Monday, 27 July 2020

Recurrence: VAL-083 or CCNU? Keytruda?

Hello all,

A few questions for my friend who is unfortunately having a recurrence.

1) Following surgery, is it better to go with VAL-083 since he is unmethylated or stick with CCNU since that is more the standard protocol for recurrent GBM? Any experiences with VAL-083 out there? 

2) Is the tumor genetic sequencing provided by the University of Pittsburgh considered the best, or should he request a Caris report?

3) Have any of you or your loved ones tried Keytruda pre-operatively to activate the immune system? How did you feel about it? Any significant side effects? 

For background purposes:

My friend was diagnosed in August 2018 - age 48. He had a total resection followed by SOC, Optune, supplements and 11 months of TMZ. A second tumor developed slowly  in the occipital area and was removed in November 2019. Unfortunately, the tumor recurred at the second site shortly after the surgery. However, following a second course of radiation and TMZ, it remained stable for six months. Avastin was used to control swelling and reduce tumor growth. In addition, a PARP inhibitor, Olaparib(Lynparza), was added after SOC as indicated by the genetic analysis. The tumor was unmethylated and IDH mutated.

The second tumor location recently started showing activity again. So a third surgery is planned in the next couple of weeks. We are looking at which chemotherapy to pursue afterwards and whether to use Keytruda before or after, as well. We have a friend that had a very positive response following a recurrence on the VAL-083 MD Anderson trial. He was unmethylated, as well, and has had clear scans for six months since completing VAl-083.

My friend was advised to stop using Avastin, although we have seen some studies that continued to use it in combination with CCNU. He is now age 50 with no deficits. He continues to use Optune. Any thoughts, experiences or pertinent studies relating to the chemo options for recurrence, VAL-083 and Keytruda would be greatly appreciated. We are grateful for the combined wisdom of Stephen and this community.




  1. Hi Evelyn,
    For MGMT unmethylated recurrent GBM, CCNU alone has a pretty small chance of being effective.
    In the EORTC26101 trial reporting in 2017, for MGMT unmethylated recurrent GBM patients treated only with CCNU, only 2.3% were progression-free at 6 months, versus 30.4% for MGMT-methylated tumours.

    This data is from Supplementary Table S7 of the Appendix of the trial results

    On the other hand, VAL-083 has a mechanism that does not depend on MGMT methylation status. The clinical trial data is still rather preliminary, but you can find all the presentations and talks on the Del Mar website:
    including a transcript of a talk from the 2019 SNO meeting.

    I would probably take my chances on VAL-083, rather than accept the very low chance of benefit with CCNU.

    I'm wasn't familiar with the University of Pittsburgh sequencing panel, but with a quick search I found this:
    This is probably sufficient, seeing that it is specifically designed for central nervous system tumors and includes all the most common mutations, copy number variations, and gene fusions found in CNS tumors.
    One advantage of Caris or Foundation One tests is that they report on tumor mutation load/burden (TMB, TML) which indicates if the tumor is hypermutated or not. An MGMT unmethylated tumor is less likely to become hypermutated though.

    I would just like to confirm that is not a typo, and this his tumor is IDH1 mutated? In previous correspondence about your friend I thought the tumor was considered IDH1 wild-type (non mutant). IDH1 mutant tumors are more likely to have methylation of the MGMT promoter. Was MGMT methylation status tested only once? Results of this testing are not always so cut and dry - tumors may have heterogeneity in MGMT expression, more methylated in some areas, less methylated in others. Also sometimes results are borderline between "methylated" and "unmethylated".

    There is some data IDH1 mutant tumors may be more responsive to PARP inhibitors, and this is likely the reasoning for adding in olaparib previously. PARP inhibitors may also resensitize tumors to temozolomide.

    Unfortunately IDH1 mutant tumors are less likely to to be highly immunoreactive, or to have high levels of infiltrating T-cells that are being suppressed by the tumor with immune checkpoints like PD-1/PD-L1.
    For an IDH1-mutant tumor I would think of VAL-083 as being a better bet than Keytruda. However if insurance would cover the expense of Keytruda, it still might be worth a shot.

    TMZ + PARP inhibitor could be a strategy if VAL-083 falls through.
    It could also be good to confirm MGMT status a second time with the most recent tumor sample. I wouldn't be surprised to see results conflicting with the results of the first MGMT testing.

    Please keep up posted,

    1. Hi Stephen,

      Thanks so much for your very thoughtful response. I don’t know how you keep up with everything, but we certainly appreciate your input very much!

      My apologies; you are correct — my friend’s tumor is IDH1 wild-type (non-mutant). (Again, not sure how you remember these things!) He had been using a PARP (Olaparib) not due to his IDH1 status, but because it is indicated for his rare BRCA1 mutation. Unfortunately, he was not able to obtain Niraparib, even though we were told it may be better at crossing the blood-brain barrier. He was briefly using Olaparib with TMZ, but his blood levels began to drop. Then he experienced some swelling, so was switched to Olaparib with low-dose Avastin every three weeks. That seemed to keep him stable for about 7 months prior to this recent recurrence.

      We appreciated your thoughts on VAL-083. His doctor is working with the manufacturer to hopefully obtain it through the expanded access program. It is a lengthy process requiring FDA and hospital approval, but we are optimistic that hopefully he will get it in time to start using it once he has recovered from surgery. Surgery is this Wednesday, Aug. 12—probably tomorrow by the time you are reading this!

      My friend looked closely at a couple of clinical trials, including the herpes virus and polio virus trials, but decided for now to try a full resection, hopefully VAL-083 and Optune (he has been using Optune all along). He has tolerated surgery well in the past.

      In addition, he did get Keytruda last week and may continue it post surgery depending on the tumor sequencing. A Dana Farber physician had encouraged pre-operative Keytruda based on this study: .

      Thanks again for all of your thoughts. We will keep you posted as his journey continues.

      Best regards,

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  3. Hi Stephen, (my question is similar about lomustine). My dad (IDH wildtype; MGMT unmethylated; p53 mutation) was told that his treatment has stopped working and the tumor is now growing according to perfusion MRI scan (it is now just over 17 months since diagnosis). The last thing they tried was avastin with a daily low dose of TMZ. I had told the doctors that because of the p53 mutation that potentially it means his tumor is a secondary GBM? (I don't know if that is correct given the IDH wildtype?) And therefore that perhaps CCNU would therefore work? So far they have agreed to try CCNU in 2 weeks. However based on your response to this question it looks like CCNU most likely will not do anything? Therefore perhaps we are better to look into the VAL083 trial? I noticed they have a few trials and 2 were withdraw with the comment due to making changes (one was with TMZ and avastin). Should this be a concern? I cannot see the reason why they stopped those two? Perhaps that just want to see the treatment by itself?

    Also I like to add thanks again for this site and your continued support. I dont think we would have gotten this amount of good quality of life with my dad to this point if it wasnt for this site and the community and their knowledge.

    1. Expected response to CCNU has more to do with MGMT methylation status than TP53 status or primary versus "secondary" GBM. But even MGMT methylation status is not always a foolproof guide to predicting chemo response. As I mentioned sometimes the tumor is heterogenous and can have some parts of the tumor more methylated than others.

      But yes VAL-083 is said to have a mechanism that doesn't depend on MGMT status, and so might have a higher chance of working in MGMT unmethylated tumors.

      There is an expanded access protocol for VAL-083 that you could try if he is not eligible for the trials.
      This is pretty much the same thing as compassionate use. It is available to patients with recurrent disease who are not eligible for any VAL-083 clinical trial (for whatever reason).

      As for the trials that were terminated, I don't feel like "change in clinical development plan" necessarily says anything about the drug's efficacy.
      There is a phase 2 still recruiting at MD Anderson.

      Thanks for your kind words, I'm glad this site and the accumulated experience and knowledge here has been of help to you and your dad.

  4. Hi Stephen I read the link you provided for Glioseq and it seems Primary GBM (IDH Wildtype) can have about 23% patients with p53 mutation. The literature i have found just seems to mention it but it doesnt say anything that this means it has secondary GBM characteristics? Therefore CCNU might not have any benefit - i suppose if the hospital still is willing to offer it we night still take it as without trying we will not know.

    I can contact the company doing Val-083 trial and get information - maybe they can explain why 2 of their trials were stopped? (If you see why i would gladly appreciate the explanation)

    I noticed on Facebook Survivors to trivors some people decided not to use it which is why we had decided to not follow up at the time.

    Any further advise you can give is much appreciated

    1. The term "secondary glioblastoma" strictly means that the tumor was lower grade at the time of diagnosis, and then evolved later to grade 4. It doesn't really say anything about genetic characteristics.

      Lower grade astrocytomas often have a TP53 mutation, but this is usually in the context of an IDH1 mutant tumor (they have both IDH1 and TP53 mutations together). Having a TP53 mutation without an IDH1 mutation does not suggest to me "secondary glioblastoma". In any case the term "secondary" refers to the fact that the tumor was not a glioblastoma (grade 4) at the time of diagnosis and evolved from a grade 2 or 3 to a grade 4 after diagnosis. In my opinion, the term doesn't really mean that much from a biological perspective, as most glioblastomas probably go through a phase of being lower grade, but they are evolve so quickly they are not discovered until they are grade 4.

      A more important distinction than "primary" versus "secondary" is IDH1 mutant versus IDH wild-type. The typical adult IDH wild-type glioblastoma has its own defining genetic characteristics, such as gains of choromosome 7, loss of chromosome 10, and mutations in the promoter of the TERT gene, plus frequent EGFR amplification or mutation.

      As mentioned in my other comment, MGMT status is more predictive of response to both TMZ and CCNU than the "primary" or "secondary" distinction which has more to do with timing of diagnosis rather than any biological characteristics.

      With an MGMT-unmethylated tumor, I would be more inclined to try VAL-083 through the expanded access protocol than take a chance on CCNU, but might try CCNU if no other option was available. For an MGMT-methylated tumor, CCNU would be a reasonable option.

  5. Thanks so much for the reply. I contacted the Val083 trial but they said it is only open to people situated in the USA and not to Europeans as it is overseen by the FDA. It is a real pity as i never thought location would be an issue these days to get onto a trial with the possibility to do skype calls and fedex things.

    1. Have you tried calling the manufacturer to see if your dad might be eligible for the expanded access program? I’m not sure if that is available outside the U.S., but it does allow Val-083 to be used outside of a clinical trial.

    2. Thanks for the reply. Yes i contacted the manufacturer (named in the trial) and also on the recommendation from MD Anderson who are in the trial. But was told from the manufacturer that due to FDA regulations the drug is not to be used outside of the USA. It is a real shame as my dad has started Lomustine but we know for unmethylated MGMT that the alkylating agents are not promising. :(