (p53wt) M0-1, adult WNT M0-1, adult Group 4 M0-1.
Radiotherapy to the cranio-spinal axis of 35.2 Gy in 22 daily fractions of 1.6 Gy, followed by an additional boost to the tumour site of 19.8 Gy in 11 daily fractions of 1.8 Gy, summing up to a total dose of 55.0 Gy in 33 daily fractions of 1.6/1.8 Gy.
Criteria: Post pubertal < 18 y SHH (p53wt) M0.
Radiotherapy to the cranio-spinal axis of 23.4 Gy in 13 daily fractions of 1.8 Gy, followed by an additional boost to the tumour site of 30.6 Gy in 17 daily fractions of 1.8 Gy, summing up to a total dose of 54.0 Gy in 30 daily fractions of 1.8 Gy.
arm group label: experimental arms
arm group type: Experimental
description: Radiotherapy Criteria: Adult and post-pubertal SHH (p53wt) M0; adult WNT M0, adult Group 4 M0.
Radiotherapy to the cranio-spinal axis of 23.4 Gy in 13 daily fractions of 1.8 Gy, followed by an additional boost to the tumour site of 30.6 Gy in 17 daily fractions of 1.8 Gy, summing up to a total dose of 54.0 Gy in 30 daily fractions of 1.8 Gy.
SMO-inhibitor Criteria: Adult and post-pubertal SHH (p53wt) M0.
Sonidegib 200 mg/day (daily) from first day of radio-chemotherapy until end of maintenance chemotherapy, including 6w chemotherapy break.
intervention type: Drug
intervention name: Sonidegib
description: Sonidegib is a selective smoothened inhibitor that inhibits the sonic hedgehog-signaling pathway. It is used in patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.
arm group label: experimental arms
intervention type: Drug
intervention name: Cisplatin
description: Cisplatin (CIS) is a platinum derivate used in the treatment in several epithelial tumours. The application route is through the veins.
arm group label: experimental arms
arm group label: standard arms
intervention type: Drug
intervention name: Lomustine
description: Lomustine is a nitrosourea used in the treatment of brain tumours and Hodgkin's disease. The application route is oral.
arm group label: experimental arms
arm group label: standard arms
intervention type: Drug
intervention name: Vincristine
description: Vincristine sulfate (VCR) is an inhibitor of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage. Vincristine sulfate is indicated in acute leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor. The application route is through the vein.
arm group label: experimental arms
arm group label: standard arms
intervention type: Radiation
intervention name: radiotherapy
description: Radiotherapy to the cranio-spinal axis of 35.2 Gy in 22 daily fractions of 1.6 Gy, followed by an additional boost to the tumour site of 19.8 Gy in 11 daily fractions of 1.8 Gy, summing up to a total dose of 55.0 Gy in 33 daily fractions of 1.6/1.8 Gy.
arm group label: experimental arms
arm group label: standard arms
criteria: 
gender: All
minimum age: 15 Years
maximum age: N/A
healthy volunteers: No
last name: Peter Hau
role: Principal Investigator
affiliation: EORTC study coordinator
last name: EORTC HQ
phone: 003227741611
email: eortc@eortc.org
facility: 
status: Recruiting
contact: 
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status: Recruiting
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status: Recruiting
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status: Recruiting
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investigator: 
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facility: 
status: Recruiting
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facility: 
status: Not yet recruiting
contact: 
country: Australia
country: Germany
country: Switzerland
responsible party type: Sponsor
mesh term: Medulloblastoma
mesh term: Vincristine
mesh term: Lomustine