Options for first recurrence

I’ve been following along here for the majority of my Dad’s 7 month long battle with gbm. I cannot express how grateful I am for the information, and for the people that contribute all that they do.  

We are looking at tumor recurrence for my Dad.  Our NO is Dr. Stupp and he was kind enough to reach out to UCSF, Dana Farber, Duke, and Mayo for second opinions/possible trial options since Northwestern did not have any other trials they liked for Dad. This is the email he sent out for us…

Diagnosis

Glioblastoma left temporal lobe

· s/p gross total resection on 5 May 2017.

· Histology:

· WHO, Grade IV, MGMT unmethylated, Ki-67, 30%.

· Gliaseq: EGFR ++, ATRX mutated,  copy number losses in CDKN2A and PTEN.

· Status post post NSC-adenovirus injection on 5 May 2017 (Phase 1 Protocol)

· Status post  TMZ/RT 30 x 2 Gy on 15 May – 26  June 2017 with concomitant TMZ

· status after 2 cycles of adjuvant TMZ.

Current Problem

· Suspected tumor recurrence at site of primary tumor location

o Contrast enhancement 1.5 cm approx., no edema, perfusion +, spectroscopy non-contributory.

· Adjuvant Optune™ treatment start suspended due to suspicion of recurrence.

Our Plan

·         Resection of contrast enhancing lesion in order to allow for

o    “Debulking” (not much bulk)

o    diagnostic clarification of post-therapeutic inflammation (warranted) and pseudo progression vs true recurrence

o    further second-line therapy in case of recurrence by either

§  ABT 414 (expanded access)

§  Irinotecan or other non-aklylating agent chemotherapy (unmethylated tumor, progressed under TMZ)

§  (CCNU)

§  other ?

add Optune as part of first line standard adjuvant therapy

I would imagine that’s a better summary than I could write. We’re hoping to find some input here because we have options open to us and we’re unsure which path to take.

Stupp initially advised surgery, but then our surgeon at Northwestern who we met with separately said he didn’t think the lesion was that dramatic and would prefer to wait 2 months to see on the next MRI what it looks like. He also felt with how well Dad is doing, and where the tumor is located, that surgery is too high risk for interfering with quality of life. Dad has not been on any meds (other than the temodar), goes to work daily, and has really not shown any new symptoms since his initial diagnosis.   He mainly just has some world retrieval issues, very minor comprehension issues, and a more difficult time reading and writing.

Duke, UCSF, and Dana Farber all said they may have trial options. Dr. Friedman did mention the polio trial was not an option, because they cannot do it in the left temporal lobe. 

Anyhow, coincidentally Dad already had trips to San Francisco and Boston planned back to back, so I joined him to meet with UCSF and Dana Farber. Both saw the scans and advised surgery to find out if this is recurrence or pseudo-progression. They also both recommended the Abemaciclib trial. I asked about MDNA-55 at UCSF, and they said the tumor board had discussed this, but had concerns. One was that Dad already participated in the NSC-adenovirus trial and they had no idea what this may look like or how it could behave in the brain, therefore their concern is that if it’s still active that there could be an unknown interaction with MDNA-55. At that time there was still the question of whether or not this was true progression as well, which is also why they hesitated on it. They did however send us home with a consent form, and left the option open.

In the time that has passed, we reached 4 weeks last Tuesday since the initial MRI, still without a plan of action. So I requested another MRI to which Stupp agreed. It showed the lesion was slightly more prominent, at 1.5 x 1.7 x 1.0 cm, formerly measuring 1.4 x 1.6 x 1.1 cm. There was also irregular curvilinear enhancement along the margins of the resection cavity. Stupp consulted our surgeon, and he still said no to surgery. So our option in Chicago is a second line therapy, as there are no more trials they have for Dad. I should mention that Dad has had no treatment of any kind  since Sept 3- his last day of temodar. He was delayed starting his 3rd cycle due to a work conference, then low platelets, then we had the MRI showing suspected recurrence so treatment was suspended. He does take a long list of supplements and some medical marijuana (which UCSF strongly supported when we met with them!)

Dad felt very confident with the team at UCSF and decided we should head there for treatment so we can participate in another trial. Stupp supports this, and advocated that Dr. Berger do the surgery if that’s recommended. We’ve been in touch with the NO there, Dr. Bush. She just revisited Dad’s case with the tumor board, and said that while MDNA-55 certainly could be done, based on the cystic component of his tumor, it is felt that the more aggressive option would be to do a surgery with a following clinical trial Abemaciclib, and that would be the approach they would favor.  When I showed Dr. Stupp both trials he also said he would favor abemaciclib.

I have thought all along that the MDNA-55 trial appeared to be more promising, and felt it could be a good opportunity. I also liked it because we could avoid resection, which Dr. Stupp said he’s not even sure if there is a survival benefit to multiple resections. Dad’s tumor is in an area where our surgeon in Chicago felt surgery could impede his speech/comprehension abilities. Whereas the surgeons at UCSF felt confident the surgery was low risk.  I’m sure you can tell that while we’re grateful for options, we are also a bit overwhelmed at making the right decision. Should we push for the CED of MDNA-55? Or should we simply trust in our doctors, who are all pushing us towards abemaciclib – which would involve another resection? I also know Dad would prefer not to be on a chemotherapy drug – but at the same time he is willing to do “whatever is best”. Of course we also still have the option of no surgery or trial at this time, and trying a different drug with Dr. Stupp. My concern with that is that we will miss an opportunity, while Dad is still very healthy and able to travel and participate in trials. 

I’ve hesitated posting here until I truly felt it necessary, as I very much appreciate the time and effort people put into this small community and have not wanted to utilize your time until we truly felt like we were at a crossroads. As such, I apologize for how lengthy this was. I just wanted to supply as much information as possible in hopes of finding some insight.  

Thanks so much,

Jaclyn

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.

ᐧ

SNO 2017 Highlights, episode 3: Marizomib +/- bevacizumab for recurrent GBM

Full enrollment results from the phase 1/2, multicenter, open-label study of marizomib (MRZ) +/- bevacizumab (BEV) in recurrent WHO grade IV malignant glioma

Daniela Bota of UC Irvine presented these results.  The trial was divided into three parts: Part 1 was a dose escalation and dose expansion trial of the brain penetrant proteasome inhibitor marizomib added to bevacizumab and consisted of 36 patients.  Part 2 was a trial of single-agent marizomib consisting of 30 patients.  Part 3 was an intra-patient dose escalation of marizomib combined with bevacizumab consisting of 35 patients.

In Part 1, 27 out of 36 patients (75%) were treated with 0.8 mg/m2, while 9 patients (25%) were treated at lower doses in the dose escalation phase.  Patients in Part 1 also received standard dose bevacizumab.  The overall response rate for the 36 patients receiving marizomib and bevacizumab was 16/36 or 44.4%.  11/36 or 31% had stable disease.  Response plus stable disease rate is 27/36 or 75%.  Median progression-free survival was 3.9 months and median overall survival was 9.4 months.

In Part 2, 30 patients were treated with marizomib alone.  In this cohort there was only 1 partial response (1/30 or 3%) and 6 with stable disease (6/30 or 20%), for a response plus stable disease rate of 23%.

Patients in Part 1 experiencing central nervous system related adverse events (including ataxia, balance disorder, dizziness, fall, gait disturbance, hallucination) had increased PFS and OS compared to those who did not suffer from these side-effects, and this observation provided a justification for Part 3 of the study, an intra-patient dose escalation of marizomib combined with bevacizumab. In Part 3, 10 out of 35 patients were escalated to 1 mg/m2 of marizomib, but only 1 patient was able to tolerate this dose.  No patient reached 1.2 mg/m2.   The intra-patient dose escalation can therefore be said to have not succeeded, as the next higher dose of 1 mg/m2 was largely not tolerated.

It appears that single agent marizomib has some activity, but only for a minority of patients, while adding bevacizumab to marizomib leads to much higher response rates and increased survival at 12 months, but still leads to an average median overall survival statistic for recurrent glioblastoma.

SNO summary, episode 2: AG-120 phase 1 trial for IDH1-mutant glioma

AG-120, a first-in-class mutant IDH1 inhibitor in patients with recurrent or progressive IDH1 mutant glioma: updated results from the phase 1 non-enhancing glioma population.

Summary by SW who attended the presentation and took photos of the slides.

Ingo Mellinghoff of Memorial Sloan Kettering Cancer Center presented results of a phase 1 trial of AG-120 (ivosidenib), a mutant IDH1 inhibitor, for IDH1-mutant cancers.  The presentation specifically focused on a subset of patients in the phase 1 trial: those with non-enhancing (no contrast enhancement on MRI images) IDH1-mutant gliomas.  This analysis included 11 patients in the dose escalation phase, and an additional 24 patients from the dose expansion phase, a total of 35 patients.  The primary study objective was to evaluate safety and tolerability of AG-120, and determine the maximum-tolerated dose and/or the recommended phase 2 dose.

28 out of 35 patients (80%) of patients in this analysis were treated with 500 mg of AG-120 daily.  The majority (24/35, or 69%) of patients in this non-enhancing glioma cohort were WHO grade 2 gliomas.  An additional 23% were WHO grade 3.  Only one grade IV glioma (3%) was included.

Most patients in this analysis had been previously treated with either radiation (57%) or chemotherapy (69%) and the median number of prior systemic therapies was 2.

AG-120 was well tolerated, and the maximum tolerated dose was not reached. The majority of adverse events were low grade, and only 20% of patients experienced a grade 3 or higher adverse event. 

Pharmacodynamic analysis of tumor tissue in two patients revealed that AG-120 treatment strongly suppressed 2-hydroxyglutarate levels in the tumors.  2-hydroxyglutarate is the oncometabolite produced by the mutant IDH1 enzyme.

By far the most common response to AG-120 treatment in this cohort was stable disease, which was achieved in 83% of patients. Only two patients (5.7%) achieved a minor response, including one grade 2 and one grade 3 glioma. Only four out of the 35 patients (11%) had progressive disease with neither stabilization or response.  

More important is the duration of stable disease without progression.  Median duration of AG-120 treatment for all 35 patients is 16 months. For the grade 2 gliomas, representing nearly 70% of the population of this study, median progression-free survival has not yet been reached, and looks to be at least 19 months at the time of the analysis (data cutoff May 12 2017).

When volumetric growth rates pre- and post AG-120 treatment were calculated by imaging studies for the 24 patients in the dose expansion group, the mean percentage change in tumor volume per six months was found to be 24% prior to treatment, and 11% after AG-120 treatment.  In the 1p/19q intact (that is, the astrocytoma) subgroup of 15 patients, before and after AG-120 growth rates per six months were 38% and 14%.  This confirms that the primary effect of AG-120 in this group of non-enhancing (mostly) lower grade gliomas is to significantly slow tumor progression, which was deemed to be a disease stabilization in the majority of cases.

A different drug by Agios Pharmaceuticals, called AG-881, is a dual inhibitor of mutant IDH1 and IDH2, is more brain penetrant than AG-120, and is also being studied in clinical trials for IDH mutant gliomas.

SNO summary, episode 1: CeTeG trial (CCNU + TMZ versus TMZ alone)

Phase III trial of CCNU/temozolomide (TMZ) combination therapy vs. standard TMZ therapy for newly diagnosed MGMT-methylated glioblastoma patients: the CeTeG/NOA-09 trial presented by Ulrich Herrlinger for the Neurooncology Working Group (NOA) of the German Cancer Society.

The summary below written by SW, who was in attendance at the presentation by Ulrich Herrlinger and took photos of the slides presented.

The CeTeG trial (also known as NOA-09) is a randomized phase 3 trial for newly diagnosed glioblastoma with methylated MGMT promoter, testing CCNU (lomustine) combined with temozolomide (TMZ) versus TMZ alone. This trial was conducted at 17 centers in Germany and was a follow-up to a non-randomized phase 2 trial which had results published in 2006 and 2009. The CeTeG trial was relatively small for a phase 3 trial, with a sample size calculation of 128 patients total, and this sample size was based on expectations of a significant increase in survival rate at 2 years as seen in the phase 2 trial compared to historical controls. 

Patients in this trial had relatively good prognosis, with high rates of complete resection and high average KPS.  Overall the arms were well balanced, with the only significant imbalance between the two arms being gender, which was not prognostically relevant.

In the combination arm receiving CCNU + TMZ, cycles were 6 weeks in length, with 100 mg/m2 oral CCNU given on day 1 of each cycle and TMZ on days 2-6 of each cycle, with a starting TMZ dose of 100 mg/m2 and possible escalation up to 200 mg/m2 in later cycles. Cycle 1 starts at the same time as radiation.

In the control arm of TMZ alone, cycles were 4 weeks in length, and used the standard TMZ schedule (daily at a dose of 75 mg/m2 during radiation, and 150 mg/m2 on days 1-5 of the first adjuvant cycle and possible escalation up to 200 mg/m2 in later cycles.

Importantly, this trial achieved its primary endpoint of increased overall survival. Survival in the CCNU + TMZ arm was statistically superior to TMZ alone, with a p value of 0.049.  Hazard ratio for death from any cause was 0.6 in the CCNU + TMZ arm.

Median reported survival was 46.9 months for CCNU + TMZ versus 30.4 months for TMZ alone, a difference of 16.5 months.  As seen in the Kaplan-Meier survival estimates, the curves did not separate until after the 2 year mark.  1, 2, 3, 4, and 5 year survival rate was 88.8, 71.4, 57.4, 48.8 and 34% in the CCNU + TMZ arm versus 84.4, 65.4, 42.3, 31.4 and 27.7% in the TMZ arm.  Differences in the survival rate between the two arms were greatest at the 3 and 4 year mark, with 15% more patients surviving to 3 years and 17.4% more patients surviving to 4 years in the combination arm versus the TMZ alone arm.

Given the significant overall survival differences, it's surprising to note that progression-free survival was not significantly different between the two arms (p=0.41), although the progression-free survival curves separated somewhat at about 2 years (a phenomenon also seen in the overall survival curves), after which time CCNU + TMZ shows a slight superiority over TMZ alone. Some potential explanations given by the authors for the lack of a strong PFS signal included: "problems with PFS assessment according to RANO?" including potential undetected pseudoprogressions; and "long-term effects of CCNU?", noting that in studies of low grade gliomas treated with CCNU, responses were sometimes seen months or years after the end of therapy.

  

The percentage of patients receiving further lines of therapy after progression was similar in both arms (59.1% in the CCNU + TMZ arm, 63.5% in the TMZ arm).  More patients underwent re-resection in the CCNU + TMZ arm (31.8% versus 22.2%), and more patients received re-irradiation in the TMZ alone arm (23.8% versus 18.2%). More patients in the TMZ alone arm received further chemo or targeted agent therapy (60.3% versus 48.5%).  The percentage of patients receiving bevacizumab after progression was similar in both arms (27% in the TMZ alone arm, 30.3 % in the TMZ + CCNU arm).  The authors concluded that differences in treatment after progression are not an explanation for the superior survival in the TMZ + CCNU arm.

Combination therapy with TMZ + CCNU approximately doubled the rate of low-grade (but not high-grade) hematoxicity (including neutropenia and thrombocytopenia) and nausea.  However no deaths due to treatment toxicity were observed, and no severe infections, liver failure, or lung fibrosis. More brain edema was observed in the combination arm, and more low-grade alopecia (patchy hair loss).

The authors concluded by noting that acute toxicity of the combination treatment was rare, and importantly, "the primary aim of CeTeG/NOA-09 was achieved: the OS superiority of CCNU/TMZ for MGMT promoter methylated newly diagnosed GBM could be demonstrated".

This may well be the most significant trial outcome reported at the 2017 SNO conference. Since TMZ was approved for newly diagnosed glioblastoma in 2005, it has been exceedingly rare for a phase 3 trial in the newly diagnosed GBM setting to achieve statistically significant prolongation of survival with a novel regimen.  More work needs to be done to explain why progression-free survival benefit was more modest than overall survival benefit in this trial. A potential hypothesis for the improved survival results for the combination therapy is a possible synergistic interaction between TMZ and CCNU, whereby cells escaping sensitivity to TMZ through mismatch repair defects are thereby rendered more sensitive to the CCNU treatment (Stritzelberger et al. 2017). Now that the results of CeTeG have been reported to the international neuro-oncology community, the mechanisms behind the improved outcomes with the combination chemotherapy will likely become the subject of more intense investigation.

SNO conference, San Francisco and Optune compliance

Myself and a friend who also frequents this blog are at this year's SNO conference in San Francisco. I will be reporting on the conference very soon.

To get us started, here is a report from Novocure showing increased survival in the EF-14 trial for patients who achieved 90% or more compliance with Optune (that is to say, wore the Optune device for an average of 90% of the time each day).

Median survival (from randomization, which was 3.8 months after diagnosis), was 21.7 months with 70-80% compliance and 24.9 months with 90% or more compliance.  5-year survival rate in the 90% compliance group was 29.3%.

This dose-response effect is a powerful argument against those who would argue that the positive results in favor of Optune seen in this trial could be a result of a lack of a placebo control, or the result of increased supportive care in the Optune arm.

https://www.novocure.com/patients-who-used-optune-more-than-90-percent-of-the-time-had-the-greatest-chance-of-survival-in-novocures-ef-14-trial-a-median-survival-of-24-9-months-from-randomization-and-a-five-ye/

Disulfiram + copper + radiation + TMZ case report

While not providing definite evidence of disulfiram activity, this case study on the use of disulfiram + copper for an IDH1-mutant, MGMT-unmethylated glioblastoma does show that disulfiram therapy can be initiated at the time of radiation.  The disulfiram dose was 250 mg daily, and the dose of copper gluconate was 3 mg twice daily.

Evidence for the efficacy of disulfiram and copper combinationin glioblastoma multiforme - A propos of a case

First Recurrence, Clinical Trials? No more treatments?

Hello, I have posted before trying to find out more about Val-83 but have not been able to find much information. My husband-unmethylated, IDH Wildtype, no actionable mutations except FIG-ROS1, .51 mutational burden-has had a recurrence and I would appreciate any insights into possible options. 

Quality of life over quantity is our guiding force and I would also appreciate any advice towards not doing any more treatments if you feel that way. My husband keeps saying he has had a great life and he is grateful and if now is his time he is at peace. I, however, am a fixer but I don't want to pressure him into doing things he is not comfortable with and have no proven outcome.

The clinical trial that seems the best suited for Tim is the one for the chemo drug Val-83 at MD Anderson. It is the drug that Al Musella at virtualtrials.com said he would try if he were unmethylated. It is a small molecule drug that was used in the 70s I think. Unfortunately I can find out very little about side effects or benefits. It is Phase 2. We have an appointment with them.

I have also contacted Duke and Dana Farber to see if they have anything to offer. Tim's NO said he was not a good candidate for an immunotherapy, I think because his tumor mutational burden is not high. He is pre-approved for Nivolumab. He probably does not have enough tumor frozen to make a vaccine and his gut reaction is he does not want another surgery plus his NO thinks the new tumor may be too deep and inoperable.

Other choices are the old chemo drugs CCNU/Lomustine. I have also heard of people using it with Avastin concurrently.

A basket drug, entrectinib, I know little about and is not used for GBM but one that could be used because of his FIG-ROS-1 mutation.

Avastin, of course, I hear more good things than bad but am always worried about the worse case scenarios as Tim seems to be sensitive to drugs.

I have also read about 3BP as a miracle drug but don't know if it is even available or if it was just an anomaly or a great story or what?

Thanks, Dianne

Salinomycin

Hi everybody,
Has anyone tried salinomycin infusion for GBM? One clinic offers this protocol, but I only found this article
https://www.ncbi.nlm.nih.gov/pubmed/24351423
Nothing about it in humans, BB barrier, etc.
Hope for us all
Bb

Recurrent Glioma with leptomeningeal spread ?

Hi all,

Thank you for the kind reply on my previous post. Updating on my brother situation (diagnosed GBM March 2016, radiation, temodal, theracim), MRI show spot on February 2017.  He decided to undergo surgery just two weeks ago on 31 October 2017 with mass approx. 1.7cm . What confused us is the laboratory report just out and it stated, 'recurrent glioma, with leptomeningeal spread'. But they cannot decide what grade it is as the cell is too damaged by previous chemoradiation and it is 'too small'. Even the neurosurgeon itself not sure what the conclusion means. Do anyone familiar with this term or understand what it means? as I have searched over the internet but still confused if it is a bad things or just a normal explanation. The laboratory also collect another sample stated as 'Scar' and  'Surrounding Brain' which come out as benign tissue. Thank you for the time and attention.

considering other options

Dear all,
I again need your advice - currently my son (17 , approaching 18) has a recurrence of his H3K27 glioma, "very low methylation" ( a rather strange phrasing of pathology from UPenn. I would still consider it unmethylated like H3K27 gliomas are)  . It is multifocal now and because it involves cerebellum we cant do polio trial or City of Hope Car-T cells. We are currently on Temodar and CCNU and have just finished 10 whole head radiation sessions with Dr.Lederman . We managed to get him ONC 201 earlier, but in September he had bleeding in the brain, so they pulled back ONC201. It was, in my opinion, too early to tell if ONC 201 worked or not. We also had Avastin twice ( before starting ONC201), but our NO won't give Avastn again due to the risk of bleeding. We are also on Keppra and a few CUSP 9 drugs.
We are considering the following options:
1. Just continue with CCNU and Temodar
2. Try getting into adult trial of Val 083 - we had success getting ONC201 being under 18, so we are determined to try getting it now.
3. Try to get ONC 201 again to add to Temodar and CCNU
4. Any other ideas?
I really would appreciate suggestions as to what else we might try - any ideas of other trials? Over the last year we have been completely excluded from any adult trials, but now we are almost at the point where he is almost 18.
Thank you!

Where can we buy methadone without prescription ?

Does anybody know where we can buy methadone without prescription?

Immunotherapy at IOZK Cologne

Hello all,

My 38 year old brother has been diagnosed with a Glioblastoma six weeks ago. Since then he has had total surgical resection and is currently finishing his second week of temodar and radiation. He has also added quite an extensive amount of additional medication as a cocktail approach (I am sure that he will write a more detailed post about the drugs he is taking, when he finds the time). We have found the information in this blog to be extremely helpful. Thanks a lot to Stephen and all of you participating in this great resource.

Right now we are thinking about additional options for the time after his chemo/radiation phase. One thing that we are quite interested in is immunotherapy. Unfortunately my brother’s resected tumor tissue hasn’t been frozen but conserved in paraffin so that options are somewhat limited. We have contacted IOZK in cologne and they have said that they could produce a vaccine without the tumor tissue, using only a blood sample. Cologne is not too far from where we live.

I have read various comments, in this blog, about the IOZK clinic and I know that some of you have been, or have had family members being treated there. I would be very grateful if you could tell me about your experience with the clinic and whether you would recommend giving it a try.

Thanks!

Phil

Surgery, Avastin or Study Drug Abemaciclib ?

My husband (54yr.) is ~12 months post total surgical resection of GBM unmethylated (got standard treatment of radiation, temodar, and additional 1 mo. of  study drug -IV plerixafor-to enhance radiation effects) Over the past 4 months. MRI is showing increased changes that appear to be evolving treatment changes probably from Plerixafor enhancement of radiation  (+ more swelling) and it appears ther could be a small nodule of  GBM tumor recurrence. His symptoms have also increased (some speech stumbling, small focal seizures, plus a grand mal).  Thus he was put on dexamethasone (steriod 4 mg twice daily (now down to 6mg daily)  and increased Keppra from 2000mg daily to 3000mg daily) .  Next the NO wants to start Avastin (the NO is NOT for surgery).  We are trying to decide on a few options and will get one more MRI  and possibly PET CT to see if tumor recurrence is more definitive.

Choices:
1.  If MIR confirms additional growth, then Surgical removal of tumor first (surgeons recommendation)
2.  Avastin for swelling and to shrink tumor and perhaps add on Optune (NO's recommendation)
3.  2nd opinion of NO at UCSF site suggests Study drug Abemaciclib  due to gene testing of my husband's tumor pathology that shows CDKN2A, CDKN2B.  If we take this route then NO AVASTIN can be used.

Trying to figure out best option for highest functioning and quality of life.

Your Thoughts Appreciated.

Clinical Trials for Low KPS recurrent GBM patients

Hi all,

Is anyone aware of any Clinical trials taking place on the West Coast (USA) that consider low KPS recurrent GBM patients?

I've had my eye out for any reasonably non toxic options, but almost all trials have an entering criteria of >60-70kps score even for recurrent patients. My Father is closer to a 50.

I understand why 60/70 kps is standard, I'm just curious if others have heard of non toxic options for patients who cannot fully care for themselves.

We currently take various supplements and THC/CBD oil based on research from this forum, but are always open to more ideas.

My Dads original profile here, although he has since had a recurrence and is no longer taking TMZ:
http://btcocktails.blogspot.com/2017/02/tom-wangerin-cocktail-profile-and.html

Thank you to all

Ari

A few pathology questions and suggestions for course of action on newly diagnosed AA3

My wife(45), in all other aspects healthy and fit, was diagnosed with right temporal  lobe AA3 after >90% resection mid july 2017. Early june she suffered from an epileptic seizure which was the first ever symptom of a tumour  – actually they suspected a rare venous thrombosis for three weeks and treated her as such after first CT/MRI.

Second MRI the mass was constant and they suspected a low grade glioma. MRI Radiologist described it as non- enhancement and welldefined borders 5X3X2cm.
She was transferred to The National University Hospital where we met with the neurosurgeon, who felt sure it was low grade based on the characteristics of the tumour
During surgery frozen sample couldn´t determine grade 2 or 3. Final pathology report concluded grade 3 with the following characteristics (loosely translated from Danish)

Microscopic:

Braintissue with  diffuse infiltrating nature with small microcysts. In areas the tumour has more cell density, the nucleous are light pleomorphic and hyperchromatic – there are mitosis and apoptopsies(?). There is no microvascular carprofilation or necrosis. In the most cell dense areas a moderat high proliferative activity is observed determined by KI67 colouring and up to 6 mitosis per 10/HPF are identified I PHH3 colouring

The tumour tissue is positive in immunestaining for GFA, Maj 2, P53, IDH1 mutation and ATRX mutation

Analysis of  DNA methylation: the average methylation is 33% so methylated MGMT promotor  is found in the analyzed tissue.

The analysis is conducted with pyrosequencing of 4 CpG sites in the MGMT promotor with Therascreen. Cut of value in the analysis is 10%.

MLPA analysis: IDH1 mutation ( c.395>A,p.R123H) has been found in the analyzed tissue. There is no deletion of 1p/19q in the analyzed tissue.

Macroscopic:
Leptomengial sample tissue measuring 34,25,16 mm. Central cut to freeze+ imprint. Freezediagnosis Diffuse glioma grade 2-3. Freeze sample to biobank.

Diagnosis:
Diffuce Astrocytoma and based on proliferative activity classified as Anaplastic Astrocytoma WHO gr III.

1 month after surgery she did 6 weeks of daily TMZ (125mg) and proton treatment weekdays (~59gy). She is now at home with chemo pause until nov 8^th where she will start 6-12 rounds of 300>400mg TMZ by Stupps protocol (5/28). She has no icognitive nor neurologic ssues except for a little mild vertigo at times, which NO suspect to be her Keppra medication.

Question 1:

MRIs were not made within 72 hours post op. MRIs were made on aug 1^st and sept 15^th during proton treatments, but these were merely in regards to tracking the preciseness of the proton treatment. No further feedback except that there was no change between the two scans, but also that it would be impossible to differantiate post-op scartissue, radiation effects and actual tumour at this point. Next scan is scheduled at Jan 4^th. Is that also your experience?

Question 2:

After surgery and pathology neurosurgeons and oncologist all expressed that her tumour was in the greyzone between grade 2 and 3. But as there is limited actual data e.g. “moderate high” rather than percentage of KI67 staining, further genomic data and a relatively high(?) mitosis count is most dense areas it is hard to compare to data in online datasets. Do you have an idea of what they would base their statement on? Is it the IH,MGMT,ATRX combination, the resection degree and relatively welldefined borders or something else?

Question 3:

Based on the latest NOA-9 trial would it make sense to push for a CCNU/TMZ combination instead of Stupps or are the results yet to vague and even untrialed for AA3? What would be the prime candidate for a trial in case of recurrence for a tomour with the above characteristics – Tocagen (good results – 50% or 2/4 - on high dose IDH AAs), DCVAX, MDNA-55 or something else?

DNX-201 With Pembrolizumab (Keytruda)

Hello All,

I am looking for any comments, experience and suggestions with the DNX-2401 trial.

The Phase II just opened and I am enrolled for the procedure on Monday.

My GBM was resected in June 2015 and there has been some mass increases in the area between my cavity and skull.  Shows some signs of tumor and some signs as necrosis.


Of the couple of trial options offered to me, (southern California) these seems like the best, like the biopsy aspect of this trial.

When I asked a GBM research scientist friend of mine, I got the following comment:

Paraphased:

 - DNX-2401 is a one shot try.  If it comes back up the biopsy hole, then nothing is going to happen.

So this makes sense, that if no DNX-201 then nothing for the PD1 to work on.

But is this really a concern?

Any, why cannot you just re-inject if this happens?

Marc

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).

new paper on IDH305, mutant IDH1 inhibitor

abstract on pubmed here

sci-hub download here

Temodar and CCNU

We finally convinced our NO to give our son Temodar and CCNU for his recurrence. Our NO wants to do it every 42 days. However, we are uncomfortable with such long gaps, especially considering his platelets are good. Do you know of any studies with shorter periods between administration that I can refer our doctor to? Thank you !

ABT-263 experimental drug or feasible solution in the near future?

Hi.

Just stumbled across this article. Published a while back but just recently made available online.

https://www.nature.com/articles/s41467-017-00984-9

I know it is still about saving mice ;), but it is indeed interesting given the preliminary results.

However I can´t really distill whether ABT263 is an existing drug developed for other purposes (http://www.selleckchem.com/products/ABT-263.html), if it is experimental but in human trials or if its experimental and to this point only applied to xenographs.

Any views/perspectives on the application of ABT-263?

Hello all-

My mom was diagnosed with glioblastoma in February. She underwent surgery than had standard temodar plus radiation. Her tumor was unmethylated and IDH1 negative. My parents live in Massachusetts and we enrolled her into the Survax trial:

https://clinicaltrials.gov/ct2/show/NCT02455557

I have attached her original tumor genetic analysis in jpeg format (sorry)

Unfortunately, 8 months after diagnosis she has had recurrence at original tumor site. She is undergoing surgery again for tumor debulking and symptom control next week.

She is functionally still active with her main symptom being a left visual field defect.

I would appreciate any thoughts/recs on what clinical trials and treatment options we should pursue.

Thanks in advance

Immunotherapy and cannabis

Hi,

Does anyone have information on concurrent use of immunotherapy and cannabis? I read that cannabis can have anti-inflammatory effects primarily due to it suppressing the immune system. This seems worrisome if the patient is on immunotherapy. All I could find is one retrospective study on cannabis and opdivo use: http://oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/The-effect-of-cannabis-use-on-tumor-response-to-Nivolumab-in-patients-with-advanced-malignancies

Has anyone's doctor mentioned a possible contraindication?

Thank you.

Accessing clinical trials in US from overseas

My wife started off with a Grade 2 astrocytoma but throughout the years has now progressed to a Grade 4 GBM that isn't responding well to TMZ. We are looking into clinical trial options but there aren't many options where we live, so we are exploring options in the US.

Has anybody else had the experience of travelling to the US to access clinical trials? I understand that it will be extremely expensive, and a logistical challenge to organise. We are willing to take on the expense if it is a trial that is worth it. Really wanted to hear from anybody else who have gone down this path.

We are also only starting to look through trial options, primarily in the US. If anybody has any recommendation as to the most promising trials that are happening at this point, we would really appreciate any guidance and advice.

Avastin, CCNU or Carboplatin (via port)?

Dear all,
My son's H3K27 glioma has recurred, in and outside of the original tumor bed. He was treated with ONC201 ( for only about a month or so), and then had a bleeding in the brain. Hence ONC201 was stopped ( even though we are positive it was bot caused by it).
We are looking into radiosurgery and are continuing with sativex, cusp9 etc. Our radiosurgery oncologist thinks Avastin offers the most hope. However, our NO refuses to use it de to the bleeding. He is only willing to do one agent - either Irinotican, or CCNu or carboplatin via port.
We are looking into some other NO willing to do avastin - or is it better to go with carboplatin?
Thank you!

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.

CCNU+TMZ - impressive outcomes for MGMT-methylated GBM

A reader of this blog kindly directed my attention to this breaking news, the first results of the phase III NOA-9 trial in Germany testing the combination of TMZ with CCNU (lomustine) for newly diagnosed MGMT-methylated glioblastoma.

"The mean median survival time in patients receiving CCNU was 46.9 months compared to 30.4 months in the control group with monochemotherapy."

The "mean" in the Google translation of the German language news report actually refers to the median (mittlere), as confirmed at the SNO 2017 presentation.

Although this was small for a phase 3 trial (only ~140 patients), a gain in median survival of over 16 months is unprecendented.

This will undoubtedly become the new standard of care for MGMT-methylated GBM.

https://clinicaltrials.gov/ct2/show/NCT01149109

https://forum.hirntumorhilfe.de/neuroonkologie/breaking-news-fortschritte-in-der-glioblastombehandlung-12606.html   (news article in German)

Psilocybin and end of life care

I'm aware that (like cannabis) psilocybin is illegal in most countries.  Psilocybin being the active ingredient in hallucinogenic magic mushrooms.  However, I've just became aware of an increasing body of literature (this research has really exploded since 2016) on the investigation of psilocybin for depression and anxiety, including studies on its use in terminal cancer patients.

There seems to have been an entire issue of the Journal of  Psychopharmacology (December 2016) devoted to this with original research papers:

"Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial."

"Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial."

and commentaries:

"Psilocybin-assisted psychotherapy for dying cancer patients - aiding the final trip."

"The role of psychedelics in palliative care reconsidered: A case for psilocybin"

"Psilocybin for depression and anxiety associated with life-threatening illnesses."

"Psilocybin and palliative end-of-life care."

"Psilocybin in end of life care: Implications for further research."

"Psilocybin for anxiety and depression in cancer care? Lessons from the past and prospects for the future."

This should be of considerable interest to the cancer care-giving community.  I plan on thoroughly reviewing this literature and writing more about it in the future.

Update: methadone

Hi,
my dad has just had his fourth MRI since being on methadone and it was very positive again. This time the tumor is stable but as the three MRIs before this one showed shrinkage, his tumor is now smaller than it was in the beginning. The latest MRI also showed that the edeme is decreasing in size. So we're happy :)
My dad was diagnosed in December 2015 with an inoperable glioblastoma (corpus callosum) and all doctors (neurosurgeon, oncologist, GP) are very pleased with the results. He's not using methadone alone but we've notived an improvement since he started taking it. He also takes Temodar, some other supplements and uses Optune TTF. So it might be the combination that helps him. I'll keep you updated on our experiences with methadone!

Trivalent CAR T-cells

This study, called Trivalent CAR T-cells Overcome Interpatient Antigenic Variability in Glioblastoma, just appeared as an accepted manuscript in Neuro-Oncology.  See abstract here.

This was a preclinical study tested in mice, but is an exciting development, as this CAR T-cell cocktail approach is more likely to be effective than CAR T-cells targeted to a single antigen.

I'll upload the full study to the Library (Immunology and Immunotherapy folder, in a new CAR T-cell subfolder).

New study from the Costello lab (UCSF) on IDH1 mutant low grade glioma

The study is called Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1.  View abstract here.  I've also uploaded this to the Brain Tumor Library, Pathology folder, IDH-mutant glioma subfolder.  This data was presented at the SNO conference in Phoenix last year.  I'll be following up with comments, and perhaps an Astrocytoma Options update on this.

Immunotheraphy combo

Do you have any experience or thoughts about this study?
http://www.practiceupdate.com/c/57122/67/12/?elsca1=emc_enews_weekinreview&elsca2=email&elsca3=practiceupdate_braincancer&elsca4=braincancer&elsca5=newsletter&rid=MjMxMDE2NzMzNjcyS0&lid=10332481

Has anyone tried this combo?
Best wishes to all
Brainbutton

FIG-ROS1 Chromosomal Fusion Significance? Actionable?

My husband's genetic testing came back with a .51 Tumor Mutational Burden. He has a 66.40% TP53 Allelic Fraction and 45.76% PTEN. His NO said these are common in many cancers and said neither are very actionable.

He was intrigued by the FIG-ROS1 as it usually shows up in small cell lung cancer and with recurrence might be eligible for a bucket trial with entrectinib.

He also has CDKN2A and CDKN2B Copy Loss.

I am just starting to look into what all this means. I have not looked into clinical trials much but am pursuing possibly getting a PD1 Inhibitor although once again I am told he needs recurrence.

He is 7 months out, stopped adjuvant TMZ after 2 rounds, unmethylated, IDH Wildtype, doing Optune, supplements and cannabis oil and overall doing very very well. Thanks.

Suggestions for a Cocktail that does not include TMZ

Hello, my husband has stopped taking TMZ after 2 adjuvant rounds after having debilitating fatigue, dizziness and nausea. He is doing much much better. He is unmethylated and IDH Wildtype. When he was taking the TMZ he did take disulfiram and copper. He is also taking metformin and celecoxib. I know some of these drugs are meant to help the TMZ do what they are supposed to do. Does anyone have suggestions on what off-label drugs he should take if not taking TMZ?

He is taking the standard supplements as well as cannabis oil and wearing the Optune. Thanks.

Treatment Options for Glioblastoma and Other Gliomas - 2017 edition

This is the in-depth summary of treatment options that Ben Williams began years ago, and which I have taken over lately.  Download the 2017 update over at virtualtrials.com  , or click here for PDF download.   This can be discussed on Al Musella's BrainTumorTreatments yahoo group .  (Of course comments welcome here as well).

Partner due to have first vaccine as part of Duke Elevate trial on Wednesday.  He went through SOC and had 1st five day Temodar.  Duke said MRI two weeks after final radiation showed pseudo progression with swelling.  My question is does swelling eventually go down without steroids?  Symptoms have gotten worse in last week.  Concerned steroids might not fit with immunotherapy.  Haven't talked to doctor yet.

The Blood-brain barrier (BBB) and glioblastoma, a review

Another review appearing online as an accepted manuscript for Neuro-Oncology, on a tremendously important topic.  It's called "Is the blood-brain barrier really disrupted in all glioblastomas? – A critical assessment of existing clinical data" and shares my view:

"This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated"

Abstract here, and again I can email the full study if anyone would like a copy.

Key quotes below:

Combined with the surgical experience, these data support our central contention that all GBM have a clinically significant tumor burden ‘protected’ by an intact BBB.

Accepting the importance of drug distribution across an intact BBB into brain is a critical first step in developing effective therapies for GBM and must be a key consideration in any clinical trial design for newly diagnosed or recurrent GBM.

The impact of complete resection most important for IDH-mut astrocytoma

There is an important new study, just published as an early preliminary manuscript online in Neuro-Oncology, called "The impact of surgery in molecularly defined low-grade glioma: an
integrated clinical, radiological and molecular analysis".  This was a large retrospective study including 228 adult low-grade glioma patients undergoing resection since 2003.  The tumors were classed as A) IDH-mutant oligodendroglioma (with complete 1p/19q codeletion),  B) IDH-mutant astrocytoma (no 1p/19q codeletion) and C) IDH wild-type (GBM-like).

The most important finding of this study was that complete resection (0 residual tumor), was most critical in the IDH-mutant astrocytoma group, as seen in the following figures.  In the first figure shown below, even a small amount of residual tumor post-resection negatively affected survival for IDH-mutant low grade astrocytoma.

The next figure also shows outcomes for IDH-mutant low grade astrocytoma, by various amounts of residual tumor post-resection.  (My snip only shows the first 3 images in the series). 

The next figure shows that complete resection also improves survival in low grade IDH-mutant oligodendroglioma, but the difference in survival between 0 residual tumor and small amounts of residual tumor is not a large as for the astrocytoma group as we saw in the first figure.

The abstract is available here.  I can email the full study if anyone wants it.

GBM possible recurrence help

Hi all, my brother diagnosed with gbm last year april 2016 and got his surgery, radiation and temodal immediately after that. This year around feb 2017 during his 3months mri checkup the doctor noted a 0.75cm mass suspected as gbm. Bc its too small the doctor decided to wait for next mri to see how it goes. At may 2017 my bro undergo another mri and found out it was clear! But at next mri aug 2017 they found the 'dissapeared' mass to have grown to 1.4cm. The doctor have decided that it must be gbm recurrence, and he said that the missing mass in between these mri must be the gbm 'hiding'. Is it really possible gbm to be 'missed' during mri?

And we also really confused to the best solution in handling this 'possible gbm recurrence'. We have asked diff doctors including neurosurgeons and oncologists. Doctor A said we should go with gamma knife, Doctor B said we should go with Surgery instead cause Gamma knife wont guaranteed as clear as Surgery. Doctor C said Surgery is dangerous cause the mass is in a critical location that can 'paralyzed', and Gamma knife not effective so we should go with Cyberknife instead. Anyone who have experienced gamma or cyber which one is actually more effective for gbm? And for gamma knife do the patient need to undergo chemotherapy after the gamma knife operation like using Avastin? Or they can only wait for the gamma to works? We really appreacite any recommendations or sharing of experience. Thank you!

Regards,
Milee

ONC 201 plus ?

Dear all,
My son is currently on ONC 201 compassionate use trial (H3 K27 tumor recurrence). While our NO will most likely insist on just doing one-agent trial, I feel we should push for at least a consideration of adding another chemo to it. I think a combo of Avastin and Irotican could be reasonable - I read
that in mice, Avastin added to ONC 201 showed trifold efficacy. On the other hand , I am concerned about the long-term effect of Avastin. Any other ideas? I am just afraid to only stick with one gent. We can certainly just try to continue with CUSP 9 or medendazol.  Thanks!