Chlorpromazine trial

Repurposing Chlorpromazine in the Treatment of Glioblastoma (RACTAC)
https://clinicaltrials.gov/ct2/show/NCT04224441

This is a phase 2 trial being conducted in Italy.

Two interesting points to remember:
Chlorpromazine is an old off-patent drug, in clinical use since the 1950s.

Like the new drug ONC201 (which is in several trials and an expanded access program for H3 K27M mutant gliomas and DIPG), it is an antagonist of dopamine receptor D2 (DRD2).

Feb 5 2020 edit:

See also
https://www.ncbi.nlm.nih.gov/pubmed/32005270
Repurposing chlorpromazine in the treatment of glioblastoma multiforme: analysis of literature and forthcoming steps.

Irina's mom genomic sequencing report

Dear Stephen! Dear all!

1) Could you please help me with genomic sequencing report!
Probably you could advice any beneficial drugs for our sitation.
Now we use DCA, metformine, chloroquine, celebrex, prozak, boswellia, pterostilbene, EGCG, BroccoMax, berberine, omega 3, milk thistle, cannabioids with high thc - 74%).












Options 1 and 3 have the most pathological nature.

• Option number 1 is located in the KDR gene, which is an oncogene, and involved in tumor angiogenesis processes.
• Option number 3 is in the gene PMS2, which belongs to the tumor suppressor genomes, and is involved in the repair of unpaired
• bases (edits DNA replication errors). Associated with many tumor diseases. This option, as follows from sources (column PMID) often has a germinal nature (is congenital).
• Option number 4 is located in the gene ROS1, which is a proto-oncogene, and encodes a number of tyrosine kinase receptors. He might be both congenital and acquired. 

These mutations currently have no targeted drugs.

Mutation load (Tmb) - high: 3.79 m/Mb (with a threshold value of 0.8 m/Mb)

Microsatellite instability (MSI) - presence (bottom line):

- 11.9% / 12% repeat

- mutations 2 reparation genes of 4

2) How do you think is it worth to try ONK201 drug for my mom if she don't have h3k27m mutation? I read on the forum on face book that many adults with glioblastoma without mutation use it and have positive results. 

Does it really kill tumor stem cells?

Thank you so much!

H3K27M diffuse midline glioma

Hello everyone!

My wife (30 years old) was diagnosed diffuse midline glioma (H3K27M).

The story so far:
27/10/2018 MRI, evidence of brain tumour in brainstem.
11/11/2018 stereotaxic biopsy. According to the results of histological examination: diffuse midline glioma WHO IV H3K27M. H3K27M immunostain is strongly positive.
27/11/2018 MRI, tumour increased as well as brain swelling after biopsy.
03/12/2018 - 06/12/2018: chemotherapy course. Temozolomide (280mg) + Carboplatin injection (300mg).
12/12/2018 VP shunt placement.
29/12/2018 chemotherapy course. Temozolomide (250mg) + Bevacizumab injection (400mg).
09/01/2019 MRI, short decrease of tumour size.
10/01/2019 chemotherapy course. Bevazicumab injection (400mg)
25/01/2019 chemotherapy course. Bevacizumab injection (400mg)
08/02/2019 chemotherapy course. Temozolomide (100mg) + Bevacizumab injection (400mg).
22/02/2019 chemotherapy course. Bevacizumab injection (400mg).
27/02/2019 end of radiotherapy treatment. Truebeam, 31 session, 55,8gr.
07/03/2019 chemotherapy course. Bevacizumab injection (400mg).

Also we made Foundation One Cdx genome analysis. In the accordance with the results:
Microsatellite status - MS stable
Tumor Mutational Burden - TM-Low (5 Must/Mub).
Gene alterations:
CD274 (PD-L1) amplification - equivocal
FGFR1 - N546K
NF1 - Q1993
PDCD1LG2 amplification - equivocal
H3F3A - K28M
JAK2 amplification - equivocal

We have ended radiotherapy about three weeks ago and we must decide what to do next. Our chemotherapist in Moscow suggests to continue taking Bevacizumab every two weeks with no additional treatment.
We are planning to do MRI next week (22.03.2019).

1) Will the immonotherapy be effective in our case? We have contacted IOZK and Verita Life clinics in Germany. There is also an option of immunotherapy in Moscow.

2) Are there any promising ways (clinical trials for example) of treatment of H3K27M?

3) My wife took dexamethasone (8mg daily) for 3,5 months. We quit dexamethasone for three weeks now. Now she has moon face and big belly. When does usually these symptoms go away?

Thank you so much and best wishes to everyone,
Alexander 

Diffuse glioma of the brain stem

Dear Stephen, dear all!

I ask for advice for my friend, she has a child (8 years old). Diffuse glioma of the brain stem (diagnosed 2015).
March - April 2015 received a course of radiotherapy 54 gray. No chemotherapy.
In January 2017, a new tumor on MRI - less than 5 mm (doctors decided just to observe). In December 2017, MRI showed almost 7 cm tumor.
On January 24, 2018, a biopsy was performed - midline glioma, mutation H3K27M.
March-April 2018, repeated radiotherapy course of 54 gray. No chemotherapy.
November 2018 negative dynamics on MRI.

Mutations:
ATRX - contained in the cores
H3.3 - Mutations detected in the H3.3_K27.M gene
IDH1 - no
p53 - accumulation in nuclei (70% of cells)

1) What can be done in this situation (third radiation therapy, chemotherapy, avastin, dendritic cells, viruses)?
2) Please advise promising clinical studies or clinics that deal with such cases?
3) What drugs could be added due to his mutations?

Thank you!

Advice for a 8 year-old boy with diffuse midline glioma, BRAFV600E and H3K27M mutation

Dear Stephen, dear all,

Anatole, my 8 year-old son has been diagnosed in May 2018 with a diffuse midline glioma on the right thalamus. We are French and based in Stockholm, Sweden. We followed the proposed protocol with the local medical team who works in partnership with Gustave Roussy institute in France but we want to go further now, and we need your advice. The local medical team is not very aware of alternative medication but is willing to help.

Molecular status of the tumour:

BRAFV600E and H3K27M mutation

NF1 and MLH1 mutation

We have little chance to find new targetable alterations by a deeper sequencing. It is possible now that the V600E BRAF mutation is lost in the resistant cells but anyway we do not think it is wise to treat with a V600E BRAF inhibitor which in our experience could speed up tumor growth.  

History:

18/05/09 Diagnosis: MRI tumour size 3.3x3.7x3.7cm, unusual calcification

18/05/16 Biopsy, leading to light hemiparesis

Proton-therapy 18/07/02-18/08/13, 1.8Gy x 30 = 54Gy. Almost fully recovered from hemiparesis

18/09/07 Headaches

18/09/07 MRI tumour size about 4cm

18/09/12 Ventriculostomy

18/09/19 Beginning og Dasatinib (100+70mg/day), after 18/11/06 alternating with Everolimus (5mg/day) every 2 weeks (Biomede protocol)

18/09/22 Beginning of hemiparesis

18/10/03 Wheelchair for walks more than 20m

18/10/12 MRI tumour size 5 to 6cm unsure if pseudoprogession

18/10/22 Beginning of Bevacizumab then once every 2 weeks

18/11/06 Beginning of Everolimus  

18/12/03 MRI tumour size 4 to 5cm unsure if pseudoprogession

18/12/17 Crook for walks less than 20m

19/01/14 MRI tumour size 5x6x5cm

19/01/22 Stop all current chemo (Dasatinib and Everolimus, last Bevacizumab 19/01/02)

24/01/24 PET scan (methyonine)

New plan established by Gustave Roussy Institute: Mebendazol, investigation for debulking of calcification before re-irradiation, eventually ONC201
Any comment on this plan?

Supplements:

Anatole is 30kg 132cm  

D3 vitamin since 18/12/24: escalading from 40µg/d to 100µg/d now

Fish oil since 18/12/24: 1g

Melatonin since 19/01/10: escalading from 2mg/d to 5mg/d now

Turkey tail since 19/01/25: 500mg/d

We plan to add soon:

Longvida Curcumin: 800mg/d

Milk thistle: which dose would you recommend? 

Green tea extract: which dose would you recommend? 

Broccoli sprouts: which dose would you recommend? 

Metformin: Is it worth considering for a child?

Anything else you would find suitable considering his condition (celebrex, chloroquine, clomipramine, berberine, selenium, probiotics, etc?

Diet:

We follow a light low carb diet now (no refined sugar or flour, very limited sugar, no processed food, only bio food). We are planning to begin a ketogenic diet soon, we are ready to change all our habits. We will contact a dietetician specialist in this diet. Anybody else with an experience of ketogenic diet with children?

Thanks to all of you for your precious help, any contribution could help.

Fabrice

GBM treatment options with a moderate budget

My 29 years old husband was diagnosed on 3/26 with a multifocal, thalamic GBM. We are from Hungary. He has undergone surgery on the 5th of April. 80% of the walnut-sized tumor was resected from his thalamus. His other, frontomediobasal tumor seems to be inactive (although it's pretty big, too) so the surgeon didn't resect it and it didn't received radiation either. He has completed SOC and currently is on his first cycle of 5/23 TMZ monotherapy. He has no EGFR amplification. His tumor is IDH negative and indeed very aggressive. Only 3 weeks after surgery he was hospitalized because of edema which was caused by tumor regrowth. So now he has quite a few smaller tumors around his thalamus besides the remaining 20% piece. 

His first post-radiation MR is scheduled for the middle of August. Since I've not yet received the information regarding his MGMT methylation status (long story) I'm constantly worrying and seeking for opportunities in case of tumor progression since in my country there's no protocol for recurrent glioblastoma other than Avastin. I mean no PCV or other chemos, no immunotherapy, no clinical trials, no Optune device (I requested an offer from Germany and it turns out that it costs 30 000 € /months and you need a technical and medical support at home).

I'm aware that we need to manage our finances cleverly in this situation. If you had up to 20,000-30,000 USD which option or options would you go for?

- Immunotherapy in Germany (It seems to me that only Nesselhut Clinic fits into our budget but reviews are not so convincing as nothing in the world of GBM.) 

- Keytruda / Opdivo immunotherapy + TMZ 

In Hungary it's not part of the protocol but hopefully we can find a doctor who will prescribe it at our own expense. As I can see Opdivo has kind of failed; is Keytruda. better? Do we need PD-L1 testing to get it?

- We have gamma knife in Hungary and it can be paid through National Insurance (so patients who qualify don't need to pay for it) but doctors are reluctant to let GBM patients to choose this option. It's usually used for small and simple tumors and for brain metastases. If our NO will advise against it or will be not so eager to help maybe I can search for other European gamma knife possibilities although I can't find too many comments on gamma knife and GBM.

- Neuroblate Laser Ablation. As far as I know it's exactly for problematic tumors, like thalamic ones. I'm planning to send them an inquiry but I have concerns about whether it is an adequate alternative to surgery for inoperable tumors. Can it prolong life or is it just a palliative treatment? How much would be the estimated cost? Has anybody personal experiences with it? Is laser ablation superior to gamma knife? 

Our NO said my husband's thalamic tumor is no accessible for surgery anymore and considering his bad reaction to the first surgery maybe laser ablation or gamma knife wouldn't be the best option for him. What are your thoughts on it? 

- SPMF treatment in India. It's quite cheap but no statistics are available and it's so hard to believe for me that the same effect is achievable with 1-2 hours of treatment for 28 days as with the Optune cap which you need to wear almost all day long up until it works. I've read about a young patient with thalamic tumor on Inspire who had Optune and it didn't do any good for him because of the location. I suppose that the same applies for SPMF, too. 

- I sent an inquiry to Duke's polio virus trial.

My clinical trial applications have been ignored from all over the world so I was tricky enough to mention that "I'm aware that non-U.S. citizens should cover their costs on their own in case of qualifying for a clinical trial and I hope I can manage it with the help of my family. "

I got this answer from doctor Friedman personally "We would not have a trial for you at this time since the surgery was so long ago and the tumor is not growing If it ever does regrow please let us know"

Maybe it was just a polite "no" or maybe this possibility is truly open for us in case of a recurrence but the truth is that I have no idea how much a treatment like this could cost in one of the world's best institutions for cancer. Anybody has any idea about their fees?

- Ask the Brazilian doctor to come to Hungary and teach us to administer Perillyl Alcohol. I've read that the brave persons who tried to make it themselves found it unbearable to use.

Any and all help is very much appreciated. Thank you in advance and sorry for my grammar mistakes.

ONC 201 or Avastin?

Stephen and all,
We are trying to decide between treating our son (recurrent glioma, H3 K27 mutant, mutations in ASXL 1 and PIK3CA among others) with Avastin +Irotican  or the new ONC201 trial. We tend to think that ONC201 is a better option. What do you think? Thanks!

ONC201 expanded access for H3 K27M mutant gliomas

This is rather big news for H3 K27M mutant gliomas (including a high percentage of DIPG).

Expanded Access Program for ONC201 to Treat Recurrent Histone H3 Mutant Glioma (click here)

In a phase two trial of ONC201 for recurrent GBM, a 22 year old female with secondary H3 K27M mutant GBM achieved a partial response to ONC201, which has been sustained for over 6 months. One of her two tumors regressed by 85% and the other tumor regressed by 75% after 8 and 11 months of therapy.

A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma  (click here)

Note that the H3 K27M mutation (also known as H3F3A K27M) is most common in brainstem gliomas of young children and young adults, including diffuse intrinsic pontine glioma (DIPG).  This treatment could turn out to be a breakthrough, as there is currently no known effective treatment for this tumor type.