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Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma (PersoMed-I)

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ClinicalTrials.gov Identifier: NCT04402073
Recruitment Status : Not yet recruiting
First Posted : May 26, 2020
Last Update Posted : May 26, 2020
Sponsor:
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

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.

Condition or disease Intervention/treatment Phase
Medulloblastoma Drug: Sonidegib Drug: Cisplatin Drug: Lomustine Drug: Vincristine Radiation: radiotherapy Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 205 participants
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
Masking: None (Open Label)
Primary Purpose: Health Services Research
Official Title: Personalized Risk-Adapted Therapy in Post-Pubertal Patients With Newly-Diagnosed Medulloblastoma (PersoMed-I)
Estimated Study Start Date : September 1, 2020
Estimated Primary Completion Date : December 1, 2028
Estimated Study Completion Date : December 1, 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
standard arms

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.

Drug: Cisplatin
Cisplatin (CIS) is a platinum derivate used in the treatment in several epithelial tumours. The application route is through the veins.

Drug: Lomustine
Lomustine is a nitrosourea used in the treatment of brain tumours and Hodgkin's disease. The application route is oral.

Drug: Vincristine
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.

Radiation: radiotherapy
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.

Experimental: experimental arms

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.

Drug: Sonidegib
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.

Drug: Cisplatin
Cisplatin (CIS) is a platinum derivate used in the treatment in several epithelial tumours. The application route is through the veins.

Drug: Lomustine
Lomustine is a nitrosourea used in the treatment of brain tumours and Hodgkin's disease. The application route is oral.

Drug: Vincristine
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.

Radiation: radiotherapy
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.




Primary Outcome Measures :
  1. Progression Free Survival [ 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 Outcome Measures :
  1. 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. ]
  2. 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. ]
  3. 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. ]
    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.

  4. 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. ]

    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.


  5. 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. ]


Information from the National Library of Medicine

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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04402073


Contacts
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Contact: EORTC HQ 003227741611 eortc@eortc.org

Locations
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Switzerland
University Hospital zurich
Zürich, Switzerland, 8091
Contact: michael Weller, PI         
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Investigators
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Principal Investigator: Peter Hau EORTC study coordinator
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Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT04402073    
Other Study ID Numbers: 1634
First Posted: May 26, 2020    Key Record Dates
Last Update Posted: May 26, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
brain
medullobalstoma
MRI
radiotherapy
biomarkers
Additional relevant MeSH terms:
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Medulloblastoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neuroectodermal Tumors, Primitive
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Vincristine
Lomustine
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents