Development of Randomized Trials in Adults with Medulloblastoma—The Example of EORTC 1634-BTG/NOA-23

Round 1

Reviewer 1 Report

This is an very well designed and ambitious trial. The submitted manuscript provides a excellent overview of adult medulloblastoma and a detailed description of trial design and outcomes. No suggestions for improvement.

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This manuscript describes in real detail a very ambitious trial of radiochemotherapy with sonidegib in young adult and adult patients with newly diagnosed medulloblastoma to be conducted in Europe and Australia. This is a very rare disease in adults and international cooperation is required Because this disease is so rare, no clear standard treatment  exists, and with molecular subgrouping and the potential for targeted therapy, a study such as this needs to be conducted. This is a very complex and challenging trial to undertake, and in addition to the primary endpoint, the efficacy of sonideib in SHH subgroup, the feasibility of RT de-escalation, including comparison of efficacy and toxicity of photons vs. protons, and many correlative and translational endpoints are being evaluated. Of note, this is a phase II study with a limited number of patients in each arm. and with a two-sided alpha of 20%, I am not sure whether results will be definitive. Nonetheless, this is a good trial that I would endorse. I have no questions for improvement of the man script and would recommend acceptance as is.

Author Response

Many thanks for this very positive response.

Indeed, the number of patients in each arm is limited in this phase II-trial, and the primary endpoint PFS-3 with a two-sided alpha of 20% is ambitious, however substantiated by published data. Even if the primary endpoint should be negative, the trial will collect a substantial unprecedented dataset including translational research that will be used to inform future trials on medulloblastoma.

Thank you again for this positive review.

Reviewer 2 Report

Authors here review a novel clinical trial, EORTC 1634-BTG / NOA-23, which will be the first prospective randomized clinical trial in post-pubertal pediatric and adult patients with medulloblastoma. It will study a targeted therapy, sonidegib against SMO, in combination with radio-chemotherapy in a randomized setting. It will also be personalized and look at reduction in radiation therapy and tolerability of sonidegib. Authors do a good job of reviewing each component of this trial and how they came up with each arm of the trial. Minor suggestions to improve it follow:

1. "Depending on genetic subgroups, adult and pediatric medulloblastomas are prognostically distinct." - please provide a few examples of the ways adults and pediatrics MB are distinct.

2. "Treatment has therefore been extrapolated from experiences in children, and personalized or molecularly stratified therapies have not been invented in adults." - what is the most common treatment regimen for MB in adults? for SHH MB in adults? 

3. Please specify the Packer-based adjuvant chemotherapy. 

4. "SHH-tumors have a better outcome in infants (5-year overall survival (OS) rate of 77%) than in children (5-year OS rate of 68%) and adults (5-year OS rate of 34%)." Reference? According to Cavalli et al Cancer Cell 2017, SHH(infant) 5-yr OS 67-88%, SHH(child) 5-yr OS 70%, and SHH(post-pubertal) 5-yr OS 88.5%.

5. It remains unclear why Group 3 MB patients are excluded from this trial. Can the authors include the inclusion/exclusion criteria for the trial?

6. While obtaining CSF for biomarker determination is a good idea, what about collecting blood at the same time for the same purpose? Or to compare levels of the biomarkers isolated in CSF with those circulating in blood?

Author Response

Many thanks for this very positive response and your important notes. 

We would like to address your suggestions as follows:

Question 1: Depending on genetic subgroups, adult and pediatric medulloblastomas are prognostically distinct." - please provide a few examples of the ways adults and pediatrics MB are distinct.
Answer: We have added in the respective section: „In addition to molecular differences, clinically relevant features clearly differentiate adult from paediatric medulloblastoma. E.g., adolescents and adults have a higher incidence of lateral localization of the tumour in the hemispheres of the cerebellum than children. This localization relates to the known overrepresentation of the SHH-subgroup in adults. In addition and in contrast to children, SHH mutations in adults are at the level of SMO or upstream in the vast majority“.

Question 2: "Treatment has therefore been extrapolated from experiences in children, and personalized or molecularly stratified therapies have not been invented in adults." - what is the most common treatment regimen for MB in adults? for SHH MB in adults? 
Answer: the most common treatment regimen in adults are radiotherapy of the cranio-spinal axis only or radiotherapy combined with the Packer or Taylor chemotherapy regimen at this time. This paragraph has also been included in the manuscript.

Question 3: Please specify the Packer-based adjuvant chemotherapy. 
Answer: the Packer regimen has already been specified in the legend of figure 1. We now have included the same text in the respective section of the manuscript. 

Question 4: "SHH-tumors have a better outcome in infants (5-year overall survival (OS) rate of 77%) than in children (5-year OS rate of 68%) and adults (5-year OS rate of 34%)." Reference? According to Cavalli et al Cancer Cell 2017, SHH(infant) 5-yr OS 67-88%, SHH(child) 5-yr OS 70%, and SHH(post-pubertal) 5-yr OS 88.5%.
Answer: The reviewer is right with his/her most recent citation, and we have added the dataset of Cavalli to the new version of the manuscript. Our date (which were distinct for adults) were derived from older publications, but the one of Cavalli may indeed be more representative. We therefore have also attenuated our wording in this section now saying "SHH-tumors have similar outcomes in infants (5-year overall survival (OS) rate of 67.3-88.0%), children (5-year OS rate of 69.8%) and adults (5-year OS rate of 88.5%) (Cavalli et al., 2017), with differential - and sometimes worse - outcomes for the adult subgroup in the older literature.“ 

Question 5: It remains unclear why Group 3 MB patients are excluded from this trial. Can the authors include the inclusion/exclusion criteria for the trial?
Answer: The exclusion of Group 3 was initially based on data that Group 3 does almost not exist in adults. We will amend that in the next version of the protocol based on the very small number of Group 3-patients also in this age group, and have added „Group 3“ to the respective section of the manuscript.

Question 6: While obtaining CSF for biomarker determination is a good idea, what about collecting blood at the same time for the same purpose? Or to compare levels of the biomarkers isolated in CSF with those circulating in blood?
Answer: The reviewer picks up an important point. Of note, we will also collect blood at the same time and for the same purpose as CSF. This fact has accidentally not been mentioned in the manuscript and has now been added.

Many thanks again for your notes that helped to improve the manuscript.