Saturday 26 November 2016

Considering treatment options for high grade diffuse midline glioma H3k27m for my 8 year old daughter

Hi all,

Thanks so much to Stephen for your in depth reply to my questions about my 8 year old daughter and invitation to this blog. We moved to Norway in July and my daughter was diagnosed in early September with high grade diffuse midline glioma with H3K27m mutation after an extended biopsy, where it was determined that the tumor was not resectable. She underwent 3 further operations to have a double valve shunt put in to relieve hydrocephalus symptoms. She finished 6 weeks of radiation and Temodal about 10 days ago. The doctors want to start her on Temodal/Lomostine 4 weeks after radiation finished. If we follow this path, we could also have a full molecular analysis done and, upon recurrence, may possibly be able to access a trial using afatinib for BI1200.120, if applicable, or another targeted agent. I would also push for using repurposed drugs in the cocktail approach if possible and our conservative doctors could be convinced. 

We are trying to explore other options, and thanks to Stephen, learned about a new phase I peptide vaccine trial opening for paediatric glioma patients with mutation H3.3K27m based in San Fransisco. It is for patients who have completed 6 weeks of radiation and have not yet started chemo again, which is exactly where we are now. https://clinicaltrials.gov/ct2/show/NCT02960230

I am finding it so difficult to determine what would be the most promising, preferably least toxic option for my daughter. Any input on how promising a peptide vaccine targeted to this kind of mutation could be? Compared with temodar/lomostine/cocktail approach?

Many thanks in advance for your input.


Jeni

13 comments:

  1. Jeni,
    I understand enough tissue was removed in the biopsy procedure to test for the H3 K27M mutation. Was MGMT methylation status tested as well? If the MGMT status of the tumor is unmethylated, the tumor is much less likely to have a response to alkylating agents like Temodal or Lomustine.

    Do you have a link to the afatinib trial? I'm not sure that afatinib (an EGFR and HER2 inhibitor) would be the best choice for DIPG/diffuse midline glioma. I attended a presentation at the recent SNO conference which described a role of PDGFRA in K27M mutant midline gliomas:

    "PDGFRA expression is highest in stem-like/undifferentiated cells in all K27M midline gliomas (not in hemispheric gliomas)

    PDGFRA is not expressed in differentiating tumor cells

    Genetic overexpression of PDGFRA is associated with a lack of differentiation

    PDGFRA might cooperate with K27M to block differentiation capacity of cells"

    Based on this, I would think a PDGFRA inhibitor would be a better choice than afatinib. However, approved drugs with potent PDGFRA inhibiting activity, such as sorafenib, dasatinib, imatinib, nilotinib etc. were all developed for non central nervous system tumors, and their ability to cross the blood-brain barrier is likely limited at best. Afatinib has the same problem.

    Another targeted therapy with better (preclinical) evidence for DIPG is the HDAC inhibitor panobinostat. This drug has already been approved and could theoretically be prescribed off-label.

    I just found out there is a new multi-center trial about to start in the US testing panobinostat for DIPG.

    https://clinicaltrials.gov/ct2/show/NCT02717455

    There's no way of knowing how effective the H3 K27M vaccine will turn out to be, but is more interesting to me than chemotherapy, which has repeatedly failed to improve survival in DIPG. The H3 K27M vaccine has potential to be more effective for DIPG than rindopepimut is for EGFRvIII+ glioblastoma, as the EGFRvIII alteration is only found in a subset of cells and the H3 K27M mutation may be more widespread in a higher percentage of tumor cells.

    A lower dose metronomic schedule of TMZ could potentially benefit through anti-angiogenic effects independently of MGMT status, and a very low dose of metronomic TMZ could benefit through beneficial effects on the immune response, also independently of MGMT status. Although such effects alone wouldn't likely be enough, it could be a component of a multi-drug cocktail. Ideally we would know the MGMT promoter methylation status of the tumor.





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  2. I think Stephen has given very careful, sophisticated advice. A bit above my pay grade, in fact.

    It would be useful to know a more complete analysis of the tumor's makeup. Therefore, you might be interested in another trial I came across, which your child appears probably eligible for:

    Molecular Profiling for Individualized Treatment Plan for DIPG
    https://clinicaltrials.gov/ct2/show/NCT02274987

    I can't see which four FDA-approved agents will be selected on the basis of the tumor analysis, but this personalized approach may have merit, and the analysis results will, I imagine, be available for you in selecting further approaches in the future.

    Another advantage might be that there's an East Coast site (Children's in DC). This might be easier for you to travel to. Certainly, the specialists there (in general) have a top-notch reputation.

    Best wishes in this difficult challenge,

    Steve

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  3. Thank you so much Stephen for this thorough response. It is really so extremely helpful. I really appreciate the time you take. Our doctors keep telling me that MGMT status isn't so relevant for this tumor type, which is so difficult for me to understand when everything I read indicates that it is important. When we have the tumor analysed again (full molecular analysis) I hope to find out the MGMT status.

    Looking at the following treatment options, which would you choose in our position? Most promising/not too high toxitity?:
    - panobinostat trial
    - K27M vaccine
    - PDGFRA inhibitor if there is some way to help it to better cross the BBB?
    - Metronomic TMZ as part of a multi-drug approach (which other drugs would be the most relevant for this case?)

    With much gratitude,

    Jeni


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    1. The evidence for the relevance of MGMT in this tumor type might be lacking, but MGMT serves the same role in cancer cells of all types and healthy cells - it has a pretty specific function of removing alkyl groups on a specific location on DNA, regardless of tumor type.

      The experience so far in GBM makes me somewhat skeptical that a single targeted agent will make a lasting difference. Most people here would probably agree given that this is a blog about the cocktail approach. Panobinostat may be promising, but I wouldn't want to rely on that alone, and the problem with most clinical trials is that they specifically exclude the multi-agent approach that is probably necessary to make a lasting difference in this disease.

      Therefore I would be more inclined to find someone to prescribe panobinostat off-label rather than join the trial, which could present a challenge in itself (it's not a standard treatment for DIPG). The same challenge applies to off-label use of a PDGFRA inhibitor.

      I think I'd put the K27M vaccine first on my list, given it's a now or never opportunity. Everything else we're discussing you could theoretically get outside of a trial.

      Second option would ideally be a multi-agent cocktail including panobinostat, perhaps a PDGFRA inhibitor, additional agents to help both of these get into the tumor, perhaps metronomic TMZ, and some other agents based on evidence from adult GBM. Unfortunately there's been very little preclinical or clinical work showing what would be most effective for K27M type tumors.

      I said "ideally" because realistically, panobinostat and PDGFRA inhibitors are expensive oncology drugs in the price range of $5000-$10,000 US dollars per month, and they aren't standard of care for glioma. It would be a challenge to get one of them prescribed, let alone both.

      The panobinostat trial looks more attractive in view of these considerations, yet the vaccine trial is recruiting newly diagnosed cases and the panobinostat trial is recruiting patients progressive after standard treatments. This is another point in favor of vaccine now, and perhaps panobinostat trial later.

      In addition to the trial Steve mentioned - and I have questions about which drugs are on their panel, and if they've been selected for ability to penetrate into the central nervous system - see my list of pediatric trials here, rather inconveniently located for those outside the US:

      http://astrocytomaoptions.com/currently-recruiting-trials-pediatric-glioma/

      A little closer to you is a trial in Spain, although I'm not sure if one can join this trial post-radiation. It is a dendritic cell vaccine pulsed with allogeneic tumor lysate, meaning the dendritic cells (obtained from the patient through leukapheresis) would be pulsed with lysate from other glioma cell lines, and doesn't require tumor tissue from your daughter. This same approach is being tested in a clinical trial at Mayo clinic. While closer, I'm not sure I'd prefer it to the H3 K27M vaccine.



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    2. Link to the trial in Spain:
      https://clinicaltrials.gov/ct2/show/NCT02840123

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  4. Thank you so much, Steve. I just saw your comment now and am also contacting the researchers regarding the individualized treatment trial.

    Many thanks again,

    Jeni

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  5. H3 K27M is certainly considered as a tumor antigen. This is the European situation. In Heidelberg, researcher develop a DC-peptide vaccine. In Barcelona, a DC trial is started in which the DCs are loaded with lysates derived from allogeneic DIPG cell lines. In IOZK, about 22 children have been treated with multimodal immunotherapy consisting of Newcastle Disease Virus infusions + modulated electrohyperthermia + DC loaded with serum-derived antigenic microparticles. The results at first October, show that the children treated with immunotherapy in an adjuvent setting in conjuction to radiotherapy do much better than children who started immunotherapy at time of progression after the primary treatment. In the primary treatment group , one child died after 4.3 months. All other children are alive with median follow up of 9.1 month (4.3-17.0 m). In the disease progression group , median overall survival was 5.8 months. Two children from group 2 are alive with 14 resp. 6.3 months follow up. Of course, these results should be interpreted with caution as the follow up is still very short, and the survival curves certainly will change. Further: the CED team from Bristol moved to Harlem Street Clinic in London. Finally, several countries participate in the BIOMEDE study (targeted therapy - the drugs you mentioned) from Paris but the inclusion requires biopsy. However, a lot of drugs that were mentioned above have already shown no effect, both the targeted therapies as well as the HDAC inhibitors. So I can fully support the statement of Stephen to choose as first option an immunotherapy approach.

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    1. Thanks SVG for filling in more details on the European situation.

      It does seem the Heidelberg team is also developing a H3 K27M peptide vaccine, is this the vaccine you refer to? I wonder if they have tried this in patients yet?
      http://neuro-oncology.oxfordjournals.org/content/18/suppl_4/iv5.1.abstract

      For Jeni, the link to the Barcelona trial we both mentioned is here:
      https://clinicaltrials.gov/ct2/show/NCT02840123

      IOZK in Koln Germany is certainly an option to explore, as SVG mentions they can derive antigens from serum, and may not absolutely require tumor tissue to create an individualized dendritic cell vaccine.
      http://www.iozk.de/en/start/home

      The BIOMEDE study sounds very limited to me. As far as I can tell they are only selecting drugs from a list of 3 possible options: erlotinib (EGFR inhibitor), everolimus (mTOR inhibitor) and dasatinib (multi-kinase inhibitor with targets including SRC and PDGFRA), and you would only get one of these, no combinations. I would certainly prefer a vaccine to this option.
      https://clinicaltrials.gov/ct2/show/NCT02233049
      https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-001929-32/DK


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  6. Thank you Stephen W and SVG for this input. I have been in contact with the San Fransisco trial (peptide vaccine for H3K27m) and am waiting on the results of a blood test to find out if my daughter is HLA A2 positive and thus qualifies for the trial. Unfortunately, I am told this can take 1 to 2 weeks. In the mean time, I am trying to sort out plans B and C. I will be speaking with IOZK tomorrow. SVG mentioned a trial IOZK were doing with multimodal immunotherapy. Was this with DIPG patients? If you have a link to that study, I would really appreciate it. I’m also keeping in mind the DC vac. for DIPG trial in Barcelona.

    I am trying to wrap my head around the differences between a peptide versus a multimodal DC-virotherapy approach and which could be more likely to be more effective in my daughter`s case with an aggressive unresectable tumor. Any thoughts?

    Also, I am wondering if there are any suggestions for how to potentially manage edema resulting from immunotherapy using off label or over the counter supplements. I have been talking to our Dr. about using Celebrex.

    Also, I am assuming it should it be possible to continue taking over the counter supplements while participating in a trial?
    I currently have her on:
    - Turkey tail
    - Boswellia
    - Curcumin
    - Berberine
    - Melatonin
    - Guarbean (meant to have similar effect as Metformin)
    - Omega 3
    - Spirulina
    - Chlorella
    - probiotics
    - Beta Glucan
    - Vitamin C
    - multi vitamin
    - selenium + vit E

    Many thanks again for your time, effort, and support. It is very much appreciated!!

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  7. Dear Jeni,
    We are in a very similar situation - my 16-year old son has H3K27 mutant glioma ( resected from cerebellum) so I am following this as well - looking at all the options across the world
    Olga

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  8. Dear Jeni,
    Can we maybe connect to share our thoughts and research results? My number is 908-392-6030. Please call me any time
    Olga

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  9. my e-mail address is olgaph15@hotmail.com

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  10. thank you, Stephen, so much! I just e-mailed him. I hope our tumor is "good enough"

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