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.
I had seen this clinical trial before and was looking forward to the results:
ReplyDeletehttps://clinicaltrials.gov/ct2/show/NCT01430351
"Memantine is designed to block the activity of a protein found on the surface of cells that may control tumor growth and survival. This may stop further spread of tumor cells.
Mefloquine is designed to block a protein that helps to clean the waste in the cells and to destabilize the cell membrane. Blocking this protein may cause tumor cell death.
Metformin is designed to block a protein in tumor cells that is important in tumor growth and blood vessel development. This may cause cell death or reduce the spread of the disease."
This is interesting, why was mefloquine used instead of chloroquine? Maybe that's why:
"Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and given their superior blood-brain barrier penetration compared with CQ may prove more efficacious as chemotherapeutic agents for GBM patients."
2010 https://www.ncbi.nlm.nih.gov/pubmed/20406898
I was looking for scientific paper supporting Hydroxychloroquine during radiation and TMZ. What does it do?
ReplyDeleteMy husband is taking mementine prescribed by RadOnc as preventive for cognitive issues from radiation. He's taking Metformin from Care Oncology.
Also looking for supporting scientific publication for verapamil. Meeting with my husband's GP and going to ask him to switch to Verapamil for his blood pressure meds
Send me an email:
Deletebraintumorcocktailsblog@gmail.com
and I'll share the Brain Tumor Library with you, where you can view and download papers on chloroquine and other drugs.
Cells under stress (from nutrient and oxygen deficiency, or therapeutic stresses) can use autophagy for survival. Chloroquine and hydroxychloroquine are proposed to be inhibitors of autophagy and sensitizers to standard treatments. Autophagy is thought to be especially important for tumors with EGFRvIII mutations, or otherwise driven by EGFR.
There was one clinical trial with hydroxychloroquine that failed to increase survival beyond historical values for newly diagnosed GBM.
https://www.ncbi.nlm.nih.gov/pubmed/24991840
On the other hand several small clinical trials and retrospective studies in Mexico in the 1990's/early 2000s seemed to show survival benefit when chloroquine was added to standard radiation and chemotherapy with BCNU.
Another study showed good outcomes in 3 patients taking standard treatments in combination with hydroxychloroquine and sirolimus (rapamycin), which has led to a clinical trial proposed to start in Taiwan. https://clinicaltrials.gov/ct2/show/NCT03008148
https://www.omicsonline.org/open-access/sirolimus-and-hydroxychloroquine-as-an-addon-to-standard-therapy-for-glioblastoma-multiforme-case-report-2167-7956-1000141.php?aid=73417
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805523/
There are also several clinical trials testing chloroquine.
https://clinicaltrials.gov/ct2/show/NCT03243461
https://clinicaltrials.gov/ct2/show/NCT02378532
https://clinicaltrials.gov/ct2/show/NCT02432417
For verapamil as a chemosensitizer, see:
https://www.ncbi.nlm.nih.gov/pubmed/2366081 (in vivo, combined with BCNU)
https://www.ncbi.nlm.nih.gov/pubmed/8388231 (clinical trial, lung cancer)
"Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma."
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pubmed/30359477
http://sci-hub.tw/https://onlinelibrary.wiley.com/doi/abs/10.1002/cncr.31811
"Although the primary objective of this phase 1
Deletestudy was to determine the tolerability of combinations
of TMZ with the 3 repurposed drugs, efficacy data also
were collected. With a median follow-up duration of >57
months, the median OS was 21 months, and the 2-year
survival rate was 43%. Thirteen percent of our study population
had IDH-mutant GBM, and MGMT testing was
not performed for 88% of patients. In addition, this was
a single institution, phase 1 trial and was not powered
to evaluate efficacy; therefore, at this point, we cannot
definitely declare improved treatment efficacy with these
combinations. The efficacy results of our study should
be interpreted with caution, taking into consideration
the inclusion of a high percentage of patients with IDHmutated
GBM (13%), the unknown MGMT status in
the majority of tumors, the high Karnofsky performance
status (>80 in the majority of patients), and the enrollment
after completion of chemoradiation with allowance
of pseudoprogression events. Currently, a phase 1b/2
clinical trial of metformin and chloroquine is enrolling
patients with IDH1/IDH2-mutant glioma.41 Future
phase 2 clinical trials with larger cohorts of patients who
have GBM or other gliomas of other grades treated at
homogeneous doses are needed to evaluate the efficacy of
these drugs in combination with TMZ."
Thanks for the link Semyon. Unfortunately its impossible to compare the various arms because there were too few patients/too many arms, and a lack of information on MGMT status. The study does give us important information on dosing and safety.
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