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Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma

NCT04402073

Description:

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.

Related Conditions:
  • Desmoplastic/Nodular Medulloblastoma
  • Large Cell/Anaplastic Medulloblastoma
  • Medulloblastoma
  • Medulloblastoma with Extensive Nodularity
  • Medulloblastoma, Non-WNT/Non-SHH
  • Medulloblastoma, WNT-Activated
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 1634
  • NCT ID: NCT04402073

Conditions

  • Medulloblastoma

Interventions

DrugSynonymsArms
Sonidegibexperimental arms
Cisplatinexperimental arms
Lomustineexperimental arms
Vincristineexperimental arms

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
standard armsOtherCriteria: 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.
  • Cisplatin
  • Lomustine
  • Vincristine
experimental armsExperimentalRadiotherapy 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.
  • Sonidegib
  • Cisplatin
  • Lomustine
  • Vincristine

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 (>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 ≥ 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 x ULN or creatinine clearance (CrCl) > 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 < 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 ≥ 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:15 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival
Time Frame:91 months after the date of recruitment of the first patient
Safety Issue:
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.

Secondary Outcome Measures

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.
Safety Issue:
Description:
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.
Safety Issue:
Description:
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.
Safety Issue:
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.
Safety Issue:
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.
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:European Organisation for Research and Treatment of Cancer - EORTC

Trial Keywords

  • brain
  • medullobalstoma
  • MRI
  • radiotherapy
  • biomarkers

Last Updated

May 20, 2020