Saturday, 18 November 2017

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

Wednesday, 15 November 2017

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

The research suggests the cancer drug olaparib could be an effective treatment for a common type of brain tumour known as glioblastoma.

Ovarian cancer drug could treat brain tumours -- http://www.bbc.com/news/uk-scotland-41885927

Sunday, 12 November 2017

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


Friday, 10 November 2017

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.

Wednesday, 8 November 2017

Oryx’s oncolytic virus treatment for the aggressive form of brain cancer, glioblastoma, has demonstrated safety and efficacy in a clinical trial.

Oryx is developing three exciting candidates for the treatment of cancer. One of these, an oncolytic virus, ParvOryx, has demonstrated its safety and efficacy in patients with glioblastoma – a particularly aggressive form of brain cancer. The Phase I/IIa results, published in Molecular Therapy, showed that the treatment safely improved patient survival and support its progression through the clinic.

More info:  https://labiotech.eu/brain-cancer-oncolytic-virus-oryx/ 

Tuesday, 7 November 2017

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!