IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215606/#!po=0.595238
Has this been shared here yet?

The AKT/mTor pathway is related to glucose metabolism. 5- Fu is the chemo ancient used in the Tocagen trials which have had complete responses in all IDH1 patients. It’s probably safe to assume that these patients had IDH1 mutations.

It is also interested to me because I’ve been in contact with a number of IDH1 mut patients who are having good success with a keto diet. It was been a little counter intuitive since it’s said that IDHmut tumours use glutamine as their metabolic preference. I have read that rather than using glutamine to profilerate perhaps they use it to invade surrounding cells but this seems to have lost out in favourite of using it for their metabolism.

Maria

Pathology Report

Hi all,

I had the tumour out on Nov. 10 and just received my completed pathology report today. I’m diagnosed with an AA3, not an Oligo 2 as previously thought. Can you all review the report and help me make my next steps from here? Thanks.

IDH1 R132H positive
ATRX - negative (lost, suggestive of mutation)
P53 - highlights scattered background of glial cells (negative in tumour, suggestive of try care by mutation)
MIB-1 proliferation index is 7.7%
504 kb gain of SOX2
1.9 mb gain of OKI (no gene disruption)
21.2 Mb broad gain of 7q, an
8.7 Mb gain of 12q

Let me know if I should give you anything else. That’s is all that is listed though.

Thank you!

SNO summary: Durable responses with Toca 511 + Toca FC

I already posted on this data at the end of October, but here is my long form write-up.

Durable responses observed in IDH1 wildtype and mutant recurrent high grade glioma (rHGG) with Toca 511 & Toca FC treatment

Timothy Cloughesy of UCLA presented updated results for the phase 1 trial of tumor resection followed by injection of Toca 511 into the tumor resection cavity.  This trial (NCT01470794) treated 56 patients with recurrent glioblastoma or anaplastic astrocytoma (WHO grades 3 and 4).  

Pooling results across all three phase 1 dose escalation trials (n=127 patients), Toca 511 was found to be well tolerated, with only 25% of patients experiencing grade 1 or 2 treatment-related adverse events (including fatigue in 11%), and 7% of patients experiencing a grade 3 or higher treatment-related adverse event (including one case of headache, one case of fatigue, and two cases of vasogenic cerebral edema). Administration of the fluorouracil prodrug, Toca FC, was also associated with a low incidence (3.3%) of grade 3 or higher treatment-related adverse events.  Only three out of 122 patients discontinued therapy due to adverse events associated with Toca FC.

In the NCT01470794 trial of resection followed by injection of Toca 511 into the resection cavity, 46/56 (82%) of patients had recurrent glioblastoma, and the remainder had anaplastic (grade 3) or other gliomas.  50% were at first recurrence, 23% were at second recurrence, and 27% were at third or more recurrence.  

This trial included the endpoint of durable response rate, defined as a response lasting at least 24 weeks (5.5 months).  Remarkably, all responders (6 out of 53 patients evaluable for efficacy, 11.3%) are in complete response and still alive, with a median duration of response of at least 35.1 months (nearly 3 years). An additional 18.9% had stable disease as best response, for a clinical benefit rate of 30.2% (response plus stable disease).

In the subset of patients (n=23) treated with higher doses of Toca 511 and meeting the eligibility criteria for the ongoing phase 3 Toca 5 trial (at first or second recurrence, no prior Avastin, and tumor no larger than 5 cm), there were 5 out of 23 patients (21.7%) with durable complete response lasting for a median of 35.7+ months.  An additional 21.7% had stable disease as best response, for a total clinical benefit rate (response + stable disease) of 43.5%.  In this subgroup of 23 patients, three of the complete responders had wild-type IDH1, and two had anaplastic astrocytoma with mutant IDH1. These responses occurred gradually over 6-19 months, consistent with an immunologic mechanism of action.  Median survival from Toca 511 treatment in this subgroup is 14.4 months, which compares favorably with historical benchmarks of 9-10 months for recurrent GBM with standard treatments.

The safety profile, increased median survival relative to historical benchmarks, and relatively high rate of complete durable responses lasting for a median of at least three years is encouraging.  The randomized phase 2/3 Toca 5 trial for recurrent glioblastoma or anaplastic astrocytoma (NCT02414165) recently re-opened in November 2017 to new recruitment and the phase 1 Toca 7 trial for newly diagnosed high grade glioma (NCT02598011) is scheduled to open sometime in 2018.

The Toca 5 randomized phase 3 trial has re-opened

The Toca 5 Trial: Toca 511 & Toca FC Versus Standard of Care in Patients With Recurrent High Grade Glioma (Toca5)

This trial is now open again, although only at 2 centers according to the clinicaltrials.gov listing (Edmonton Canada, and New Jersey).

NCT02414165

SNO 2017 Highlights: Intravenous administration of Toca 511

Intravenous delivery of Toca 511 in patients with high grade glioma results in quantifiable expression of cytosine deaminase in tumor tissue

Tobias Walbert of Henry Ford Hospital presented results of this phase 1 trial, which tested administration of the Toca 511 virus by intravenous injection.  Toca 511 is a retroviral replicating vector that transmits a gene to infected tumor cells.  This gene, cytosine deaminase (CD) causes the cell to convert orally administered Toca FC (an extended release version of 5-fluorocytosine) into the active chemotherapy agent 5-fluorouracil.  Following intravenous injection for 1, 3, or 5 days, tumors were resected and additional Toca 511 was injected into the tumor cavity walls.  This pre-resection intravenous administration allowed investigators to analyze tumor tissue for detection of cytosine deaminase (CD) within tumors.

17 patients were included in this trial.  14 of these patients (82%) had diagnoses of GBM and the remaining three had grade 3 gliomas.   47% were at first recurrence while 53% were at second or more recurrence.  

11 of 17 (65%) resected tumors were positive for cytosine deaminase, showing that intravenously administered Toca 511 successfully entered into tumors in the majority of cases. Analysis of resected tumor tissue following intravenous Toca 511 injection found that tumors with high T-cell infiltrate did not limit the ability of Toca 511 to enter tumor cells.  Conversely, the presence of immunosuppressive regulatory T-cells (Tregs) were also not required to allow entry of Toca 511 into tumor cells.  

The maximum tolerated dose of Toca 511 was not defined and grade 3 or higher adverse events were rare, occurring in only 3 patients (17.6%). 

Stable disease was achieved in 3 of 17 patients (17.6%) and late onset (>12 months after treatment) radiologic responses were seen in two of 17 patients (11.8%), consistent with an immunologic mechanism of action.  The responding patients were an IDH wild-type anaplastic astrocytoma patient at 3rd recurrence, whose response was noted on MRI 9 months after discontinuing Toca FC and was on no other anti-cancer therapy;  and an IDH1-mutant GBM patient at first recurrence who had onset of response 13 months after initiating Toca FC.  Complete response was eventually achieved in this patient, and response has lasted for 16 months and counting. This patient remains on Toca FC and no other anti-cancer therapy.  Median overall survival from trial entry for this group of 17 patients, 53% of whom were at second or more recurrence, is 13.6 months.

This trial is one of three phase 1 trials of Toca 511/ Toca FC for recurrent malignant glioma, which are all now closed to recruitment.  Currently recruiting patients is the Toca 6 trial for recurrent solid tumors, and the randomized phase 2/3 Toca 5 trial for recurrent malignant glioma, which has just reopened as of November 2017.  A phase 1 trial of Toca 511/ Toca FC for newly diagnosed malignant glioma (Toca 7) is scheduled to open in 2018.

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Complete responses in Tocagen phase 1 trial

Tocagen just released data showing that in their phase 1 trial for injection of Toca511 into the resection cavity (NCT01470794), two of the partial responders became complete responders, bringing the total number of complete responses up to 6 out of 56 patients in the trial.  However, in a subanalysis of the higher dose cohorts, 5 out of 23 were complete responders (22% complete response rate).  These responses are also durable, with median duration of response being not yet reached at a median follow up of 35.7 months.

View press release here, and download the full PDF of the presentation here (Oct 27 2017 presentation).

TG6002 oncolytic and vectorized virus, clinical trial for recurrent GBM in France

This upcoming trial in France is comparable to the Toca511/TocaFC trials in the US, in that it uses a viral vector to transmit a "suicide gene" to tumor cells that cause them to convert 5-fluorocytosine into the chemotherapy drug 5-fluorouracil.  The virus used in this trial, TG6002, is also oncolytic, meaning that it can kill tumor cells, even without the suicide gene + prodrug component.

https://clinicaltrials.gov/ct2/show/NCT03294486

More information on the lab studies with this therapy can be found here.

Complete responses to Toca 511 for IDH1 mutant gliomas

This was an abstract from this year's ASCO conference.

Durable complete responses observed in IDH1 mutated high grade glioma at first recurrence undergoing treatment with Toca 511 and Toca FC  (click here for the abstract)

"All 4 IDH1 mt patients treated at 1st recurrence had CRs [complete responses]"  !

Tocagen Trial News

I saw this posted on the Musella website (virtualtrials.com Brain Tumor news blast 5600):

"
Tocagen wins "Most Successful Early Phase Trial" and "Excellence in Rare Disease Drug Development" awards!         I am proud to say that the Musella Foundation has supported the development of this treatment with $130,000 in grants over the last 5 years. Winning the "Most Successful Early Phase Trial" is really impressive when you consider this is across all cancer types, not just brain tumors. Congratulations  to Tocagen!"

Stephen, do you happen to know any details of the results?

Mike B

Tocagen, a Mission Beach biotech company, is using immunotherapy to kill brain cancer cells,(Published Wednesday, July 20, 2016)

Has anyone seen this clip? I found it on the Musella site.

http://www.nbcsandiego.com/news/local/Local-Biotech-Company-Develops-Therapy-to-Increase-Life-Expectancy-of-Brain-Cancer-Patients-387740632.html

They are looking for more people for the next phase of their trial. Since my husband's tumor is inoperable, I'm assuming that he wouldn't qualify based on the news report but others might.

Phase 1 trial results for tumor resection + Toca511 and TocaFC

Study results were just published today in Science Translational Medicine.  Find the study in the main area of the Library.

Looking for advice to get cocktail started for my mom with recurrent GBM

Hi everyone. First off thank you all for your thoughts, information and advice. You guys keep hope alive. I'm here to try and figure out what else we (my sister, brother and I) could be doing for my mom.

I'm hesitant to make this post because I do not know the make up of my moms tumor(s) however, I do know that we need to do more for her now, before it's too late. I can try to get the pathology report from UCLA and post more on that when I do. I couldn't tell you what methylated or IDH-mutated mean but I do know my moms situation seems to be getting worse.

Without a pathology report I will try to give a brief backstory so you get a picture of what's going on here. I hope this is the right place for this and I will try to keep it as brief as possible. 

Jan 2008: Ended up scraping off side mirror on the car and realized peripheral vision was gone. Eyes checked, no problem. MRI showed brain tumor. Surgery Jan 11, 2008 at UCLA with Dr. Daniel Kelly (Now at St. Johns Santa Monica) with complete (or as close to complete) resection as possible. Diagnosed at age 51 with Stage 4 GBM and received all the scary statistics about her being lucky to make it a year. She bounced right back from the surgery as if nothing every happened. Up and about within a day or so back to her normal routine. 2 years of Temedor 5 days out of the month and around 60 rounds of radiation later, life was good and stable MRI's became the norm although every MRI was never any less scary awaiting results. We thought perhaps she was in the clear. Her vision also came back :)

My dad, her caretaker passed away unexpectedly in June 2012. I only bring this up because I believe stress may have played a big factor in the next update.

Jan 2013 MRI was clear. In fact, we celebrated 5 years remission. She then missed a scan in Feb '13 due to an insurance mix up, and finally had a scan in March '13 which showed a pea sized recurrence in the original tumor location. Prior to this she was doing so well that the doctor was going to allow her to get MRI scans less often. She was off Temodar for 3 years before this recurrence. So she went right back to several more radiation treatments and another year of Temodar (one week each month) and MRI scans monthly. Her scans showed the tumor to be shrunken and the site to be stable with no new growth.  

March 2015 MRI showed new but small growth in a new location close to the original tumor site but a bit deeper in. Oncologist tried new chemo, CCNU and were to follow up in one month. We were told she has had her lifetime max of radiation so that was out. Next scan showed the Tumor almost tripled in size. Options were try another chemo, surgery if the Tumor Board deemed it appropriate and a clinical trial going on at UCLA, Toca 511 where they inject a virus into the tumor cavity directly after resection. The remaining virus was to infuse itself in remaining cancer cells later to be killed by pills she took. We got word that surgery was an option and were able to enroll in the clinical trial. Surgery was performed at UCLA on May 14th, 2015 with Dr. Linda Liau. MRI before surgery showed more growth. Surgery was as successful as possible and Dr. Liau was somewhat surprised as she said so much of the tumor she pulled out was "dead." My mom had more trouble recovering from this operation. Memory loss for a few days, permanent vision loss and basically a big blow to her spirits because she didn't bounce back. She was still very much interested in recovery and getting stronger. As part of the study every 6 weeks she got an MRI and she took pills that were I guess anti-fungal in nature however, they were to head to the implanted virus, that had infused itself in remaining tumor cells and form a chemotherapy to destroy left over cancer cells. My mom began recovering, walking more normal and getting back to normal life minus navigating differently due to a permanent visual field cut from surgery. 

Things were looking great until October 8th 2015 when a scan showed some "changes." We were told it was nothing to be concerned of yet and that they weren't sure what was going on actually. Not the most comforting news. We were to follow up in a month or sooner if things got worse. My mom began to walk more poorly (always veering to the left) and crashing into walls, her memory became worse, most scary she just started acting odd like throwing away her fork and knife and looking for things around the house that were in completely different areas like the telephone for instance. She is aware that she is getting worse and is depressed and spends most of her awake hours crying. (We saw my grandma die from a metastatic brain tumor from lung cancer and it was not pretty) We tried to get my mom in for a scan, this time they wanted to do a DOPA-PET scan, which we were told might be the future of monitoring brain tumors. Insurance went back and forth for around 2 weeks on approving and denying and then approving only to have UCLA "run out of the DOPA injection dye."

This brings us to now. Nov 3, 2015 new scan shows growth and not just one area. The larger area is the one that appears to be messing up her walking. Our oncologist stated there looked to be a lot of inflammation around the area along with necrosis. He states that surgery on that area is probably not an option and may do more damage than good. We will seek a second opinion of course.

Nov 3, 2015 she had an Avastin infusion and was put back on Temodar 5x per mo. The Toca 511 trial has been put on hold. Her spirits are destroyed.

Throughout the course of this she has taken many supplements (mostly the first few years) Lots of different mushroom powders and something called Ave, some type of wheat germ for boosting her immune system. March of this year she started the CBD/THC Cannabis oil off and on. She can't stand feeling "high."

As of now she's taking:
Temodar 
Avastin 
Keppra 750mg 2x daily 
AHCC mushroom supplements. 

She was taking Wellbutrin but I'm not sure how consistent she is. 

It's probably too early to tell if the new drugs have done anything however, prior to them we were seeing a steady decline. Since getting them a few days ago she at least doesn't appear to be any worse symptom wise. 

We were told if she responds to treatment, great. If not she could be gone in a few months. I'm hoping this could at least buy us some time to get her back on the right track. 

So, what would you guys recommend we add in immediately along with her Avastin and Temodar? 

I'm sorry this is long and thank you. If someone would like to email or talk on the phone I'm sure that could be arranged. 

For Those Interested in the Toca 511 Trial

Update 12-05-2015

Well, Friends, it's been a challenge. About a month ago, Chance had a severe seizure while at the gym and ended up in the hospital. Fortunately, we got him transferred to UCSF but a lot of problems resulted.

They increased his Decadron to 16 mg per day and his Keppra to 2500. It was scary. Dr. Taylor wanted him to go on Avastin because the 16 mg Decadron was not sustainable, so two weeks ago, Chance has his first Avastin infusion.

Stephen helped me add DCA and Honokoil, and change the cannabis from THC:CBD to CBD only. We looked to add Chloroquine but I couldn't get a prescription. When I asked Dr. Taylor for a prescription, she resisted because of possible liver toxicity. Stephen countered but in researching, we found Chloroquine sometimes caused vision problems, and that was a side effect we couldn't consider.

Chance's vision has been worsening. For a short time after the last seizure, it was vision and comprehension (left temporal tumor), but ultimately it was blurry vision, both eyes. He loves to read. This was a big loss. We visited a neuro-opthamologist last Wednesday. He had a very kind manner, but broke the news that there was nothing he could do. A field of vision test revealed he had lost a lot of vision on the right side, even though it didn't appear to Chance as right-side loss only. The doctor said it was a function of the tumor. If the tumor gets smaller, his vision could improve.

I was at the bottom of the barrel. Chance had an MRI scheduled yesterday and I was more anxious than ever. Chance, however, couldn't wait for the results - and knew they would be positive. Chance has been working with an acupuncturist (and amazing healer) for five or six weeks. He sees her once a week and it is the high point of his week. She told him this MRI would show improvement, but the next one would show vast improvement. I wanted to believe her, of course, but it seemed nothing was really making his symptoms better.

Yesterday was the longest day. He was in the MRI department over two hours and then there was a long delay before we saw Dr. Taylor. When she called us in, Chance said, "I know why you took so long to call us in. You couldn't find my tumor!" She laughed and said, "Well, not exactly, but your scan was much improved!"

I told Stephen how amazing it was that a few words can change EVERYTHING!

Dr. Taylor believes the Avastin and Toca 5-FC are working perfectly. Chance believes he and his acupuncturist are working perfectly. For me, who cares?! We have improvement the first time since his September scan.

Last night he began his second round of the 399 Toca 5-FC pills. After being at UCSF three times this week, we don't have to return until after Christmas! Our Holidays are looking very happy indeed.

-----------------
Original Post 10-30-2015

Hi,
I mentioned Chance was enrolled in this study earlier, but I thought I would create a Toca 511 thread so I can post his progress.

UCSF identifies the study in this manner: CC#09102 A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511 in Patients with Recurrent High Grade Glioma.

General information: Toca 511 is a live virus that has been built to carry a gene into cancer cells. This process is called gene transfer. This gene carries instructions that cause the cancer cells to turn the flucytosine (5-FC) into a chemical that may kill cancer cells.

Chance was enrolled in Cohort 7 - the first cohort to receive the virus intravenously. Earlier cohorts required surgery to place the virus in the tumor bed. Chance had an infusion each day for three days (infusion took about five minutes, then you rest in place for one hour before release) on September 28, 29, 30, 2015.

He had no side effects of any kind from the virus infusions.

Last Monday, Chance was supposed to start the 5-FC pills - the next step in the process. Unfortunately he had a seizure at the gym on Sunday night and ended up in a local hospital followed by transfer to UCSF.  He was released on Wednesday, then we returned today to start the 5-FC process.

When we talked about it originally, UCSF staffers said he would have to take a lot of pills during the process. Chance laughed and said it couldn't be more than his mom had him taking already, could it? Today we found out. These are big white pills, and he is to take 19 of them three times a day for seven days (399 pills!). He does this once every six weeks for three rounds. He will get an MRI every six weeks. If the 5-FC is working as it should, he can join a continuation arm of the study (which was a very big selling point for us).

It will be six weeks until we can determine if the 5-FC is doing its job. I'll be back then to update.

(Just for further information, this trial is being offered at a number of sites. They are currently enrolling Cohort #8 for surgical injection into tumor bed. Cohort #9 is the next one to inject intravenously. This time it will be given over five days instead of three.)

It was suggested to me by a doctor that Xeloda can be used for glioblastoma.

Can Xeloda be used for glioblastoma. Are there any studies showing its efficacy for glioblastoma?

Chance's latest (this month) MRI showed edema

At Chance's MRI on 9/11, edema was found. Chance had been getting increasingly dizzy. Within the last couple of weeks he left his job on short term disability because he had several times he referred to as his brain not working. He could not put words together to explain he was having a problem comprehending or communicating. His position was in high stress software sales, so it was probably the last thing he should have been doing, but of course he wanted to keep working as long as he could.

His NO suggested he increase the Decadron to 4mg a day (he was finally down to 1 mg a day).

A worrisome MRI happened once before, last spring, so we prayed we could wait 30 days and have him retested, but his case went to the UCSF tumor board on 9/17 and it was agreed edema was caused by progression and that his tumor was now inoperable because of it's location - near language and memory.

The board suggested Avastin and CCNU.

Based on what I've learned these last few months, I had no problem saying NO!

Stephen gave me some trials to consider, two at UCSF and two at Duke. All but one required some sort of surgery, so we went with the least invasive: Toca 511 at UCSF. Chance will be the first participant in Cohort 7, which means they will use an infusion in hand or arm, rather than placing the virus directly into the tumor. They say it has been proven that the virus gets to the brain regardless of where it is given. He will have the virus infusion over three days starting next Monday. A month later they start a dosing with an anti-fungal that becomes a powerful chemotherapy agent to kill dividing cells. He will take the anti-fungal pills every six weeks for four cycles. The beauty of this particular trial is that it has a continuation arm.

For those unfamiliar with Toca 511, there is a lot on YouTube you can find by searching "Toca 511". It is being offered at nine locations in the U.S.

We are consulting Duke for a second opinion and treatment options just to get a foot in the door in case we want to pursue in the future.

I wanted to update Chance's status and include a huge shout-out for Stephen, Ben, Rich and Cheryl and so many others for everything they have done and are doing for their GBM sisters and brothers. I am grateful beyond measure.