Semyon's mom's profile.

My mother had an operation (in Germany, Frankfurt am Main) - removal of the tumor by 99%, and then - the rapid growth of the tumor to its former size (for 3 weeks)! The doctors were in shock.
(Glioblastoma, MGMT methylated)
10 days after chemoradiotherapy, MRI still showed tumor growth. The doctors decided that TMZ did not work in our case and suggested urgently switching to Avastin and Irinotecan.

Thinking, we decided to use a low dose of Avastin + CCNU.
I also decided to add 5 days of low TMZ after every day of CCNU.

The OncoDeep report showed the likely effect of Sirolimus, Olaparib and Trametinib.
I flew to Delhi (India) and bought at low price LYNPARZA Olaparib (1 bottle of 112 capsules of 50 mg) and MEKINIST Trametinib (1 bottle of 30 2 mg tablets).

Unfortunately, it is very difficult to interpret MRI. 3 doctors who watch my mom's MRI say sometimes the opposite conclusion!

Comments:

1. Suppression of T4 is very slow. We spent 3.5 months to reduce T4 from 12.4 to 3.3pmol / l. Also, T3 has fallen dramatically, although we take synthetic T3. Because of this, drowsiness and lack of appetite.

When suppressing T4, you can not take selenium, since it increases the production of the hormone T4! We started taking selenium and the hormone T4 took off from 3.3 to 5.14! Now with great difficulty again we need to knock it down((

2. For all treatment, my mother lost a lot of weight. From 65 kg (in January) to 52 kg (now). However, I do not see anything that we could refuse.

3. We bought a special meter and ketone strips to check that the mother is ketosis.

4. I ordered Mebendazole chewable tablets from Thailand for 500 mg / tablet. Maybe we will try to take large doses: 2-3 grams per day.

5. We use a higher dose of perillyl alcohol than Dr. Dr. Clóvis Orlando: 30 drops instead of 21. No unpleasant sensations! We plan to increase the dose to 40 drops. Dr. Clóvis Orlando wrote that they use perillic alcohol of 96% from Sigma Aldrich and that the other perillyl alcohol will not have an effect on GBM.

MRI-1: https://drive.google.com/open?id=1tPKrQgjIZzBgefhkknxNlQKbaC04XMI_

MRI-2: https://drive.google.com/open?id=1t3SgxGgJFi19i9qIwc47JucsV6ZCbLFa

MRI-3: https://drive.google.com/open?id=1JbRYk3DCUK87ndeRQK-Q7V7130oObiMV

MRI-4: https://drive.google.com/open?id=1Q6WFd9qtFAd18czkd5ouKYloIVBKuFS1

MRI-5: https://drive.google.com/open?id=1L-O1BgoVMohI7eXxH35qN__rNBDy3hrM

MRI-6: https://drive.google.com/open?id=1xWYd5_UsrAYb-c4wv49DSWTeJEN8Dl_F

MRI-7: https://drive.google.com/open?id=1MCpzZxPnl7eI1iigzJVWrOo2o4s8hKWz

MRI-8: https://drive.google.com/open?id=1De95kb-iZ30X7scIbZkeXxFq4KV5fgdT

11C-methionine PET 17.05.2018:
https://drive.google.com/open?id=18AaVybu5nvBH_cAe5QIfzO-efiwsUfkc

OncoDEEP report: https://drive.google.com/open?id=1A3dophOME6gY1GNdOHWE48wVYJUu_nHc
http://btcocktails.blogspot.ru/2018/02/our-report-oncodeep-what-do-you.html

 

MDMX and PD-1 inhibitors

So the genetic testing came back on my partner’s tumor (GBM, first recurrence), and while researching the mutations, I found Stephen W’s account of the hyperprogression study linking use of checkpoint inhibitors with accelerated progression in people with certain mutations, including amplification in MDM2 or MDM4.  All 6 of the people in the cohort with MDM2/MDM4 amplifications experienced hyperprogression (across 5 different cancer types, none of which were primary CNS, although several had metastases in the brain; 5 were MDM2 amplified, 1 was MDM4).

My partner’s genetic report includes copy number gain in MDM4.  No indication of the size of the gain; I’ve asked the company if they can clarify.

As it happens, we started pembrolizumab 2 weeks ago.  I figured the worst that would happen was that it was ineffective; it never occurred to me that it might accelerate progression.

The study doesn’t prove that checkpoint inhibitors caused the hyperprogression.  It’s possible that MDM2/MDM4 amplification caused the hyperprogression on its own.   The possible mechanism seems understood: MDM2 suppresses p53, a major tumor suppressor (p53 is mutated in over 50% of all cancers).  I found one study that showed MDM2 amplification is prognostic for poor survival in breast cancer.  On other hand, the chart at the end of the hyperprogression study sure makes it look like acceleration began with the onset of checkpoint therapy.

My partner’s tumor showed high expression of PD-L1 (50%), and also has mutations in NF1 and TERT.  All three of those are correlated with better response to PD-1 inhibitors in other cancers.

The next pembro infusion is scheduled for March 19.  We have to decide by then whether to continue with it or not.  Thankfully we’ll have an MRI that morning.  The tough call will be if there’s no evidence of progression.  I know there’s no clearcut rationale for making a decision either way, but I’m curious if anyone here has any advice.

Other biologically relevant mutations found are TERT, PTPN11, NFE2L2, PTEN, and CDKN2A.  IDH1 is wildtype.  MGMT is reported as unmethylated by sequencing.  The tumor mutational burden increased from 2.05 to 5, and the MSI status is stable (i.e., no mismatch repair defect).  

Our current regimen: CCNU, pembrolizumab, Vitamin D, melatonin, PSK, curcumin (also levetiracetam, Vimpat, Xarelto)

Planned additions: boswellia

Actively considering: ECGC, THC/CBD, Hydro+ALA, celexocib, metformin, everolimus

Thanks,

Brandon

Dabrafenib and trametinib in BRAFV600E mutated glioma.

I started looking for information about Trametinib and found encouraging information about the treatment of BRAFV600E mutant tumors with a combination of Dabrafenib and trametinib.

2017 http://www.jnccn.org/content/16/1/4
"BRAF V600E mutations have been successfully treated with targeted therapy in melanoma, non–small cell lung cancer, and thyroid cancer. Interestingly, these mutations have also been identified in a subset of pediatric and adult brain tumors, with several cases reportedly responding to targeted therapy. However, these reports have been limited to single-agent BRAF inhibitor therapy and recurrent disease. Herein, we report dramatic clinical and radiographic responses to combination dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in 2 adults with high-grade gliomas (HGGs), with 1 patient treated in the first-line setting. These observations, together with prior case reports, advocate for routine screening of BRAF point mutations in adult HGGs, and suggest that treatment with dual-targeted therapy, even in newly diagnosed cases, is safe and effective."

2017 https://www.ncbi.nlm.nih.gov/pubmed/28984141
"BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib."

2017 https://www.ncbi.nlm.nih.gov/pubmed/28062673
"A phase I/II clinical trial suggests that dabrafenib shrinks or stabilizes low-grade gliomas in children with the BRAF V600E mutation. Objective, durable responses occurred in 38% of patients, and the side effects were less severe than with chemotherapy. The researchers have started a second trial for patients with glioma and other BRAF-mutant tumor types, this time evaluating dabrafenib combined with trametinib."

To determine which dose of Trametinib can be tolerated and effective, for my mother who does not have the BRAF mutation, I began to look for reports on the treatment of patients. I found two such reports. Unfortunately the articles are paid:
https://www.ncbi.nlm.nih.gov/pubmed/28984141
https://www.ncbi.nlm.nih.gov/pubmed/26936308

Have you seen information about the used doses of trametinib in these reports and clinical trial?

I also found a pediatric clinical trial:
https://clinicaltrials.gov/ct2/show/NCT02684058
But here too, unfortunately, no dose is indicated.

In this studies, not related to the brain, such doses are suggested:
https://clinicaltrials.gov/ct2/show/NCT02034110
Dabrafenib is a 150 mg twice daily capsule administered orally on a continuous basis.
Trametinib is a 2 mg once daily tablet administered orally on a continuous basis.

https://clinicaltrials.gov/ct2/show/NCT02124772
Trametinib Dose-Escalation: Trametinib is administered orally once daily (OD) under fasting conditions. The starting dose of trametinib (0.0125 milligram per kilogram per dose [mg/kg/dose]) is 50% of the recommended fixed dose in adults (2 mg OD). The second dose level (0.025 mg/kg) is equivalent to the recommended dose in adults (2 mg PO daily). The third dose level (0.040 mg/kg) is equivalent to the maximum tolerated dose [MTD] in adults (3 mg PO daily).