On 08/29/16 my 41-year-old brother in perfect
healthy suddenly presented with a massive headache which ended up as a 5-cm R
frontal GBM (+MGMT; wtIDH, EGFRvIII amplified, PD-1/PD-L1 negative, HLA A*02:01
negative), 90-95% resection on 8/31/16 at Cedars-Sinai, remainder 5-10% abuts
the ventricle, Caris & Foundation testing done, did not qualify for or
declined upfront clinical trials, started w/ stupp protocol w/ in 4-weeks after
surgery, but upped radiation dose in week 5 of 6, 1st MRI showed stable findings
but new nearby tiny satellite lesion seen, Keppra for first 2-months, 2nd cycle
of TMZ completed yesterday (1/16/17), 7-week delay between TMZ cycle 1 & 2
due to a 2.5-week experimental T-cell / stem cell immunotherapy out of states,
added Nivo (Opdivo) during the end of RT & going on 6th infusion now (insurance
not covering), starting Pomalyst this week (pending insurance approval), Optune
ordered end of Nov 2016 but still delayed due to insurance denial, started high
dose Vitamin C infusion 10-days ago and working up to 100 g, CBD/THC oil 1:1,
life-style modification, difficult to follow restricted ketogenic diet, has had
no seizures and no requirement for steroids beyond the post-op taper,
tolerating treatment very well, has no symptoms, labs are normal, and only
neuro deficit is subtle mild cognitive impairment. MRI last week had not
changed but most likely viable tumor tissue seen, hoping it is
pseudo-progression, awaiting result of second liquid biopsy. Inquired and/or consulted with Duke, MD
Anderson, UCLA, CSMC, NIH, Dana Farber, Cleveland Clinic, Hoag, UCI, USC and
some international sources, in addition to attending SNO 2016, but walked away
with very little. So we started our own
prescription drug cocktail early on and have kept adding. Did pharmacogenetic (PGT) testing and do
frequent labs to monitor for drug-drug interaction. Current NO has no objection to the cocktail
and in-fact recommended a few on the list. Current cocktail includes:
- Celebrex 200 mg twice daily
- Metformin 500 mg twice daily
- Imipramine 100 mg at bedtime
- Mebendazole 100 mg twice daily
- Livalo 4 mg daily
- Ondansetron 8 mg as needed for nausea
The non-Rx part of the cocktail includes (still trying to fine tune the dose)
- CBD/THC 1:1 oil
- Coconut oil
- Ashwagandha
- Turmeric (curcumin)
- Boswellia serrata (Indian frankincense)
- L-Proline
- L-Lysine
- Selenium
- Zinc
- Resveratrol
- Tart cherry
- Colloidal silver
- Green tea extract and will be adding Melatonin 20 mg
Will be doing an early follow-up MRI 3-weeks from the last one on a 3-Tesla w/ DTI, spectroscopy and perfusion weighted, for whatever it is worth. Meanwhile, trying to be proactive and need to start considering options in case of “recurrence” as will be excluded from most trials since we’re already doing immunotherapy. Thinking of adding intravenous Resveratrol and Curcumin infusion which I just found got my hands on. Was thinking of adding Yervoy but hesitant given potential for serious side effect in combo w/ Nivo. Hope our path ends up helping you and truly appreciate all of your guidance and feedback.
Welcome to our group Bahman and thank you for contributing. It helps to have such a clear and detailed picture of your brother's situation.
ReplyDeleteQuestion: how was MGMT tested? Was the MGMT protein positive by immunohistochemistry, or was it positive for methylation of the MGMT gene promoter? "MGMT+" could mean either of these two very different things.
Did the Foundation report tell of any other mutations, amplification or deletions other than the ones you've already mentioned?
I'm surprised to see Pomalyst (pomalidomide) on your list given the expense of this drug and the limited data as a GBM therapy (don't think I've seen a trial of it for GBM, though there have been a couple trials with lenalidomide for GBM).
Also surprised to see insurance companies still denying Optune, now that it's approved for both recurrent and newly diagnosed GBM, and was added to the official NCCN guidelines for newly diagnosed GBM back in July.
https://www.novocure.com/nccn-guidelines-recommend-optune-as-a-standard-treatment-option-for-newly-diagnosed-glioblastoma/
There's really no excuse to deny it anymore.
Seems as though you've got an extensive cocktail in place already. Another drug you may want to consider is chloroquine, which retrospective studies have indicated as being particularly effective in EGFRv3 positive GBM.
I would have the same hesitations with Yervoy. The preliminary data so far has shown no increased efficacy with adding Yervoy to nivo (in fact slightly worse efficacy, but this is based on a very small number of recurrent GBM patients), and increased toxicity to the patient.
Thank you Stephen W.
ReplyDeleteMGMT was "up to 2%" on IHC. The Mayo Clinic lab report states "MGMT promoter methylation present". Also shown to be methylated as tested by PyroSeq (NGS).
Foundation reports Genomic Alterations Identified: EGFR amplification, EGFRvIII and truncation exon 24, CDKN2A/B loss, and TERT promoter -124C>T. There was no alteration in IDH1 and PDGFRA on Foundation testing. Caris showed mutated BRCA2, EGFR amplified, EGFRvIII variant transcript detected, ERCC1 negative, and TOPO1 positive.
Pomalyst is in phase I (see: https://clinicaltrials.gov/ct2/show/NCT02415153) for pediatric GBM and no data yet so we're trusting the NO who recommended it. Thalidomide and lenalidomide were first recommended by a community oncologist. I realize glutamic acid derivatives have shown limited efficacy in GBM thus far, but they do have multiple immunomodulatory, anti-inflammatory, and anti-angiogenesis effects.
It's not surprising that someone would think to add thalidomide or its relatives to a GBM cocktail. It would be more surprising if insurance actually approved pomalidomide for off-label use in GBM, given a minimum pricetag of ~$14,000 per month at the standard dose of 4 mg, 21 days out of 28.
DeleteAlso, glad to see MGMT promoter methylation present. As we know, this predicts a much better response to TMZ chemotherapy.
DeleteThe BRCA2 mutation on the Caris report is interesting. I'm not sure if Caris also tests healthy cells for each patient to determine germline versus somatic mutations. In any case, we know that BRCA1/2 mutations predict sensitivity to PARP inhibitors in ovarian and breast cancer.
DeleteIf the Foundation report failed to detect BRCA2 mutation (check in the appendix though under "variants of unknown significance" near the end of the Foundation report), it may only be present in a minor subclone of the tumor.
How much tissue was notable labs requiring?
DeleteI'm not sure how much tissue they required, but by the time the pathologist got back to us they said no live cells remaining. We asked for it on Oct 4, 2016 and it took Cedars until Dec 17, 2016 to tell us they have no live cells remaining.
DeleteThanks for shedding light on this Steve. Both the Caris and FoundationOne NGS tests detected the K2411T variant of BRCA2 mutation [Frequency: 50%; Exon: 14). Some drug classes mentioned that may prove beneficial as based on the BRCA2 result are: DNA minor grove binding agents such as PM01183 (Lubinectedin) and Trabectedin; Platinum compounds such as Carboplatin, Cisplatin, Oxaliplatin; and PARP Inhibitors such as BMN-673, olaparib, rucaparib, and veliparib. None of these drugs have been recommended to us!
ReplyDeleteI also just noticed that the TOPO1 biomarker is positive by IHC (2+, 80%) meaning irinotecan may be used as a potentially effective option. Moreover, Jiang et al. Journal of Translational Medicine 2014, 12:13, showed that the pitavastatin (Livalo) which we are already taking, enhanced, by 40-70 fold, the pro-apoptotic activity of irinotecan, in vitro. The combination was also synergistic in inhibiting tumor growth in vivo. Compared to animals treated with high dose irinotecan, the drug combination of irinotecan and pitivastatin showed significantly less toxicity. I am unaware of any clinical trials looking at this, but adding irinotecan to our cocktail seems to be an educated option. Have you see this combo before?
The mutations the Foundation reports put into the appendix under "variants of unknown significance" are mutations at locations that haven't been described in the literature or the effects are not known. This specific BRCA2 mutation may or may not be inactivating, for example. This particular variant seems to have been a germline mutation where it has described.
Deletehttps://www.ncbi.nlm.nih.gov/clinvar/variation/52294/#clinical-assertions
While a mouse study is usually more convincing than an in vitro study, unfortunately the pitavastatin + irinotecan mouse study utilized a flank injected xenograft model, not an orthotopic (intracranial) one, so the ability of these drugs to get into a tumor in the brain wasn't modelled.
Irinotecan was often used in conjunction with Avastin for GBM (often with little efficacy gain compared to Avastin alone). Now the trend seems to be to combine CCNU/Lomustine with Avastin (on the basis of the BELOB randomized phase 2 trial).
There are no trials studying the pitavastatin + irinotecan combo to my knowledge.
The most effective chemo combination in MGMT methylated newly diagnosed GBM has been the combo of TMZ with CCNU (lomustine), although this of course creates greater toxicity than TMZ alone. This was reported in phase 2 trial in 2009 and is the subject of a phase 3 trial in Germany which has not yet reported results.
https://www.ncbi.nlm.nih.gov/pubmed/19188676 (Phase 2)
https://clinicaltrials.gov/ct2/show/NCT01149109 (Phase 3)
Mainly because the phase 3 trial hasn't released data or proven statistically significant improvement in outcomes. There is a standard of care for newly diagnosed GBM that almost all institutions and oncologists follow, the exception being clinical trials. It takes a successful phase 3 trial to change that standard of care. Let's hope this particular trial is successful.
ReplyDelete