Trial investigating a personalized treatment, based on age and tumor characteristics , of newly diagnosed medullablastoma in patients that are postpubertal and/or adult consisting of lowering RT,chemotherapy doses and adding an investigative drug.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

European Organisation For Research And Treatment Of Cancer

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Nov 2022 → 15 Dec 2025

Decision date (initial)

2024-07-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Sunpharmaceuticals · EORTC-BTG

External identifiers

EU CT number

2023-506193-12-00

EudraCT number

2020-003063-26

ClinicalTrials.gov

NCT04402073

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Therapy, Safety

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.

Secondary objectives 9

1. To compare PFS by central reviewer in WNT and Group 3 & 4 subgroups
2. To compare PFS by local investigator
3. To compare overall survival (OS)
4. To evaluate safety and tolerability profile
5. To evaluate short- and long-term health-related quality of life (HRQoL) with a particular emphasis on the social functioning scale
6. 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)
7. To evaluate short- and long-term neurocognitive function (NCF)
8. To evaluate short- and long-term endocrine function
9. To assess the incidence of second malignancies

Conditions and MedDRA coding

Newly Diagnosed Medulloblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. 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 the age of legal consent, consent has to be obtained from the parent(s) or legal representative according to ICH/GCP, and national/local regulations.
2. Step 1: Registration: FFPE tumour tissue from surgical resection and whole blood for central pathology review must be available.
3. Step 2: Enrollment/randomization: Newly diagnosed, histologically proven, genetically classified, centrally confirmed medulloblastoma
4. Step 2: Enrollment/randomization: Molecular subtype: medulloblastoma, SHH-activated, M0-1; medulloblastoma, WNT-activated, M0-1; medulloblastoma, Group 3 & Group 4, M0-1
5. Step 2: Enrollment/randomization: Histologic subtype: medulloblastoma, classic (CMB); medulloblastoma, desmoplastic/nodular (DNMB); medulloblastoma, with extensive nodularity (MBEN); medulloblastoma, large cell/anaplastic (LCA)
6. Step 2: Enrollment/randomization: Post-pubertal patients (<18y of age), or adults (18 y of age and above) in SHH-activated medulloblastoma.
7. Step 2: Enrollment/randomization: Adults (≥ 18 years) in the WNT-activated, Group 3 & Group 4 medulloblastoma.
8. Step 2: Enrollment/randomization: Patients (<18 years) must have completed puberty.
9. Step 2: Enrollment/randomization: Patients (<18 years) must have a radiologically confirmed bone age of minimum 15 years for females and 17 years for males.
10. Step 2: Enrollment/randomization: Clinical status within 2 weeks of randomization/enrollment: Karnofsky 50-100
11. Step 2: Enrollment/randomization: NANO-score 0 to 9 (allowing full-blown cerebellar symptoms)
12. Step 2: Enrollment/randomization: Clinically standard-risk (centrally assessed MRI review on pre- and postoperative MRI) defined as: • Adult patients: total or subtotal surgical resection defined as at least 80% reduction of the contrast enhancing tumour and/or less than or equal to 1.5 cm2 (measured in axial plane) of residual tumour on early post-operative MRI, without and with contrast. • Post-pubertal patients: 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
13. Step 2: Enrollment/randomization: No evidence of extra-CNS metastasis
14. Step 2: Enrollment/randomization: Full recovery from surgery or any post-surgical complication (e.g., bleeding, infections etc.)
15. Step 2: Enrollment/randomization: Baseline MRI as the following: • Brain MRI: pre- and post- surgery (within 72h) MRI is mandatory. • Spine MRI: preferably pre-operative. If not available, post-operative is acceptable.
16. Step 2: Enrollment/randomization: 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 (the estimated GFR should be in mL/min/1.73m² unit, using the MDRD formula)
17. Step 2: Enrollment/randomization: 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 women of childbearing / reproductive potential (WOCBP).
18. Step 2: Enrollment/randomization: WOCBP must use two methods of adequate birth control, including a highly effective method and a barrier method. Birth control during the study treatment period and for at least 20 months after the last study treatment is mandatory for patients who receive sonidegib. For all other patients, this period is 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.
19. Step 2: Enrollment/randomization: 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 12 months after ending treatment (donation of semen for the semen analyses in the 1 b fertility project is allowed)
20. Step 2: Enrollment/randomization: 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.

Exclusion criteria 14

1. Step 2: Enrollment/randomization: Prior treatment for medulloblastoma
2. Step 2: Enrollment/randomization: Unavailability of central review pathology results
3. Step 2: Enrollment/randomization: Post-pubertal patients with known negative prognostic markers (MYC/MYCN amplification and/or TP53 germline alteration in the SHH subgroup)
4. Step 2: Enrollment/randomization: Inability to start radiotherapy within 56 days after surgery.
5. Step 2: Enrollment/randomization: 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
6. Step 2: Enrollment/randomization: Any medical contraindication to radiotherapy or chemotherapy
7. Step 2: Enrollment/randomization: Hypersensitivity to contrast medium for MRI.
8. Step 2: Enrollment/randomization: Hypersensitivity towards the active substance of any of study drugs or their excipients
9. Step 2: Enrollment/randomization: Current use of BCRP substrates such as mitoxantrone, methotrexate, topotecan, imatinib or irinotecan or if patient is within 5 times the half-life of these medications
10. Step 2: Enrollment/randomization: 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.
11. Step 2: Enrollment/randomization: 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.
12. Step 2: Enrollment/randomization: Known history or current evidence of active Hepatitis B (e.g., positive HBV surface antigen) or C (e.g., HCV RNA [qualitative] is detected)
13. Step 2: Enrollment/randomization: Known or current evidence of Human Immunodeficiency Virus (HIV) infection (positive HIV-1/2 antibodies)
14. Step 2: Enrollment/randomization: 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-Free Survival (PFS) according to RAPNO assessed by central reviewer of a personalized intensity-modulated therapy (experimental arm; sonidegib) compared to standard therapy in SHH-activated patients in post-pubertal patients with newly diagnosed standard risk medulloblastoma.

Secondary endpoints 5

1. Progression-Free Survival (PFS) by central reviewer in WNT and Group 3 & Group 4 subgroups
2. Progression-Free Survival (PFS) by local investigator
3. Overall survival (OS)
4. 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)
5. Patient reported outcomes: • Health-related Quality of life (HRQol): EORTC QLQ-C30 and 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

European Organisation For Research And Treatment Of Cancer

Sponsor organisation

European Organisation For Research And Treatment Of Cancer

Address

Emmanuel Mounierlaan 83 Bus 11

City

Sint-Lambrechts-Woluwe

Postcode

1200

Country

Belgium

Scientific contact point

Organisation

European Organisation For Research And Treatment Of Cancer

Contact name

Stéphanie Kromar

Public contact point

Organisation

European Organisation For Research And Treatment Of Cancer

Contact name

Vassilis Golfinopoulos

Third parties 4

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications