Wednesday, 22 November 2017

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 cavityStupp 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

Monday, 20 November 2017

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.

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.


Sunday, 19 November 2017

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.

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.