Saturday, 26 January 2019

Advice for a 8 year-old boy with diffuse midline glioma, BRAFV600E and H3K27M mutation

Dear Stephen, dear all,

Anatole, my 8 year-old son has been diagnosed in May 2018 with a diffuse midline glioma on the right thalamus. We are French and based in Stockholm, Sweden. We followed the proposed protocol with the local medical team who works in partnership with Gustave Roussy institute in France but we want to go further now, and we need your advice. The local medical team is not very aware of alternative medication but is willing to help.

Molecular status of the tumour:
BRAFV600E and H3K27M mutation
NF1 and MLH1 mutation
We have little chance to find new targetable alterations by a deeper sequencing. It is possible now that the V600E BRAF mutation is lost in the resistant cells but anyway we do not think it is wise to treat with a V600E BRAF inhibitor which in our experience could speed up tumor growth.  

18/05/09 Diagnosis: MRI tumour size 3.3x3.7x3.7cm, unusual calcification
18/05/16 Biopsy, leading to light hemiparesis
Proton-therapy 18/07/02-18/08/13, 1.8Gy x 30 = 54Gy. Almost fully recovered from hemiparesis
18/09/07 Headaches
18/09/07 MRI tumour size about 4cm
18/09/12 Ventriculostomy
18/09/19 Beginning og Dasatinib (100+70mg/day), after 18/11/06 alternating with Everolimus (5mg/day) every 2 weeks (Biomede protocol)
18/09/22 Beginning of hemiparesis
18/10/03 Wheelchair for walks more than 20m
18/10/12 MRI tumour size 5 to 6cm unsure if pseudoprogession
18/10/22 Beginning of Bevacizumab then once every 2 weeks
18/11/06 Beginning of Everolimus  
18/12/03 MRI tumour size 4 to 5cm unsure if pseudoprogession
18/12/17 Crook for walks less than 20m
19/01/14 MRI tumour size 5x6x5cm
19/01/22 Stop all current chemo (Dasatinib and Everolimus, last Bevacizumab 19/01/02)
24/01/24 PET scan (methyonine)
New plan established by Gustave Roussy Institute: Mebendazol, investigation for debulking of calcification before re-irradiation, eventually ONC201
Any comment on this plan?

Anatole is 30kg 132cm  
D3 vitamin since 18/12/24: escalading from 40µg/d to 100µg/d now
Fish oil since 18/12/24: 1g
Melatonin since 19/01/10: escalading from 2mg/d to 5mg/d now
Turkey tail since 19/01/25: 500mg/d

We plan to add soon:
Longvida Curcumin: 800mg/d
Milk thistle: which dose would you recommend? 
Green tea extract: which dose would you recommend? 
Broccoli sprouts: which dose would you recommend? 
Metformin: Is it worth considering for a child?

Anything else you would find suitable considering his condition (celebrex, chloroquine, clomipramine, berberine, selenium, probiotics, etc?

We follow a light low carb diet now (no refined sugar or flour, very limited sugar, no processed food, only bio food). We are planning to begin a ketogenic diet soon, we are ready to change all our habits. We will contact a dietetician specialist in this diet. Anybody else with an experience of ketogenic diet with children?

Thanks to all of you for your precious help, any contribution could help.


  1. Hi Fabrice,
    Was the genetic testing that detected the BRAF, H3, NF1 and MLH1 mutations done by his treating hospital, or was it done by one of the commercial sequencing companies like Caris, Foundation Medicine etc?
    MLH1 is a mismatch repair protein, and tumors with faulty mismatch repair may have a high mutational load (aka Tumor Mutational Burden). I wonder if there was enough genetic material sequenced to quantify the Tumor Mutational Burden (in mutations per megabase of DNA). This would be the case if it was sequenced by Caris or one of the comparable companies. If his tumor is hypermutated (has a high Tumor Mutational Burden), due to the MLH1 mutation, you might want to consider treatment with immune checkpoint inhibitors such as nivolumab or pembrolizumab.

    Given the H3 K27M mutation I would also try to get him on ONC 201 sooner rather than later. Has he been approved for this already?

    ONC 201 is a selective dopamine D2 receptor antagonist. There are quite a few DRD2 antagonists approved as psychiatric drugs, such as the phenothiazines (thioridazine, perphanazine, trifuluperazine), although they are not as selective as ONC201, so would likely have more potential side-effects. ONC201 would be preferable if you can get it.

    Which dose of mebendazole is being recommended? While low doses of 200 mg are effective against intestinal parasites, the drug has low bioavailability (which is likely the reason for its tolerability even at higher doses). In the clinical trials being done at Johns Hopkins for high grade glioma, much higher doses are being used.

    Like BRAF, NF1 is also involved in the RAS-RAF-MEK-ERK pathway. It's actually a tumor suppressor that inhibits RAS. Have you discussed the use of a MEK inhibitor such as trametinib? Unfortunately these drugs likely have limited blood-brain barrier penetration.

    1. Hi Stephen,
      1000 thanks for your comments.
      The genetic testing was performed by his hospital. The material from the biopsy was quite small but I will definitely pass your comment to the medical team.

      We have just contacted the four centers running the ONC201 pediatric trial. Ann Arbor can't take international patients, NY (Sharon Gardner) had a laconic reply saying that "Unfortunately I think the ONC201 is unlikely to work given the extent of his disease" just based on the small history similar to the one above, without even looking at the scans (which drives me really mad), and we are currently putting together a dossier for Miami and Houston. Do you have any advice for us to have more chances to be included in theses trials?

      For the mebendazole, the suggested dose, which has to be confirmed, was 1500mg/d. We will have a new meeting with the team soon to confirm and begin the treatment.

      I will also pass your comments on treatment with immune checkpoint inhibitors such as nivolumab or pembrolizumab, and MEK inhibitor such as trametinib.

      Concerning the supplements and OTC drugs, is there any drug that could have potential effects and why? metformin, celebrex, chloroquine, clomipramine, berberine, selenium, etc? So I can discuss them with the medical team. Or maybe the question could be inversed: which ones would you not recommend?

      Thanks again for everything

    2. Hi Fabrice,
      I've reached out to a few colleagues for advice on the ONC-201 question. Will let you know what I can find out.

      1500 mg for a 30 kg boy would be 50 mg/kg and this sounds quite reasonable, and this is also the dose we recommended in the CUSP-ND protocol. Depending on the tolerability of this dose you could consider even higher doses later. There are documented cases of children with hydatid disease being treated with mebendazole doses of 100-200 mg/kg/day.

      The question of which supplements and drugs to try in a cocktail is more complicated. This blog has focused on adult GBM because there is more clinical and preclinical evidence for this type of glioma than any other. Pediatric glioma with H3 K27M mutation is a separate biological type of tumor, and there is much less evidence when it comes to what might be effective in these tumors. We are only beginning to understand them, and the recent evidence of ONC-201 having a preferential effect in these tumors is hopefully only the beginning.

      I'm not sure of the legal status of cannabis in your country, but one family had good results treating their young girl with DIPG with a concentrated cannabis oil.

      I don't know any pathology details in her case but the majority of DIPGs also have the H3 K27M mutation.

    3. Thanks Stephen for your reply!
      Concerning the cannabis oil, it is not allowed in Sweden but it is in the Netherlands in other European countries so there are certainly ways to get it. We will investigate.
      Any other people here maybe who have been looking for cannabis oil in Europe and having good tips?
      Looking forward to hearing your findings about the ONC201 trial.
      Warm regards

    4. One user of this blog who lives in Europe go their medical cannabis products from the Netherlands:

      There's an expanded access protocol for patients with H3 K27M positive, diffuse midline glioma, for patients ages 3 and over, not eligible for ONC 201 clinical trials. If you have already been refused at one of the trial locations, I would call the company about expanded access. Contact and protocol details on this page:

    5. Contact: Clinical Operations Oncoceutics 1-888-ONCORXS ext 1

    6. Dear Stephen, long time without news. I just wanted to inform you that, after having been able to gather the funds thanks to a fund raise on , we will fly to Houston in a couple of days for a two weeks evaluation process at MD Anderson to check his eligibility in the ONC201 trial. We have been in contact with OncoCeutics and they say Anatole should be eligible anyway for the compassionate use if we stay in the US. We keep in touch.

    7. All the best to you and your son! Finger crossed everything goes ok

    8. Thanks for the update Fabrice, I'm glad to hear you were able to raise some funds, and have some real possibilities for getting access to ONC201. All the best of luck to you and your family.

  2. Dear Fabrice,
    My heart goes out to you and your family. While I do not have experience using the keto diet with a child, you may find these resources helpful. The Charlie Foundation ( was created to support families with children who have epilepsy (which in some cases is controlled by this diet) and the nutritionist Miriam Kalamanian used this diet effectively for years with her own son who had brain cancer ( Sending hope.

  3. Dear SJ67,
    Thanks a lot for your help!
    Warm regards

  4. Dear Fabrice,

    some time ago I wrote to dr. Jean M Mulcahy Levy, she applied chloroquine for the BRAF mutation, with apparently spectacular response
    amd further TMZ treatment possible. At the end of this article, there is a link to her research paper.

    Perhaps you may look at it, or ask the doctor for more comments. We did not decide to add chloroquine to our coctail since the BRAF was not detected in the genetic testing (posteriori)

    Kind regards,

    1. Sorry, one correction, patients of drJean M Mulcahy Levy were treated with Vemurafenib, not TMZ.

    2. Dear Stefan,
      Many thanks for your comment! I will definitely mention this article to our team.
      Warm regards