Hi folks/Stephen,
My mom is a GBM patient who is EGFRvIII amplified, and basis my research and Stephen's inputs, I realised that Chloroquine is a great adjuvant for my mom. I have been reading up on Chloroquine and had the following questions on the same:
1. I am not able to find Chloroquine in my country, but Chloroquine phosphate instead. Can they both be used interchangeably? Is the efficacy of both just as good?
Basis my research, the dosage of Chloroquine should be 150 mg. What should be the dosage of Chloroquine Phosphate, if it can be used interchangeably?
2. I also read that Chloroquine is a chemo sensitiser, but couldn't find any information on what the timing of this drug should be for maximum efficacy.
My mom takes lomustine+temozolomide in the morning. Can you please help me on when the Chloroquine/Chloroquine Phosphate should be timed for maximum efficacy?
3. How long should chloroquine be taken for? Should it just be done till the chemotherapy or should it be done post the chemotherapy too? I see different researches doing this protocol differently.
My mom has completed 3 cycles of temozolomide and 4 cycles of temozolomide+lomustine. We plan to do two more cycles of temozolomide+lomustine and stop the chemo post that.
4. My mom is also doing the supplements in the table below.
a. My major concern is Artemisia since it is an anti malarial drug too. Is it safe to do both? If yes, how I should I time them so that I get the efficacy of both for my mom?
b. Is there any drug reaction that I should be concerned of? I researched on drugs.com for the interaction list, but all that I could find were two reactions since most of the naturopathic supplements were not there in their database(Interaction list for my mom is here). The two reactions that they talk of is reaction between Chloroquine and Keppra, Chloroquine and Celebrex, how big a concern are they?
My mom is a GBM patient who is EGFRvIII amplified, and basis my research and Stephen's inputs, I realised that Chloroquine is a great adjuvant for my mom. I have been reading up on Chloroquine and had the following questions on the same:
1. I am not able to find Chloroquine in my country, but Chloroquine phosphate instead. Can they both be used interchangeably? Is the efficacy of both just as good?
Basis my research, the dosage of Chloroquine should be 150 mg. What should be the dosage of Chloroquine Phosphate, if it can be used interchangeably?
2. I also read that Chloroquine is a chemo sensitiser, but couldn't find any information on what the timing of this drug should be for maximum efficacy.
My mom takes lomustine+temozolomide in the morning. Can you please help me on when the Chloroquine/Chloroquine Phosphate should be timed for maximum efficacy?
3. How long should chloroquine be taken for? Should it just be done till the chemotherapy or should it be done post the chemotherapy too? I see different researches doing this protocol differently.
My mom has completed 3 cycles of temozolomide and 4 cycles of temozolomide+lomustine. We plan to do two more cycles of temozolomide+lomustine and stop the chemo post that.
4. My mom is also doing the supplements in the table below.
a. My major concern is Artemisia since it is an anti malarial drug too. Is it safe to do both? If yes, how I should I time them so that I get the efficacy of both for my mom?
b. Is there any drug reaction that I should be concerned of? I researched on drugs.com for the interaction list, but all that I could find were two reactions since most of the naturopathic supplements were not there in their database(Interaction list for my mom is here). The two reactions that they talk of is reaction between Chloroquine and Keppra, Chloroquine and Celebrex, how big a concern are they?
I look forward to your response!
Hi Sahil,
ReplyDeletePrescription chloroquine always comes as chloroquine phosphate. We just say "chloroquine" for short. The same way that "metformin" is always usually taken in the form of metformin hydrochloride. The common dosing of 250 mg chloroquine phosphate daily contains about 150 mg chloroquine (the remaining weight is the phosphate component). The names chloroquine and chloroquine phosphate are used interchangeably for practical purposes.
Chloroquine has a long half-life in the body, so the daily timing might not be all that important.
"Chloroquine ... is eliminated slowly from the body and is detectable in the urine for up to a year after drug administration. The terminal elimination half-life is 45-55 days for chloroquine and 59-67 days for its major plasma metabolite desethylchloroquine."
http://www.antimicrobe.org/drugpopup/chloroquine.htm
Based on the Mexican clinical trials I would suggest taking for 12 months. It may have some therapeutic benefit even beyond chemotherapy, because of the baseline reliance of EGFR-driven cancer cells on autophagy for survival.
Combining more than one anti-malaria drug is common in treating malaria although adding artesunate (an artemisia-derived drug) to chloroquine wasn't enough to avoid eventual treatment failure.
https://www.ncbi.nlm.nih.gov/pubmed/12932091
Drugs.com says celecoxib is an inhibitor of the enzyme CYP 2D6 and theoretically could increase plasma levels of chloroquine. However celecoxib is considered a weak 2D6 inhibitor and there are many other CYP enzymes that can metabolize chloroquine - I've never heard of an actual problem using these drugs together. Rich Gerber was taking high dose daily celecoxib along with standard dose chloroquine during his GBM cocktail and didn't experience a problem. See this page for comments on chloroquine and retina toxicity: http://btcocktails.blogspot.com/p/toxicities.html
According to drugs.com "Chloroquine may lower the convulsive threshold, which may antagonize the action of antiepileptic medications. Seizures have been rarely reported in patients on chloroquine therapy. The mechanism is unknown." Is your mom currently having regular seizure activity? Notice that seizures due to chloroquine is a rare side-effect.
Thank you so much for your response, Stephen! This was extremely helpful. No, my mom hasn't had any seizures in the past 1 year post diagnosis.
ReplyDeleteGuess I'll start with 250 mg of Chloroquine phosphate for my mom :)
1. About the content of chloroquine in chloroquine phosphate and hydroxychloroquine:
ReplyDeleteThe tablet chloroquine phosphate 250 mg contains 155 mg of chloroquine.
The tablet hydroxychloroquine 200mg contains 156mg of chloroquine.
Thus, the recommended dose of hydroxychloroquine 400 mg contains 2 times more chloroquine than the recommended dose of chloroquine phosphate 250 mg.
2. I recently wrote a letter to Kwan-Hwa Chi, MD (the main investigator of the HCQ + RAPA combination). He replied that he still uses 400 mg of hydroxychloroquine for his patients.
I asked him to comment on the failure of the trial https://www.ncbi.nlm.nih.gov/pubmed/24991840 with a dose of hydroxychloroquine 600mg, which did not inhibit autophagy. He replied: "The mechanism is through the M2-like Tumor associated macrophages. Not in the glioma!"
How can this be understood???
Hyroxychloroquine is not chloroquine. It is similar to chloroquine, but is a different molecule with different properties in terms of pharmacokinetics.
DeleteKeep in mind the 250 mg dosing of chloroquine phosphate is the dosing used for continuous use in diseases such as rheumatoid arthritis. Much higher doses can be initially used in malaria treatment. Similarly with hydroxychloroquine, initial doses in malaria treatment can be higher (400-600 mg daily), but long term daily use is maintained at lower doses (200-400 mg daily).
Kwan-Hwa Chi's comment is interesting, because in his 2016 publication the word macrophage isn't mentioned once.
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
I think in many cases the mechanism of action of drugs isn't fully understood. What matters more than how it works, is if it works, so clinical response is the most important thing than whether or not it inhbits or doesn't inhibit a given target. It's quite possible that chloroquine and hydroxychloroquine have more important mechanisms than autophagy inhibition, and M2 macrophages are an important non-tumor cell target.
Did he happen to say if the trial is recruiting yet, because according to clinicaltrials.gov it is not yet open.
https://clinicaltrials.gov/ct2/show/NCT03008148
We won't know if this drug combination is in fact an effective one until this trial has results. The results in three individual reported cases isn't enough proof.
Here is his short reply to my letter:
Delete"I felt HCQ/RAPA combination can work as well as CQ/RAPA but less toxicity.
The mechanism is through the decreased of M2-like Tumor associated macrophages. Not in the glioma!
Of course, our clinical trial is still on-going.
I do not have enough cases on recurrent GBM."
By the way, this is a study of this combination in 22 patients with other types of oncology:
Delete"Addition of rapamycin and hydroxychloroquine to metronomic chemotherapy as a second line treatment results in high salvage rates for refractory metastatic solid tumors: a pilot safety and effectiveness analysis in a small patient cohort"
2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599303/
My husband is 77 yr old. He was diagnosed 2013 w/GBM 4. Full Resection & Radiation. Took TMZ for 12 mos, then CCNU for 6 mos. Optune for 15 mos/stopped due to skin issues-skin cancer. Recurrence in 2018. Full resection/radiation. Now on 10th round of TMZ. Taking Ben Wms' Supplement cocktail since 2013. Only RX: Valproic Acid (never had seizures), Celebrex, Bactrim. Only issues are cognitive, motivation, fatigue. He is MGMT meth. Seattle NO says go to 12 mos (that 2 left). UCSF NO suggesting he stop TMZ due to fatigue since no validation it helps past 6 mos. Blood runs are good.
ReplyDeleteStephen, do you think we should finish the last two rds to make 12 or stop at 10?? NO's leaving it up to us. Any other recommendations based on his gene testing below? I have been ill so difficult for me to focus very well. My husband can't focus at all so leaving it up to me.
Appreciate your thoughts. Thank you kindly.
INTERPRETATION:
Tumor-only sequencing of this recurrent glioblastoma demonstrates a hotspot mutation in the promoter region of the TERT gene, focal deep deletion of the CDKN2A and CDKN2B tumor suppressor genes on chromosome 9p21, focal amplification of the MDM4 oncogene on chromosome 1q32, focal amplification of the PDGFRA oncogene on chromosome 4q12, a nonsense mutation in the PTEN tumor suppressor gene with loss of the remaining wildtype allele, a frameshift mutation in the BCOR tumor suppressor gene, and focal amplification of the EGFR oncogene on chromosome 7p11. This EGFR amplification is accompanied by a missense mutation that localizes within the extracellular ligand-binding domain and has been recurrently found in glioblastomas, often in conjunction with gene amplification as seen in this tumor [refs. 1-2]. This EGFR mutation is present on a majority of the amplified EGFR alleles given its allele frequency of 74%. Extracellular domain mutations in EGFR have been shown to correlate with resistance to type I EGFR inhibitors such as erlotinib but sensitivity to type II EGFR inhibitors [ref. 3].
The quantity of somatic mutations and mutational signature of this recurrent tumor is not suggestive of the hypermutation that is known to occur in a subset of gliomas following treatment with alkylating agents such as temozolomide [ref. 4].
Chromosomal copy number changes in the tumor include gain of 7 and losses of distal 2p, interstitial 3q, 8p, 9p, 10, portions of 11q, 13q, distal 14q, and distal
Only 11 of the 1,068 microsatellites assessed in the tumor (<2%) demonstrate instability, consistent with a microsatellite stable tumor.
Together, the genetic profile is consistent with the diagnosis of recurrent glioblastoma, IDH-wildtype, WHO grade IV. The cytogenetic alterations (trisomy 7, monosomy 10) and genetic alterations (CDKN2A deletion, TERT promoter and PTEN mutations, amplifications of EGFR, PDGFRA, and MDM4) are some of the most common seen in IDH-wildtype glioblastomas arising within the cerebral hemispheres in adults [ref. 1]. Additionally, this glioblastoma demonstrates a truncating mutation in BCOR, which encodes a transcriptional co-repressor protein that is commonly inactivated in pediatric high-grade gliomas but is not known to be a recurrently mutated or deleted gene in adult IDH-wildtype glioblastoma [refs. 5-6].
Genetic features of a diffuse lower-grade glioma (e.g. chromosomes 1p/19q co-deletion or mutations involving IDH1, IDH2, TP53, ATRX, CIC, and FUBP1) are not identified.
I'm going to re-post this as a post of its own, rather than as a comment to an unrelated post.
DeleteHi. Does Tagrisso have an effect on Grade 4 GBM.
ReplyDeleteDoc is getting use approved through compassionate care.
Thx