Friday, 14 April 2017

On Avastin/TMZ, but looking to future - Abemaciclib potential or DCVax-L/nivolumab therapy

Hi all,

My Dad's story/timeline/cocktail can be seen here:
http://btcocktails.blogspot.com/2017/02/tom-wangerin-cocktail-profile-and.html

He is MGMT methylated, not IDH1 mutated, positive for 1p Deletion, and after recently receiving our genetic testing Foundation One report back (which was completely covered by our insurance!!) shows a "CDKN2A/B loss" - which leads me to my next few topics


  • We completed standard chemo-radiation in January 2017 (radiation caused inflammation that has us struggling to get him lower than 4mg/day decadron).
  • Has finished (3) rounds of TMZ since.
  • His latest Image (March 2017) showed increased inflammation to the point where our NO at UCSF could not really see much, but it was clear the TMZ was not decreasing the tumor size.
  • A week ago on April 4th 2017 - My dad received his first Avastin infusion. The thought here is to use the Avastin in short term bursts to not only help with inflammation (lowering decadron dosage), but also clearing up the image for the NO to make a better gameplan moving forward. I want to make sure we are not going to stay on Avastin long enough for the tumor to find new pathways (become "immune") as you see happens so often. Any thoughts on this stradegy?
  • Our next image/consultation at UCSF is in a week (4/17/17) to see whether the Avastin infusion made a difference.
Moving Forward

Option 1 - Is anyone familiar with Abemaciclib? I haven't seen any posts on here about this CDK4/CDK6 inhibitor. I bring this up because our NO was surprised to see our Foundation One report mention his "CDKN2A/B loss". He immediately mentioned Abemaciclib and is looking at potential trials or best case getting it off-label in some way or another.

This drug seems to be used more often in breast cancer, but has not shown any spectacular results as far as I can find. Any thoughts?

Option 2 - DCVax-L/nivolumab therapy - Until the last time we met with our NO this was by far our most exciting find. This Phase II trial is soon to be recruiting out of UCLA 

(https://clinicaltrials.gov/ct2/show/NCT03014804?term=immunotherapy+OR+dendritic&cond=glioblastoma+recurrent&state1=NA%3AUS%3ACA&state2=NA%3AUS%3AWA&state3=NA%3AUS%3AOR&rank=1)

DCVax has been spoken about on this forum and appears to be showing better results (and more overall information out there than Abemaciclib). Here are the scary parts of the trial:
  • Our NO has said that he has been finding an overwhelming amount of his patients have serious side effect issues with Nivolumab (inflammation being one of them) and he has seen many end there usage. I did find this odd because many on this forum have spoken about it without the negative connotation.
  • To be included in this trial my Dad must get below 2mg/day of steroid use, which I'm worried might not be possible. 
  • He would need to have a recurrence and it would need to be operable which is scary in itself.... meaning all the stars will need to align for us to get accepted.
Let me know if the community out there has any opinions of our potential options and usage of Avastin.

Thank you all for reading and contributing. 

Ari Wangerin
(Oakland, California)




3 comments:

  1. I have a few thoughts that may be of use:
    1. Abemaciclib does indeed appear to be promising for GBM. I frankly hadn't heard of it before your post, but a Pubmed search for that agent and "blood-brain barrier" yielded a single article:
    Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft.
    https://www.ncbi.nlm.nih.gov/pubmed/26149830

    2. I agree that the UCLA trial looks promising. In our case, nivolumab/Opdivo was given in a trial simultaneously with the standard Stupp protocol. It did indeed cause severe brain edema, refractory to higher-dose decadron. We had to drop out of the trial. She then was given Avastin to treat the edema, with rapid resolution of the edema. I believe she could have tolerated the Opdivo indefinitely had it been allowed for her to be on Avastin within the trial.

    It might be possible for him to receive Avastin within the DCVax trial, in order to counter any brain edema.

    2. I think it may be prudent to use Avastin now, with an aim to reduce the decadron, and perhaps even eliminate it. Avastin is not associated with reduced overall survival, but decadron probably is.

    3. I think better outcomes are likely to be had with more aggressive, multi-modal treatment *before* the first recurrence. This would argue for going ahead with Abemaciclib now, (ideally along with Avastin, until edema is resolved and decadron is tapered down). If/when a recurrence develops, it looks as though having received these would not disqualify him from participating in the DCVax trial, but you should review the criteria of the trial carefully on this point.

    4. I'm of the firm opinion that the more treatment modalities the better, for best results, in general. So, for example, the Optune device is worthy of serious consideration in addition to the other available interventions (though use would likely have to be suspended during a clinical trial).

    I hope this helps.

    Steve

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  2. Another factor is that while two CDK4/6 inhibitors have been approved by the FDA (palbociclib and ribociclib), abemaciclib is not yet approved, so the most likely way of getting access to it would be in a clinical trial.
    https://clinicaltrials.gov/ct2/show/NCT02981940

    But such a trial would also require the tumor to be recurrent, and would not likely allow any other simultaneous treatment with other experimental therapies. Compassionate use would be better, but I'm not sure how likely that is considering the drug is not even FDA approved yet.

    Also keep in mind the DCVax/nivolumab trial is randomized with one arm getting DCVax alone and the other arm getting DCVax + nivolumab. As far as clinical trials this trial is much more exciting to me than the abemaciclib trial, although there is certainly a chance of serious side effects as you and Steve both pointed out.

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  3. Ari-

    My dad is also being treated at UCSF and just had his first Avastin infusion last week as well. We've been dealing with his radiation inflammation since November. We're also on 4mg of dex. So far I haven't seen much improvement in his quality. He's incredibly weak.
    Best of luck!

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