CMV (Cytomegalovirus) - specific dendritic cell vaccine trial summary

https://sci-hub.tw/https://clincancerres.aacrjournals.org/content/early/2020/07/25/1078-0432.CCR-20-1082.long

Once, Twice, Three Times a Finding: Reproducibility of Dendritic Cell Vaccine Trials Targeting Cytomegalovirus in Glioblastoma

"We have now observed that nearly one-third of the GBM study patient population receiving CMV-specific DC vaccines results in exceptional long-term survivors."

Levetiracetam (Keppra) + standard of care, single-arm phase 2

A pilot study of levetiracetam as a sensitizer of temozolomide for newly diagnosed glioblastoma: A prospective, open-label, phase II study (KBTS-1601 study).
https://meetinglibrary.asco.org/record/189964/abstract

This was reported at the recent ASCO virtual conference.

• Eligible patients were aged 18 years or older and had newly diagnosed glioblastoma with an ECOG performance status of 0-2
• The first dose of levetiracetam was given just after the surgery at 250mg orally twice a day and increased up to 500mg twice a day prior to radiation
• Forty-six patients were enrolled between August 2016 and January 2019
• Median overall survival (OS) was 30.0 months, and median PFS was 15.0 months

This was a single arm trial, with outcomes compared to a historical control group. A median overall survival of 30 months and median progression-free survival of 15 months does seem to be an improvement on historical results. 

For comparison, the unblinded results of the phase 3 DCVax trial (preliminary report based on 331 patients) had a median overall survival of 23.1 months from surgery. The historical control group used by the Korean team that conducted this levetiracetam trial had median OS of 17.5 months.

Urgent help for an 11 year old girl

Dear Stephen and all,

I have a question concerning my friend’s daughter. She is a Spanish 11 year old girl. She has been diagnosed with a grade IV medular glioma. She had surgery, but the tumor could not be removed. They just took a biopsy. She has had 30 sessions of radiation and 27 days of temozolomide. Parents are desperatly looking for possible clinical trials that would fit her case. Any suggestions on specific treatments or cocktails would be of much help as well. Even though they live in Spain they would have no problem travelling overseas. We are attaching pathological report, MRI and tractography report.

Please click on the following link.  Once the link takes you to the page of the girl's medical information, click on "Visualizar el estudio" to see her images and "Descargar el informe" to read the medical report:

http://resultados.healthtime.es/PortalPaciente/OpenSharedStudyRequest/a4ac550a-19f7-4d58-99ad-6e1fb2e06ccb

The picture I am including is the report of the pathologist.  It is in Spanish, but I think it is understandable.  If you have any questions, please contact me. 

Thank you all in advance.

Isabel

Clinical trial: IDH1 R132H peptide vaccine + avelumab (Germany)

A prior trial tested this vaccine (IDH1 R132H peptide vaccine) for gliomas with this IDH1 mutation.  The current trial is testing vaccine alone versus avelumab (PD-L1 inhibitor) alone versus combined vaccine + avelumab.

It is recruiting first recurrent gliomas of grade 2-4 with the IDH1 R132H mutation.

Open in Heidelberg and Mannheim Germany, and will also be open at several other centres in Germany.

https://clinicaltrials.gov/ct2/show/NCT03893903

Neo-adjuvant (before surgery) pembrolizumab

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma

http://sci-hub.tw/https://www.nature.com/articles/s41591-018-0337-7

This was a small, randomized trial for recurrent GBM at first or second relapse, who were candidates for surgical debulking and were on steroid doses less than 4 mg per day of dexamethasone or equivalent.  There were 16 patients in each arm. One arm (neoadjuvant) received pembrolizumab (Keytruda) 14 days before surgery, and further doses of pembrolizumab after recovery from surgery. The second arm (adjuvant) received pembrolizumab only after surgery.

The survival advantage of neoadjuvant pembrolizumab was statistically significant (hazard ratio = 0.39, P = 0.04).  Note that it's more difficult to achieve statistical significance in a smaller trial versus a larger one.  Patients in each arm were well-matched for typical prognostic features.

In light of the positive results of this trial, "we intend to expand the current study and pursue further clinical trials with neoadjuvant combination immunotherapeutics."

GAPVAC phase 1 trial results

GAPVAC phase 1 trial
https://www.clinicaltrials.gov/ct2/show/NCT02149225

just published results in Nature

http://sci-hub.tw/https://www.nature.com/articles/s41586-018-0810-y

Regorafenib superior to lomustine in randomized phase 2 trial for reGBM

http://sci-hub.tw/10.1016/S1470-2045(18)30675-2

This is newsworthy because I expect trials like this to fail in GBM, and I'm very biased against single agent kinase inhibitor trials for GBM, but this one showed regorafenib to actually be superior to lomustine in a randomized phase 2 trial.

DSP-7888 Dosing Emulsion?

My husband's tumor is showing progression.  His NO (Kaiser) has a study NCT03149003 "A Study of DSP-7888 Dosing Emulsion in Combination With Bevacizumab in Patients With Recurrent or Progressive Glioblastoma Following Initial Therapy (WIZARD 201G)"  All I know is that it's a cancer peptide vaccine. There's a blood test to confirm presence of HLA.

Does anyone know anything about this agent?

I'm looking at other possible trials to see if there's anything that might be a better fit, or that would keep him bevacizumab naive since using bev would further restrict his trial eligibility (multifocal and inoperable means many trials are ruled out).  We are in southern California and I'd prefer not to travel far unless it's for an exceptional option.   He unfortunately did not qualify for City of Hope's CAR-T trial.

Thanks for any suggestions or insight.

Rovalpituzumab Tesirine (DLL3 antibody-drug conjugate) for IDH1-mutant glioma

Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase mutant glioma

pubmed link

full article download

"DLL3 immunostaining was intense and homogeneous in IDH mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 non-tumor brains. Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner."

This is particularly interesting because the therapy is currently available in a clinical trial for recurrent GBM and other solid tumors recruiting at multiple locations across the USA.

https://clinicaltrials.gov/ct2/show/study/NCT02709889?show_locs=Y#locn

DNX-2401

Does anyone have any information on the trial using DNX-2401?  We are trying to decide if the risks outweigh the benefit or vice versa. Its great for the 20% that had extended life but what they won't tell us is how those people were living. Did there side effects continue where even thought they lived three more years they were miserable? If anyone has any information to shed some light on this that would be great. Thank you!

ERC1671 vaccine randomized phase 2 trial results

Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma: interim results and correlations with CD4+ T-lymphocyte counts.

Median overall survival (OS) of patients treated with ERC1671 plus bevacizumab was 12 months. In the placebo plus bevacizumab group, median OS was 7.5 months. The maximal CD4+ T-lymphocyte count correlated with OS in the ERC1671 but not in the placebo group.

CONCLUSION:

The addition of ERC1671/GM-CSF/cyclophosphamide to bevacizumab resulted in a clinically meaningful survival benefit with minimal additional toxicity.

New to the blog.  Many thanks to all who share their experiences with brain tumors.
I’m curious if anyone has information on BMQ-350.

This just in:

medpagetoday.com

ASCO Reading Room | Addition of a Personalized Vaccine to Standard Therapy in Glioblastoma

 

Poliovirus (PVS-RIPO) phase 1 update

Thanks to Al Musella for bringing this to our attention.

https://virtualtrials.com/news3.cfm?item=6529  (Al's commentary)

https://www.nejm.org/doi/full/10.1056/NEJMoa1716435  (full study, HTML)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1716435   (PDF download)

Here, as in some other viral therapy/immune therapy trials, we're seeing a long tail of survivors, in this case 21% surviving to 2, 3, 4 and 5 years (all dose levels).  This is comparable to DNX-2401 phase 1 trial, where 20% survived at 3 years, or Toca 511 + FC (13% alive at 3 years, all dose levels).

The most intriguing part of the study is the observation that some of the patients had dramatic responses to chemotherapy (including lomustine) after treatment with the modified poliovirus.  The randomized phase 2 trial open now is testing poliovirus alone versus poliovirus + single course lomustine.

This trial is open and Duke, and soon to open at Massachusetts General, UCSF, and Boca Raton.

https://clinicaltrials.gov/ct2/show/NCT02986178

SurVaxM - Update

https://mimivax.com/wp-content/themes/JointsWP-master/assets/pdf/download.pdf

First results of cocktail trial (memantine, metformin, mefloquine, temozolomide)

I'll be working on a review of the latest brain tumor news coming from the ASCO conference currently underway.  Since this is the brain tumor cocktails blog, thought I'd post these results to start off.

Phase I factorial study of temozolomide plus memantine, mefloquine, and metformin as post-radiation adjuvant therapy for newly diagnosed glioblastoma.
https://meetinglibrary.asco.org/record/164026/abstract

The abstract gives maximum tolerated doses for doublet therapy (TMZ + one of the other drugs), triplet, and quadruplet combinations.

2 year survival rate for the entire trial population (all combintions) was 43%, similar to the 2-year survival seen in the EF-14 trial for the Optune + TMZ arm.

Since some of the combinations were probably more effective than others, it will be interesting to see the results when separated by treatment arm.

DCVax Update

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6

Mike B

HSPPC-96 vaccine Phase 1 trial results in China

Heat shock protein peptide complex-96 vaccination for newly diagnosed glioblastoma:
a phase I, single-arm trial
https://insight.jci.org/articles/view/99145   (open access)

The survival results of this trial are worth remarking upon.

20 newly diagnosed GBM patients received standard treatments plus HSPPC-96 vaccine (also known as Prophage, under development in the USA by Agenus). All had total tumor resections, and the majority had MGMT unmethylated tumors and were IDH1 wild-type.

19 of the 20 were evaluable for efficacy. Median survival for the entire group was 31.4 months.  I've seen only a couple of other small trials (vaccine trials involving complete or near complete tumor resection) with efficacy outcomes comparable to this.

Clear efficacy of the vaccine was shown by tumor specific immune responses (TSIR) being increased on average by 2.3-fold after vaccination, and the fact that those with "high" TSIR (TSIR above the median) had not reached median survival (> 40.5 months), while those with low TSIR (below the median) had median survival of only 14.6 months, showing vaccine efficacy in only a subset of patients.  Median PFS are unremarkable (11 months median for the entire group, 12.3 months for the high TSIR group), but immune-related pseudoprogression could have been a factor in dropping PFS values.

Compared to the phase 2 trial published by Bloch et al. in 2017,  https://www.ncbi.nlm.nih.gov/pubmed/28193626
the Chinese trial had worse PFS outcomes but better survival outcomes, also suggesting that pseudoprogression may have been a factor in the Chinese trial.

Additionally, patients with MGMT-methylatated tumors had far better outcomes in the Bloch et al. trial, but in this Chinese trial, 14 out of 16 tested tumors were MGMT unmethylated.

A trial is currently underway testing pembrolizumab with or without HSPPC-96 vaccine, and I would expect the combination therapy  to improve even further on the efficacy results of the vaccine.
https://clinicaltrials.gov/ct2/show/NCT03018288

Update on phase 2 trial of valproic acid + standard chemoradiation for nd GBM

As reported several years ago, median survival in this trial of high dose valproic acid (Depakote) in combination with chemoradiation was 29.6 months.  This study describes 6 patients who survived over three years (median survival over 6 years for these 6 patients).  Only 1 out of 4 evaluated tumors carried the IDH1 mutation.

https://academic.oup.com/nop/advance-article/doi/10.1093/nop/npy009/4971616  (abstract only)


http://sci-hub.tw/https://academic.oup.com/nop/advance-article/doi/10.1093/nop/npy009/4971616

Note the above link takes you to a PDF download at sci-hub.  If this link fails to work in the future, check wikipedia for the current active locations of sci-hub, and swap out the ".tw" in the URL with something else.  This is technically pirating, but most of us here would agree that fighting a brain tumor calls for such measures.

Nativis Voyager clinical trial

Stephen, what are your thoughts about this trial:

Nativis Voyager® System in Patients With Recurrent Glioblastoma Multiforme (GBM)

https://clinicaltrials.gov/ct2/show/NCT02296580#moreinfo